ANCOTIL Solution for infusion Ref.[8891] Active ingredients: Flucytosine

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

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).

Paediatric populations

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.

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.

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).

Not applicable.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.