Ancotil 2.5 g/250 ml Solution for Infusion.

Flucytosine Ph. Eur. 2.5 g in 250 ml.

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

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.

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 the 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.

Ancotil is contra-indicated:

- in patients who have shown hypersensitivity to flucytosine or any of the excipients.

Co-administration with antiviral nucleoside drugs (e.g. brivudine, sorivudine and their analogues) is contraindicated (see section 4.4).

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.

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

Ancotil is a fluorinated pyrimidine effective in the treatment of certain systemic fungal infections. In fungi sensitive to the preparation, it acts as a competitive inhibitor of uracil metabolism.

Ancotil is widely distributed in body tissues and fluids (including cerebrospinal fluid). Binding to plasma proteins is minimal. Half-life of elimination is 36 hours in patients with normal renal function but this value increases in renal failure. About 90 % of the dose administered is excreted unchanged in the urine. Flucytosine is metabolised to 5-flurouracil. The area under the curves (AUC) ratio of 5-flurouracil to flucytosine is 4 %. Flucytosine can be removed by haemodialysis.

Not relevant.

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

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.

2 years.

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.

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

Ancotil for Infusion is available to hospitals only.

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

United Kingdom

PL 15142/0002

27 February 2009

December 2010