Ancotil 2.5 g/250 ml Solution for Infusion Ref.[4834] Active ingredients: Flucytosine

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.

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.

Teratogenic effects have been seen in rats, in which species flucytosine is metabolised to fluorouracil. The metabolism may differ in man: nevertheless, the use of Ancotil in pregnancy and in women of childbearing age requires that the potential benefits of therapy be weighed against its possible hazards. The drug should not be given to women breast feeding infants.

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.

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.