ANCOTIL 2.5G/250 ML SOLUTION FOR INFUSION

Active substance: FLUCYTOSINE

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Patient Information Leaflet

Information for healthcare professionals

Ancotil® 2.5 g/250 ml
(1g in 100 ml)
Solution for Infusion

Ancotil® 2.5 g/250 ml
(1g in 100 ml)
Solution for Infusion

Flucytosine

Flucytosine

Read all of this leaflet carefully before you start using this
medicine.
• Keep this leaflet. You may need to read it again.

• This leaflet tells you about Ancotil.

• It does not contain all the information about Ancotil.

• If you have any questions or are unsure of anything ask

the doctor or nurse.
• f you experience any side effect and this becomes serious,
I
tell your doctor or pharmacist.
In this leaflet:
1. What Ancotil is and what it is used for
2. Before you are given Ancotil
3. How Ancotil is given
4. Possible side effects
5. How Ancotil is stored
6. Further information

1.  HAT ANCOTIL IS AND WHAT IT IS USED
W
FOR
Ancotil Solution for Infusion contains an anti-fungal agent. It is
used to treat certain yeast and fungal infections.

2.  EFORE YOU ARE GIVEN ANCOTIL
B
SOLUTION FOR INFUSION
You should not be given Ancotil
•  you are allergic (hypersensitive) to flucytosine or any of
If
the other ingredients of Ancotil (these are listed in section 6,
“Further Information”).
•  you are breast-feeding.
If
•  you are using any medicine known as an antiviral nucleoside
If
(e.g. brivudine, sorivudine). These medicines are usually used
to treat chickenpox and shingles.
Take special care with Ancotil
Tell your doctor before you start treatment
•  you have a liver, kidney or blood problem. Your doctor
If
may need to carry out blood tests during your treatment.
Using other medicines
Tell your doctor before you start treatment if you are taking or
have recently taken any other medicines, including medicines
obtained without a prescription. In particular, tell your doctor if
you are taking the medicine cytarabine (which is used to treat
certain leukaemias), medicines to treat chickenpox or shingles
(brivudine, sorivudine) or have used them in the last 4 weeks.
These medicines may increase the possibility of unwanted effects
with Ancotil. If you are taking medicines for epilepsy containing
phenytoin, your doctor may do some blood tests.
Pregnancy and breast-feeding
You must tell your doctor before you start treatment if you are
pregnant, if you think you may get pregnant or if you are breastfeeding.
• 
Your doctor will decide whether you should be given Ancotil
if you are pregnant.
• You should not be given Ancotil if you are breast-feeding.

3. HOW ANCOTIL IS GIVEN
Ancotil is administered only in a hospital and is administered
by a doctor or nurse. It is usually given into a vein or by a
procedure called “intraperitoneal infusion” while you are in
hospital.
The usual total daily dose is 100 to 150 mg/kg bodyweight in
divided doses.
In some instances, you may be given up to a total daily dose of
200 mg/kg bodyweight in divided doses.

60018220G

Smaller doses may be given to patients with kidney problems.
The treatment period with Ancotil will vary on a patient by
patient basis, but treatment will not usually be longer than a
week.

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This leaflet provides technical information about Ancotil for the
healthcare professional.
The tear-off portion attached is intended for the patient.
Presentation
Infusion bottles containing 2.5 g flucytosine in 250 ml isotonic sodium chloride
solution.
Other excipients are sodium chloride, tromethamine, hydrochloric acid and
water for injections. The solution is colourless to slightly yellow.
Uses
Properties
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.
Pharmacokinetics
Bioavailability after a 2 g oral dose 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. Ancotil is widely distributed in body
tissues and fluids (including cerebrospinal fluid). The volume of distribution is
0.5-1.0 l/kg. Binding to plasma proteins is minimal (<5%). Typical maximum
serum concentrations are 30-50 ug/ml after oral intake or IV administration of
2 g flucytosine. Concentrations in cerebrospinal fluid, saliva and peritoneal
fluid are slightly lower. Flucytosine crosses the human placenta and accumulation
in amniotic fluid has been observed. Urinary concentrations may be up to 100
times higher than plasma concentrations (normal renal function). Only a small
proportion of flucytosine is metabolised. Enteric bacteria may be responsible
for some metabolism of flucytosine to 5-FU. Additionally 5-FU is released from
killed fungi cells. The 5-FU/5-FC ratio of plasma concentrations is low (4%).
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.
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.
Dosage and 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 bodyweight divided into four doses over the 24 hours. In patients
harbouring extremely sensitive organisms, a total daily dose of 100 to
150 mg/kg bodyweight 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
infecting 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 4 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 intervals should
remain the same.
Use in the elderly
Although no specific studies have been performed to establish the use of
Ancotil in the elderly, documented use indicates 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 is for intravenous or intraperitoneal administration.
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.
Contra-indications and warnings
Contra-indications
Ancotil is contra-indicated in patients who have shown hypersensitivity to flucytosine or any of the excipients and are being treated with antiviral nucleoside
drugs (e.g. brivudine, sorivudine and their analogues). See Drug interactions
section.
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Use in pregnancy and lactation
Teratogenic effects have been seen in rats. In this 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.
Precautions
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.
Flucytosine is metabolised to fluorouracil. Dihydropyrimidine dehydrogenase
(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 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.
Ancotil contains 34.5 mmol (or 0.8g) sodium/250ml solution for infusion. To
be taken into consideration by patients on a controlled sodium diet.
Side effects and adverse reactions
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. These are 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 has been
reported. This toxicity may be irreversible and could lead to death in patients
with pre-existing immunosuppression. Local irritation or phlebitis does not
appear to be a problem with Ancotil for Infusion.
Drug interactions
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.
An interval of at least 4 weeks should elapse between treatment with brivudine,
sorivudine or analogues and subsequent administration of Ancotil.
Increased phenytoin plasma levels have been reported with concomitant
administration of phenytoin and intravenous fluorouracil leading to symptoms
of phenytoin intoxication. This is relevant to Ancotil as flucytosine is metabolised to fluorouracil. Patients receiving phenytoin and Ancotil concomitantly
should be checked regularly for increased phenytoin plasma levels.
Treatment of overdosage
Haemodialysis produces a rapid fall in the serum concentration of Ancotil.
Pharmaceutical precautions
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.
Before administration Ancotil should be visually inspected and should not
be used in the presence of visible particulate matters, precipitation and
discolouration. For single use only. Discard any remaining contents after use.
Additives
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 BP.
No other agent should be added to or mixed with Ancotil for Infusion.
Legal category
UK: POM
Ireland: Restricted to sale or supply on prescription only.
Package quantities
Ancotil for Infusion 2.5 g in 250 ml in packs of 5.
Further information
Availability
Ancotil for Infusion is available to hospitals only.
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 azotemia. Other suitable methods should be used for
creatinine assessment. The current creatinine method used with automated
Vitros analysers is not affected by flucytosine.
Product Licence/Authorisation Numbers, Names and Addresses
Licence/Authorisation Numbers
UK: PL 15142/0002, Ireland: PA 1332/30/1, Malta: MA806/00801
The Product Licence/Authorisation holder is:
Meda Pharmaceuticals Ltd.,
Skyway House, Parsonage Road, Takeley, Bishop’s Stortford, CM22 6PU, UK.
Meda Health Sales Ireland Limited,
Unit 34/35, Block A, Dunboyne Business Park, Dunboyne, Co. Meath, Ireland.
The manufacturer is:
Meda Pharma GmbH & Co. KG, Benzstrasse 1, 61352 Bad Homburg, Germany.
Date of last review
January 2014

Ancotil can be given with a glucose and/or saline infusion. It
should not be mixed in the same solution with other medicines.

4. POSSIBLE SIDE EFFECTS
Like all medicines, Ancotil can cause side effects, although not
everybody gets them.
Your doctor will monitor your reaction to Ancotil. Possible side
effects include:
•  ausea, vomiting, diarrhoea and skin rashes may occur but
N
these usually do not last long.
Less frequent side effects include:
• 
Allergic reaction. If you have an allergic reaction you may
experience palpitations, swelling of eyelids, face, lips, mouth
or tongue, sudden wheeziness, chest tightness, lumpy skin
rash.
• Skin inflammation that may lead to severe blistering.
• Effects on the heart muscle and its pumping.
• 
Confusion, effects on your senses (e.g. seeing or hearing
things), fits, headache, sleepiness and dizziness.
• 
Tests on your blood may show changes to your liver or
certain factors in your blood.
• 
Ancotil contains 34.5 mmol (or 0.8 g) sodium/250 ml solution
for infusion. To be be taken into consideration by patients on
a controlled sodium diet.
If you are concerned about any of these side effects, or if you
notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.

5.  OW ANCOTIL SOLUTION FOR INFUSION IS
H
STORED
• ll medicines should be kept out of the reach and sight of
A
children.
• Hospital staff should store Ancotil between 18°C and 25°C.
•  his product should not be used after the expiry date shown
T
on the bottle label after “EXP”. The expiry date refers to the
last day of that month.
• 
Before administration, Ancotil should be visually inspected for
any particulate matter and discolouration.
•  not use Ancotil if you notice that there are any visible
Do
particles, precipitation or discolouration.
•  single use only. Discard any remaining contents after use.
For
• 
The product should only be handled by experienced
healthcare professionals.
• 
Medicines should not be disposed of via wastewater or
household waste. The pharmacist should provide
instructions as to how to dispose of medicines no longer
required. These measures will help to protect the
environment.

6. FURTHER INFORMATION
What Ancotil Solution for Infusion contains
Active substance: 
Flucytosine. Each infusion bottle contains
2.5 g in 250 ml (1 g in 100 ml) of flucytosine
Other ingredients:  odium chloride, tromethamine,
S
hydrochloric acid, and water for injections.
What Ancotil Solution for Infusion looks like and contents of
the pack
• 
Ancotil Solution for Infusion is a clear, colourless to slightly
yellow solution.
• 
Ancotil Solution for Infusion is available in packs of 5 bottles
of 250 ml.
Marketing Authorisation Holder
Meda Pharmaceuticals Ltd.,
Skyway House, Parsonage Road, Takeley, Bishop’s Stortford,
CM22 6PU, UK.
Meda Health Sales Ireland Limited.
Unit 34/35, Block A, Dunboyne Business Park, Dunboyne,
Co. Meath, Ireland
Manufacturer
Meda Pharma GmbH & Co. KG,
Benzstrasse 1, 61352 Bad Homburg, Germany.
For any information about this medicine, please contact the
Marketing Authorisation Holder.
This leaflet was last revised in November 2011.
56UKIE1988105-01

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14.01.14 17:09

Studio Oberländer • Rubensstrasse 33 • 60596 Frankfurt am Main • Germany
Tel. +49 69 631520-85 • Fax +49 69 631520-87 • E-Mail: info@studio-oberlaender.de
Gebrauchsinformation          mock-up
Hersteller:

MEDA Pharma GmbH & Co. KG

Benutzte Farben:

Produkt:

Ancotil 2,5 g / 250 ml

Schwarz

Meda-Nr.

56UKIE1988105-01

Hersteller-Nr. 60018220G
Laetuscode: 796

Land:

Größe:

210 x 420 mm

Korrektur: 1.

Text:

8,75 pt/9,5 pt + 10 pt/13,5 pt

Datum:

0114_GI_Ancotil 250ml_56UKIE1988105-01.indd 3

UK / IE

14. 01. 2014

14.01.14 17:09

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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