This information is intended for use by health professionals

1. Name of the medicinal product

Ancotil 2.5 g/250 ml Solution for Infusion.

2. Qualitative and quantitative composition

Flucytosine Ph. Eur. 2.5 g in 250 ml.

3. Pharmaceutical form

Infusion bottles containing 2.5 g 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 and infections due to torulopsis 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 and Children

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 in adults and children is 200 mg/kg body-weight divided into four doses over 24 hours. In patients harboring 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.

Since Ancotil is excreted primarily by the kidneys, patients with renal impairment should be given smaller doses. The following is suggested as a guide for dosage in patients with severe infection associated with renal impairment:

In patients with:

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

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

Creatinine clearance <10 ml /min: an initial single dose of 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.

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.

Neonates

The dose in neonates should be calculated in the same way as for adults and children, but the high possibility of renal impairment should be considered in this group either as intrinsic to their age or as a result of other nephrotoxic therapies. It is advised to closely monitor the serum levels of flucytosine in this group and adjust the dose according to levels. In cases where renal impairment is present the dose interval should be extended (as with adults and children). Where renal impairment is not a feature but serum levels are above those recommended, the dose should be reduced but the dosing interval should remain the same.

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.

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.

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 breastfeeding women (see section 4.6; Fertility, pregnancy and lactation).

4.4 Special warnings and precautions for use

The product should be used with great caution in patients with depression of bone marrow function or blood dyscrasias. Blood counts and tests of renal and hepatic function should be performed before and during treatment. This should occur at least weekly in patients with renal insufficiency or blood dyscrasias.

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

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.

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

An interval of at least four weeks should elapse between treatment with brivudine, sorivudine or analogues and subsequent administration of Ancotil.

Patients receiving phenytoin and Ancotil concomitantly should be checked regularly for increased phenytoin plasma levels.

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.

Creatinine Measurement:

Flucytosine may interfere with the dual-slide 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.

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 month after treatment. 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).

4.5 Interaction with other medicinal products and other forms of interaction

There is contradictory evidence concerning a drug interaction between Ancotil and 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)

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.

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. Females of childbearing potential under treatment must use effective contraceptive during treatment and for one month after treatment. Male patients (or their female partners of childbearing potential) must use effective contraception during treatment and for three months after treatment (see section 5.3; Preclinical safety data).

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

Nausea, vomiting, diarrhoea and skin rashes may occur but are usually of a transient nature.

Less frequently observed side effects include allergic reactions, Lyell's Syndrome, myocardial toxicity and ventricular dysfunction, confusion, hallucinations, convulsions, headache, sedation and vertigo. Alterations in tests of liver function are generally dose related and reversible but hepatitis and hepatic necrosis have been reported. Acute liver injury with possible fatal outcome in debilitated patients may occur in isolated cases.

Haematological changes, mainly leucopenia, thrombocytopenia, agranulocytosis or aplastic anaemia have been reported. This is more common when serum levels of flucytosine are high in patients with renal impairment and when amphotericin-B has been co. prescribed. In isolated cases, bone marrow toxicity may be irreversible and could lead to death in patients with pre-existing immuno-suppression, Local irritation or phlebitis does not appear to be a problem with Ancotil for Infusion.

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

4.9 Overdose

Haemodialysis produces a rapid fall in the serum concentration of Ancotil.

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.

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.

Most strains of C. albicans, C. dubliniensis, C. famata, C. glabrata, C. guilliermondi and C parapsilosis are initially susceptible to flucytosine. Most strains of C. krusei are intermediately susceptible, 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. Elimination via peritoneal dialysis is possible

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, hydrochloric 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 18 °C and 25 °C. If stored below 18 °C, precipitation of Ancotil substance may occur.

Prolonged storage above 25 °C 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 and other handling

Ancotil for Infusion is available to hospitals only.

7. Marketing authorisation holder

Meda Pharmaceuticals Ltd.

Skyway House

Parsonage Road

Takeley

Bishops Stortford

CM22 6PU

United Kingdom

8. Marketing authorisation number(s)

PL 15142/0002

9. Date of first authorisation/renewal of the authorisation

27 February 2009

10. Date of revision of the text

02/10/2017