LTHT Clinical guideline for the use of Uridine triacetate for the treatment of patients exhibiting early-onset severe toxicities following 5-fluorouracil or capecitabine administration

• Background information
• Flow diagram of process for prescribing and ordering
• Eligibility criteria
• Treatment summary including timelines
• Uridine Paediatric dose based on Body Surface Area (m²) (taken from SmPC)
• Preparation and Administration of 10g uridine sachets
• Preparation of uridine sachets for Paediatric doses based on Body Surface Area (m2) (adapted from SmPC)
• Pharmacy ordering process
• Pharmacy QC procedure
• Funding requirements

Background information

5-fluorouracil (also referred to as 5-FU) and capecitabine are a group of chemotherapy medicines, known as fluoropyrimidines. They are used as part of the treatment of various cancers including: (i) colorectal cancer; (ii) oesophago-gastric cancer; (iii) breast cancer; and (iv) cancers of the head and neck region. 5-fluorouracil is administered intravenously and capecitabine is taken orally. Both medicines work by stopping DNA replication which inhibits cancer cell growth.

It is common for patients receiving these drugs to experience side effects (e.g. fatigue, diarrhoea, nausea, loss of appetite) and these can usually be managed at home with supportive medicines. However, some patients receiving treatment with 5-fluorouracil or capecitabine will experience more severe side effects which require hospital admission and, in some situations, can be life threatening. The side effects include:

• Myelosuppression (Increased risk of infection and bleeding)
• Severe diarrhoea
• Severe mucositis (sore mouth meaning patients cannot swallow)
• Severe nausea or vomiting
• Severe skin reactions

One of the main causes of severe toxicity following 5-fluorouracil or capecitabine administration is a genetic variation in the dihydropyrimidine dehydrogenase (DPYD) enzyme. The DPYD enzyme helps metabolise (break down) 5-fluorouracil /capecitabine in the body and without it, or at low levels, these chemotherapy medicines can build up in the body. Tests for DPYD are available and all patients at LTHT will be tested prior to starting treatment with either 5-fluorouracil or capecitabine. However, even with testing there will still be a very small group of patients who develop severe and life-threatening side effects due to other genetic enzyme variations.

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FLOW DIAGRAM OF PROCESS FOR PRESCRIBING AND ORDERING

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Eligibility criteria

To be eligible to receive treatment with uridine triacetate, the following criteria must be met:

1. Severe or life-threatening adverse events must occur within 96 hours of the end of 5-fluorouracil infusion or the last administration of capecitabine
2. Patients must be on their first cycle of treatment with either 5-fluorouracil or capecitabine
3. Adverse events must be deemed severe/life threatening by a clinician experienced in fluoropyrimidine prescribing ie. CTCAE Grade 3 or 4 and occur in combination. These include, but are not limited to:
   • Grade 3 mucositis
   • Grade 3 palmar-plantar erythema
   • Grade 3 diarrhoea
   • Grade 3 myelosuppression.

In rare cases, uridine triacetate may be prescribed in the event of a known overdose or pump malfunction where severe or life-threatening adverse events are considered likely.

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Treatment summary including timelines

Treatment with uridine triacetate must be started within 96 hours of the development of toxicity (toxicity must start within 96hours of the end of the 5-fluorouracil infusion or final capecitabine dose as defined above) or within 96 hours of known overdose as defined above.

Dosage of Uridine triacetate will be as follows:-

Adults

• 10g orally every 6 hours for 20 doses.

Children

• 6.2g/m² of body surface (not to exceed 10g per dose) orally every 6 hours for 20 doses.

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Uridine Paediatric dose based on Body Surface Area (m²) (taken from SmPC)

* Dose by body surface area category in this table was rounded to achieve the approximate dose. Each dose is administered every 6 hours for 20 doses.

For patients under 1 year of age please discuss with the Paediatric Oncology team.

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Preparation and Administration of 10g uridine sachets

• Mix each 10g dose with approximately 100ml of soft foods such as applesauce, pudding or yoghurt and ingest within 30 minutes. Do not chew the granules. Drink at least 100ml of water.
• If a patient vomits within 2 hours of taking a dose, initiate another complete dose as soon as possible after the vomiting episode. Administer the next dose at the regularly scheduled time.
• If a patient misses a dose at the scheduled time, administer that dose as soon as possible. Administer the next dose at the regularly scheduled time.

To administer via a nasogastric tube (NG tube) or gastrostomy tube (G-Tube) when necessary (eg, severe mucositis or coma), follow the instructions below for each dose administration:

1. Prepare approximately 100ml of a food starch-based thickening product in water and stir briskly until the thickener has dissolved.
2. Crush the contents of one full 10 gram packet of uridine granules to a fine powder.
3. Add the crushed uridine granules (10grams)to 100ml of the reconstituted food starch-based thickening product. For paediatric patients receiving less than 10 grams, administer the appropriate volume dependent on the child’s dose (see table below)
4. After administration of the mixture using the NG tube or G-Tube, flush the tube with water

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Preparation of uridine sachets for Paediatric doses based on Body Surface Area (m²) (adapted from SmPC)

Pharmacy will provide a 1/4 teaspoon measure to measure out the proportion of the sachet required depending on the surface area of the patient. The table below shows the number of level scoops required using the ¼ teaspoon measure.

Measure the required dose using the ¼ teaspoon measure and mix with soft foods such as applesauce, pudding or yoghurt and ingest within 30 minutes. For doses of 8 measures or less of the ¼ teaspoon measure add to 50ml and for 9 or more ¼ teaspoon measures add to 100ml. Do not chew the granules. Drink at least 100ml of water.
Discard any unused portion of granules. Do not use granules left in the open packet for subsequent dosing.

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Pharmacy ordering process

WEP Clinical are the UK importers of uridine. They operate a dedicated 24 hours a day Vistogard® emergency ordering line.

1. To order a supply of Uridine please call the dedicated 24/7 Vistogard® emergency ordering line on 0207 887 2235.
   
   
2. You will be asked to provide the following information :-
   
   Quantity of product: 1 x 20 sachets
   Patient Initials:………………………..
   
   Delivery details
   Delivery Site Name: St James’s University Hospital
   Delivery Address: Pharmacy department, Level -1, Gledhow wing, St James’s University hospital, Beckett Street, Leeds, LS9 7TF
   Consignee/For attention of: …………………………….
   Contact telephone number: …………………………….
   Contact E-mail address: ……………………………………
   
   Billing Details
   Invoice for the attention of : Gilly Foster, Pharmacy Procurement Business Manager
   Telephone Number: 0113 3927002
   E-Mail address: leedsth-tr.pharmacyinvoiceteam@nhs.net
   Billing Address: Leeds Teaching Hospital NHS Trust
   Pharmacy Procurement Office
   Moor House
   125 Moor Road
   Leeds Teaching Hospitals
   LS10 2JQ
   
   Purchase Order Number: …………………
   VAT Number: GB: 654944112
   
   Medical Practitioner/Physician Details
   Full Name: ……………………………..
   Position: …………………………….
   Medical registration number: …………………………………
   Telephone Number: ……………………………..
   E-Mail Address: ………………………………………
   
   
3. Shipment will be supplied as soon as possible to any location in the UK within 24 hours.

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Pharmacy QC procedure

QC will need to carry out their assessment of the product retrospectively.
Upon receipt of the product in pharmacy the following steps must be completed :-

1. Scan all sides of the sachet carton and both sides of the sachet on the photocopier.
2. Email these images along with copies of all the paperwork received with the product and the PIL to leedsth-tr.ulmqcoutcome@nhs.net
3. Include in the email the name, NHS number and ward that the patient is on. This will enable QC to follow up with the ward pharmacist if there were any issues.

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Funding requirements

The BlueTeq form must be completed for all patients prior to treatment with uridine triacetate.