GUIDELINES FOR THE DOSE BANDING OF CANCER …necn.nhs.uk/wp-content/uploads/2012/11/NECN-dose... · variance that could affect toxicity or clinical outcomes. The use of banded doses

Page 1 of 15 Issue Date 20.02.13 Expiry Date Feb 2015

GUIDELINES FOR THE DOSE BANDING OF

CANCER CHEMOTHERAPY

“Quality and safety for every patient every time”

Document Control Prepared By Issue Date Approved By Review

Date Version Contributors Comments/

Amendment S Williamson / C Polwart

25/02/09 Chemotherapy Group

Feb 2011 1.1 -1.3 Pharmacy Group (NECN)

29.6.11 July 2013 1.4 Updated title page format and review date

C Polwart 20.02.13 Chemotherapy Group

Feb 2015 1.5 Adjusted rounding limit to 6% to facilitate logarithmic dose bands

For more information regarding this document, please contact:

Steve Williamson Consultant Pharmacist in Cancer Services, North of England Cancer Network NE Strategic Health Authority, Waterfront 4, Goldcrest Way, Newcastle Upon Tyne, NE15 7NY [email protected]

mailto:[email protected]


Guidelines for the Dose Banding of Cancer Chemotherapy Executive Summary

In order to meet the increasing demand for chemotherapy the North of England Cancer Network recommends that all Trusts introduce a system of standardised dose banding for prescribing and dispensing selected chemotherapy drugs. Dose banding should be undertaken before investing in staff and facilities to manage capacity. Dose banding will allow use of commercially prepared/ stock items to complement the individual aseptic dispensing by pharmacy used to prepare patient ready chemotherapy. This document gives guidelines for NECN Trusts on introducing dose banding and provides a standardised system for dose banding for use in all Trusts in NECN. 1 Background 1.1 What is dose banding?

Dose banding is a system whereby, through agreement with pharmacy and prescribers, calculated doses of intravenous cytotoxic drugs are rounded up or down to pre-determined standard doses. The maximum variation of the adjustment between the prescribed dose and the banded dose issued to the patient will not be more than 6%. A range of pre-filled syringes or infusions, manufactured by pharmacy staff or purchased from commercial sources can then be used to administer the standard dose. 1.2 How accurate is dose banding?

As chemotherapy dosing based on body surface area BSA is not totally accurate1, dose banding to within approximately 6% of intended dose will not introduce additional variance that could affect toxicity or clinical outcomes. The use of banded doses to give doses within 5% of the prescribed dose was considered acceptable practice in a study undertaken by UK oncology pharmacists and demonstrated acceptable in practice in scotland2,3. However in recent guidance on logarithmic dose banding4 a 6% limit was agreed as acceptable following a national project. 2 Benefits of Dose Banding The benefits of dose banding and the use of pre-filled syringes are well documented and include:

Reduction in waiting times for patients through improved pharmacy work flows, e.g. facilitates preparation before blood results taken

Increased pharmacy capacity for chemotherapy

Facilitates pharmacy skill mix

Allows external contractors to provide service

potential reduction of medicine waste by avoiding incomplete usage of the full contents of a vial or ampoule when preparing individual doses

Reduces waste when treatments are deferred, due to ability to re-assign pre-filled syringes if administration is cancelled

Dose banding should be undertaken before investing in staff and facilities to manage capacity.


Dose banding of chemotherapy is already being implemented in a number of cancer centres and units both within the NECN and across the UK. Although there is a common principle there can be variation in its application in practice, e.g. there are various schemes using different ways of calculating bands. Ideally there should be harmonisation of dose banding across the North of England Cancer Network which would have benefits including:

For medical staff that travel between sites there will be consistency of dose banding practice

Consensus on dose band nonograms will reduce the range of pre-filled syringe sizes required. This provides an opportunity to improve cost-effectiveness through more competitive pricing with the procurement of pre-filled syringes.

Pharmacy manufacturing units within NECN will be able to offer a single set of dose bands to Trusts.

3 Drugs most suitable for dose banding

Not all cytotoxic drugs are suitable for preparation as pre-filled syringes, infusion bags or infuser devices. The key determinant is extended stability, usually an expiry of 30 days or more. Drugs that are currently available with extended expiry include:

Cyclophosphamide syringes Carboplatin Infusions

Doxorubicin syringes 5-Fluorouracil infusors

Epirubicin syringes Gemcitabine Infusions

5-Fluorouracil syringe Oxaliplatin Infusions

Methotrexate syringes

These drugs compromise some of the main chemotherapy regimens used in NECN e.g. weekly/ Mayo 5-FU, FOLFOX and FOLFIRI, for colorectal; CMF, FAC, FEC, EC and AC for Breast; CHOP/ RCHOP for lymphoma; CE and Gem Carbo for Lung. Dose banding has also been applied to other intravenous drugs such as paclitaxel, rituximab and trastuzumab and can also be used for oral preparations e.g. capecitabine. 4 Cost Implications

It is estimated that introducing dose banding will have minimum impact on the overall cost of the Trust's oncology medicine spend. There is potentially a mark up in price for drugs that have relatively cheap raw materials costs, e.g. 5-FU, Methotrexate. The percentage increase in price is very small with drugs that have a high raw material cost, e.g. gemcitabine, Epirubicin. The ready made doses of these drugs are often competitively priced against the raw material cost paid by Trusts. In some instances the high cost drugs can be cheaper when purchased as dose bands due to the buying power of the manufacturerer to negotiate discounted prices on raw materials. Trusts in NECN are advised to contact the leading manufacturers of dose banded products and undertake a budget impact assessment based on quoted prices.


This is a competitive commercial area, use of local pharmacist contracting expertise is strongly recommended, e.g. the regional specialist purchasing pharmacist David Cook. Investment in dose banding, were appropriate, is likely to be cheaper in the first instance than investing in new facilities or additional staff. It is however acknowledged that investment may be necessary in some units. 5 Suppliers

Some of the main manufacturers of pre-filled syringes for dose banding are listed below. It is noted there are both commercial suppliers and NHS suppliers. Trusts must undertake contracting as described above, however the NECN strategy is to recommend local NHS suppliers. NHS suppliers

Newcastle Hospitals NHS Trust Pharmacy

Leeds Teaching Hospitals

James Cook University Hospitals

Commercial suppliers

Baxter Healthcare

Calea UK Limited

Dabour Healthcare

Hospira (formerly Mayne Pharma)

Qualsept UK

Disclaimer: This does not represent a comprehensive list of suppliers nor does it in anyway constitute an endorsement of any of the commercial suppliers. 6. Choice of Dose Banding Scheme 6.1 There are three types of dose banding schemes that can be used:

BSA Centred Dose Banding

Bands are set in increments of body surface area, e.g. patient’s body surface area is rounded up or down to one decimal place and a set dose band given for that BSA, e.g. doxorubicin 50mg/m2 for patient of 1.73 m2, the BSA is rounded to 1.7 and a dose of 85mg given. Drug Centred Dose Banding or ‘Target Dose’ Banding.

The patient’s dose is prescribed as per BSA and then rounded up or down to the nearest band e.g. doxorubicin 50mg/m2 for patient of 1.73 m2, the calculated dose is 86.5mg. This falls in the 82.6mg to 87.5mg range for which a dose of 85mg is given. Logarithmic dose banding

Uses a logarithmic scale to achieve a consistent relationship between doses, i.e. when doses are reduced by a consistent amount, e.g. 10% of previous dose to allow precise dose adjustments to be made if required.


In practical terms it makes no difference to the patient which of these methods is used to dose band. Within the NECN prescriber’s clinical practice is to round BSA to one decimal place, therefore the first method has been chosen as it is perceived to be most compatible with existing clinical practice. 6.2 Risk of double rounding It is recognised that when adopting either dose banding scheme here is potential for ‘double rounding’. With the BSA centred scheme many of the bands chosen for each BSA have been rounded and hence there is double rounding, rounding up or down of BSA then rounding to the band. Similarly if adopting the Drug centred scheme double rounding can occur if the prescriber has rounded BSA to give a dose higher/ lower than the one based on exact BSA which is then rounded once more to the band. The key to managing this risk is to validate the dose banding tables used and measure the maximum percentage variance from the exact dose. The aim is to ensure doses always fall within 5% of the original intended dose. The dose bands selected below will always deliver a dose with 5% of the intended dose per BSA. There will be certain occasions when a patients BSA falls exactly between the BSA bands that the variance will be between 5% and 7.5%. 6.3 Validation of dose bands chosen. NECN has prepared an excel spreadsheet to validate the dose bands, the spreadsheet calculates the range of variance from the original intended dose and demonstrates that the 5% rule is intact for the majority of doses in the scheme (86%). The spreadsheet highlights BSA dose where there is potential for a variance between 5% and 7.5% as ’amber’. 14% of doses in the scheme have potential for amber variance. At the extremes of the dose band range there are 3 (1%) doses where the variance is between 7.5% and 10% highlighted as red. Banding should be avoided for these three doses. 7 When is Dose Banding not recommended?

7.1 Children:

Advice of specialists within Paediatric Oncology and Haematology must be sought if considering dose banding. Dose banding is not prohibited in paediatrics but it is rarely used for a number of reasons. For example:

Dosing in children is difficult up to 30kg/8-10 years. UKCCLG recommends a range of dose reductions to BSA calculated doses for children < 12 months old.

A 10kg child could be a large 9 month old or an underweight 14 month old.

Most treatment is within clinical trials, banding is not approved in the protocols and methods of drug administration have not been consistent between trials

Impractically small dose increments may be needed between bands

Sites preparing batches of dose banded chemotherapy for use in clinical trials would need an IMP license

Banding across the whole paediatric age range would result in an impractically large number of dose bands

7.2 Cachexia and obesity:

Methods of individualised dose calculation may be more appropriate in severe cases.


7.3 Clinical Trials:

Dose banding can only be used in clinical trials with prior agreement of the trial chief investigator and sponsor (preferably discussed during protocol development). With the exception of pharmacokinetic trials, there is no sound reason to exclude dose banding from trials which use BSA based dose regimens, provided effects on dose-limiting toxicities are considered.

Pharmacy departments are advised to check with trial protocol and /or investigator if dose banding is acceptable for each trial that is opened.

8 Procedure for Dose Banding 8.1 For the purpose of dose banding BSA shall be calculated to one decimal place

only. The range of BSAs of the nomograms will be from 1.4m2 to 2.2m2. Note pharmacists should be checking with prescriber when validating prescriptions where dosing is based on values greater than 2.0 m2.

8.2 The pharmacist undertaking clinical verification of chemotherapy prescription

identifies drug suitable for dose banding. See appendix one for tables of dose rounding and suggested syringe sizes to be used.

8.3 If not already banded by the prescriber the prescription is amended and dose is

banded by the pharmacist according to the tables given in appendix one. 8.4 The pharmacist endorses any amendments to original prescription, e.g. doses

rounded for dose banding, with the date and their initials. 8.5 Drugs are supplied to the ward as combination of pre-filled syringes or infusion

bags for administration. Doses in syringes will often be supplied as a combination of 2 to 3 syringes each containing a proportion of the total dose. No more than 3 syringes should be supplied per dose. It must be noted that it is actually easier fro nursing staff to administer smaller volume (less than 30mls) syringe sizes, so there may be some instances where it is preferable to give more than 3 syringes for one dose. Check with local nursing staff on their preferences.

8.6 Stocks of dose banded products come pre-labelled with drug, strength, expiry

date and batch number. Pharmacy departments issuing dose banded products will need to label the products with the patient name, ward, consultant and date issued. Ideally this will be on the product and its outer wrap.

8.7 The dose banded drugs are issued to the ward for administration in the usual

fashion. There may be prescriptions where some products are banded and some are aseptically prepared.

8.8 It is acceptable round doses that will be aseptically prepared to the suggested

bands within the scheme in the absence of stocks of prefilled syringes. It is recognised that this reduces waste and increases chance of doses being reused should patients not be fit to proceed with chemotherapy.


9 Implementation and Audit. 9.1 Dose banded syringes/ infusion bags are unlicensed products know as ‘specials’.

Therefore all pharmacies using pre-filled syringes/ infusion bags for the purpose of dose banding should complete accountability records for the receipt and dispensing of syringes and ensure good practice for handling unlicensed medicines. Factors to go consider include:

Involvement of local Quality Assurance QA advice on processes

Need for increased fridge space for storage of prefills

The range of syringe sizes should be chosen to ensure that all dose bands can be delivered using no more than three syringes

Need to specify labelling requirements, light protective packaging, fill volume limits and closure type for syringes, delivery schedule.

Cold chain integrity (both from supplier and on delivery within Trust as cold chain needs to be maintained if unused doses are to be recycled)

9.2 An example of the QA documentation that can be completed when receiving

orders of pre-fills can be found in appendix two. 9.3 It is recommended that Trusts undertake a review/ audit of prescribing of drugs

suitable for dose banding. Some regimens may be used in such low volume to make dose banding not feasible. There needs to be regular use, i.e. more than once per week prescribing to ensure that stocks will be used.

9.4 Trusts are also advised to monitor wastage of prefills used for dose banding.

Due to relatively short expiry date of the products careful attention needs to be given to stock levels and stock turnaround.

9.5 The electronic prescribing system used in the network, chemocare, has a facility

to automatically dose band when prescribing. The method chemocare uses to calculate the final is target dose based, rather than BSA based but is the resulting recommended doses are consistent with the tables described below.


References

1 Body Surface Area as a basis for dosing of anti-cancer agents science, myth or habit; Ratain MJ. J Clin Oncol. 1998. 16: 2297-9 Editorial

2 Dose- Banding of cytotoxic drugs: A new concept in cancer chemotherapy. Plumridge RJ & Sewell G.J. Am J Health-Syst Pharm Vol 58 sep 15, 2001

3 Dose Banding at the Edinburgh Cancer Centre. MacLean et Al Pharmaceutical Journal 17 May 03 p691-693

4

5 Toolkit: How to Implement Dose banding of Chemotherapy. 2008. Andrew Gillian. Network Pharmacist (NELCN) on behalf of Cancer Network Pharmacists. Available at http://www.bopawebsite.org/contentimages/publications/Toolkit_Ver_3.0_FINAL.pdf

Acknowledgements

With Thanks to Mary Maclean, Regional Cancer Care Pharmacist, West of Scotland Cancer Network for permission to adopt parts of the Scottish Cancer Pharmacy Group :Guidelines For Dose Banding of Cancer Chemotherapy June 2005.

http://www.bopawebsite.org/contentimages/publications/Toolkit_Ver_3.0_FINAL.pdf


Appendix One: NECN Dose Banding tables.

CYCLOPHOSPHAMIDE SYRINGES

Dose (mg/m²)

500 600 750

BSA (m²) Dose Given (mg) Dose Given (mg) Dose Given (mg)

1.4 700 850 1100

1.5 750 900 1100

1.6 800 950 1200

1.7 850 1000 1300

1.8 900 1100 1400

1.9 950 1150 1400

2 1000 1200 1500

2.1 1050 1250 1600

2.2 1100 1300 1700

Suggested Syringe Sizes:

250mg, 300mg, 400mg, 500mg, 600mg, 1000mg*

DOXORUBICIN SYRINGES

Dose (mg/m²)

50 60 75


1.4 70 85 105

1.5 75 90 110

1.6 80 95 120

1.7 85 100 130

1.8 90 110 135

1.9 95 115 140

2 100 120 150

2.1 105 125 160

2.2 110 130 165

Suggested Syringe Sizes: 25mg, 30mg, 40mg, 50mg, 60mg, 65mg, 70mg


EPIRUBICIN SYRINGES

Dose (mg/m²)

30 50 60 90 100

BSA (m²)

Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

1.4 40 70 85 125 140

1.5 45 75 90 130 150

1.6 50 80 95 140 160

1.7 50 85 100 150 170

1.8 55 90 110 160 180

1.9 55 95 115 170 190

2 60 100 120 180 200

2.1 65 105 125 190 210

2.2 65 110 130 200 220

Suggested Syringe Sizes: 10mg, 20mg, 25mg, 40mg, 50mg, 100mg

5-FLUOROURACIL SYRINGES

Dose (mg/m²)

300 370 400 425 500 600

BSA (m²) Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

Dose Given (mg)

1.4 400 500 550 600 700 850

1.5 450 550 600 650 750 900

1.6 500 600 650 700 800 950

1.7 500 650 700 700 850 1000

1.8 550 650 700 750 900 1100

1.9 550 700 750 800 950 1150

2 600 750 800 850 1000 1200

2.1 650 750 850 900 1050 1250

2.2 650 800 900 950 1100 1300

Suggested Syringe Sizes: 250mg, 300mg, 400mg, 500mg, 600mg, 650mg, 700mg, 750mg


5-FLUOROURACIL INFUSORS

Dose

200 mg/m²/day

(1400 over 7days)

300 mg/m²/day

(2100 over 7days) 2400 mg/m² 46

hours


1.4 2000 2800 3500

1.5 2000 3150 3500

1.6 2275 3500 3850

1.7 2450 3500 4200

1.8 2450 3850 4200

1.9 2625 3850 4550

2 2800 4200 4900

2.1 2800 4500 4900

2.2 3150 4500 5250

Suggested 7 day INFUSOR Sizes: 2000mg, 2,275mg, 2,450mg, 2,625mg,

2,800mg, 3150mg, 3,500mg, 3,850mg, 4,200mg

Suggested Mod DeGramount (FOLFOX/FOLFIRI) INFUSOR Sizes

3,500mg, 3,850mg, 4,200mg, 4,550mg, 4,900mg

GEMCITABINE INFUSIONS

Dose (mg/m²)

1000 1200 1250


1.4 1400 1700 1700

1.5 1500 1800 1800

1.6 1600 1900 2000

1.7 1700 2000 2200

1.8 1800 2200 2200

1.9 1900 2200 2400

2 2000 2400 2400

2.1 2000 2400 2600

2.2 2200 2600 2600

Suggested Bag Sizes: 1500mg 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2200mg, 2400mg, (*1400mg, 2600mg are used, but potentially not economical to stock )


METHOTREXATE SYRINGES

Dose (mg/m²)

40 50

BSA (m²) Dose Given (mg) Dose Given (mg)

1.4 55 70

1.5 60 75

1.6 65 80

1.7 70 85

1.8 70 90

1.9 75 95

2 80 100

2.1 85 105

2.2 90 110

Suggested Syringe Sizes: 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg

OXALIPLATIN INFUSIONS

Dose (mg/m²)

85 130

BSA (m²) Dose Given (mg) Dose Given (mg)

1.4 120 180

1.5 130 200

1.6 130 200

1.7 140 230

1.8 150 230

1.9 160 250

2 170 250

2.1 180 280

2.2 180* 280

Suggested Bag Sizes:

130mg, 140mg, 150mg 160mg, 170mg 180mg, 200mg, 230mg, 250mg, 280mg


CARBOPLATIN INFUSIONS

Prescribed Dose Dose Supplied

425mg to 474mg 450mg





Suggested Bag Sizes: 450mg, 500mg, 550mg, 600mg, 650mg

Note Carboplatin Bands note based on body surface area as dosed according to renal function. Based upon audit of commonly used carboplatin doses at Northumbria Trust.


Appendix Two: Examples of Pharmacy documentation needed to support dose banding

Northumbria Healthcare NHS Trust Pharmacy Aseptic Services

Specials Specification Sheet No ………. Product: CYCLOPHOSPHAMIDE IV BOLUS INJECTION

The following details must be completed by an authorised person within the aseptic unit upon the receipt of each batch.

Inspection Pass Fail Initials

1. Date of inspection

2. Order Number

3. Manufacturer

4. Batch Number

5. Expiry Date Check the expiry date is 12 weeks from the date of manufacture

6. Strength and Quantity

7. Volume check Check the fill volume is correct in all syringes

8. Appearance A clear colourless liquid

9. Container 20mL, 30mL or 50mL Luer –Lock Syringe (Depending on volume in syringe)

10. Type of blind hub

11. Label Check that the label is suitable and that it complies with the specimen label below

12. Certificate of analysis or conformity Attach to this sheet if available

Comments:

Batch Complies with product specification Yes/No Product Released By Date Of Release

Page 1 of 1 Prepared By Approved By Date Approved

Specimen Label


Northumbria Healthcare NHS Trust - Pharmacy Aseptic Services

Dispensing Log Sheet For Pre-Filled Aseptic ‘Specials’

PRODUCT _______________________________________ MONTH ___________________________

Date

Dispensed

Patient’s Name Trust/Unit

Number

Cons Ward Dose

Required

Strength Qty Batch Number Expiry

Date

Dispensed

By

Checked

By

Prepared By Approved By Date Approved Pre-Filled Log Sheet V2

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GUIDELINES FOR THE DOSE BANDING OF CANCER …necn.nhs.uk/wp-content/uploads/2012/11/NECN-dose... · variance that could affect toxicity or clinical outcomes. The use of banded doses