Download Regimen: Pegylated Liposomal Doxorubicin Hydrochloride (PLDH

Regimen: Pegylated Liposomal Doxorubicin Hydrochloride (PLDH) (Caelyx®) and
Carboplatin (‘CALYPSO’ regimen)
This is NOT a NICE-approved treatment. Please ensure that this regimen is locally
funded before prescribing this treatment or discussing with patients.
Indications
Regimen details
Administration
Palliative therapy for relapsed ovarian, fallopian tube or primary peritoneal
cancer with late relapse (> 6 months) after prior platinum-based treatment.
Day(s)
1
Drug
Pegylated Liposomal Doxorubicin
Hydrochloride (PLDH)
1
Carboplatin
Carboplatin Dose=Target AUC x (GFR*+25)
Dose
30mg/m2
Route
IV
AUC = 5 or 6*
IV
* Measured GFR (calculated using a patient specific method such as a 24hour urine sample or 51Cr-EDTA/ DTPA) is preferred whenever feasible,
particularly in circumstances of co-morbidity that could affect renal function
such as dehydrated patients or patients with a either a high or low weight.
Alternatively the Cockcroft & Gault Method can also be used to estimate a
patient’s GFR.
If using 24-hour urine or 51Cr-EDTA/DTPA is used, consider dosing at AUC
5.
If using Cockcroft and Gault, consider dosing at AUC 6
Pegylated Liposomal Doxorubicin Hydrochloride is administered in 250ml
glucose 5% infusion bag.
Pegylated Liposomal Doxorubicin Hydrochloride should be given over 60
minutes or at 1mg/minute (whichever is longer) for the first cycle. If well
tolerated then subsequent doses can be administered over 60 minutes.
Infusions of Pegylated Liposomal Doxorubicin Hydrochloride must not be
filtered.
Carboplatin is administered in 250-500ml glucose 5% over 30-60 minutes
Avoid any device containing aluminium that may come in contact with
Carboplatin.
Patients should be observed closely for hypersensitivity reactions,
particularly during the first and second infusions. Hypersensitivity reactions
may occur within a few minutes following the initiation of the infusion of
carboplatin. Facilities for the treatment of hypotension and bronchospasm
must be available.
If hypersensitivity reactions occur, minor symptoms such as flushing or
localised cutaneous reactions do not require discontinuation of therapy.
The infusion may be temporarily interrupted and when symptoms improve
re-started at a slower infusion rate. Chlorphenamine 10mg iv may be
administered. Severe reactions, such as hypotension, bronchospasm or
generalised rash/erythema require immediate discontinuation of
carboplatin and appropriate therapy.
Controlled document
Document No
Version Number
ASWCS09 GYN009
1.1.a
Last printed 15/12/2011 17:02:00 *ONLY VALID ON DATE OF PRINTING*
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Frequency
Every 28 days for a maximum of 6 cycles
Extravasation
Pegylated Liposomal Doxorubicin Hydrochloride is an exfoliant (Group 4)
Carboplatin is an irritant (Group 3)
Premedication
None usually required.
Pegylated Liposomal Doxorubicin Hydrochloride can be associated with an
infusion reaction, which usually occurs during the first cycle. Carboplatin
can also be associated with an infusion reaction, particularly if patients
have previously received carboplatin. If a reaction occurs, the infusion
should be stopped until symptoms have cleared and can be recommenced
at a slower rate. Hydrocortisone 100mg IV bolus and chlorphenamine
10mg IV bolus may be administered if appropriate.
If a reaction occurs to carboplatin, hydrocortisone 100mg IV bolus and
chlorphenamine 10mg IV bolus should be given 15-30 minutes prior to all
subsequent infusions.
As both agents have the potential to cause infusion-related reactions,
consideration should be given to leaving an interval between administering
the Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin.
Emetogenicity
This regimen has moderate-high emetic potential - refer to local protocol
Additional
recommended
supportive medication
Loperamide 4mg po stat then 2mg prn if diarrhoea develops.
Mouthwashes as per local policy
To minimise the risk of PPE for the first week after Pegylated Liposomal
Doxorubicin Hydrochloride infusion:
•
Keep hands and feet as cool as possible.
•
Avoid tight-fitting gloves, sock, footwear and high-heeled shoes.
•
Avoid exposing the skin to very hot water.
•
Avoid vigorous rubbing of skin-pat skin dry after washing.
•
Avoid use of topical anaesthetics as these can worsen skin
reactions.
Pre- treatment
evaluations
FBC
LFT
U&E (inc. SrCr)
Ca125
ECHO
Baseline - results valid for 28 days
Baseline - results valid for 28 days
Baseline - results valid for 28 days
Pre D1 – results valid for 28 days
Only required if clinically indicated
Regular investigations
FBC
LFT
U&E (inc. SrCr)
Ca125
Clinical
Assessment
Pre D1 – results valid for 72 hours
Pre D1 – results valid for 7 days
Pre D1 – results valid for 7 days
Pre D1 – results valid for 7 days
Clinically assess patient prior to each cycle,
particularly focusing on whether the patient has
developed renal dysfunction, ototoxicity, marked
stomatitis, Palmar-Plantar Erythrodysaesthesia or
neurotoxicity
Controlled document
Document No
Version Number
ASWCS09 GYN009
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Last printed 15/12/2011 17:02:00 *ONLY VALID ON DATE OF PRINTING*
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Neutrophil count
Platelet count
Creatinine Clearance
Standard limits for
administration to go
ahead – if blood results not
within range, authorisation to
administer must be given by
prescriber/consultant
Bilirubin
ALT/AST
≥ 1.0x 109/L
≥100 x 109/L
> 30ml/min & <10% change in
GFR from previous cycle
< 20micromol/L
< 1.5 x ULN
Dose modifications
Haematological toxicity
Defer therapy for 1 week if:
• Neutrophils <1.0 x 109/L or
• Platelets
< 100 x 109/L
Renal impairment
GFR
Carboplatin Dose†
>30ml/min
100%
20-30ml/min
Consider alternative, nonnephrotoxic regimen
<20ml/min
Contraindicated
† If the calculated GFR falls by more than10% from the previous cycle then
consider a dose alteration.
•
Hepatic impairment
NCI Common Toxicity
Criteria
Dose modifications should not be required for Pegylated Liposomal
Doxorubicin Hydrochloride in patients with renal impairment.
Serum bilirubin (micromol/L)
Pegylated Liposomal Doxorubicin
Hydrochloride Dose
<20
100%
20-51
75%*
51-68
50%*
>68
Avoid
* If the first dose is tolerated without an increase in bilirubin or LFTs, the
second dose can be increased to the next dose increment and then titrated
to full dose on subsequent cycles if again tolerated.
• Carboplatin: Transient increases in liver enzymes have been seen
although no dose reduction is usually required. In severe hepatic
dysfunction consider a dose reduction after discussing with the
consultant.
Toxicity
Febrile
neutropenia
Definition
ANC <0.5 x 109/l plus
fever requiring IV
antibiotics +/hospitalisation
Dose adjustment
Reduce all future doses of
Pegylated Liposomal Doxorubicin
Hydrochloride to 20mg/m2 and
reduce all future doses of
carboplatin by 1 AUC.
Stomatitis
Grade 2 (painful
erythema, oedema or
ulcers, but can eat)
Treat symptomatically and/or
delay until recovered to
Grade 1. If symptoms continue,
reduce dose of Pegylated
Liposomal Doxorubicin
Hydrochloride to 20mg/m2
Treat symptomatically and delay
until recovered to Grade 1 and
Grade 3 (painful
erythema, edema or
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PPE (HandFoot
Syndrome)
Other
toxicities
ulcers, and cannot eat) then continue Pegylated
Liposomal Doxorubicin
Hydrochloride at a reduced dose
of 20mg/m2.
Grade 4 (requires
Discontinue treatment
parenteral or enteral
support)
Grade 2
Treat symptoms until recovered
to ≤Grade 1. If patient not
recovered to ≤Grade 1 by 42
days after previous dose,
discontinue treatment
Grade 3 or 4
Discontinue treatment
Grade III toxicity
Reduce dose of Pegylated
(except alopecia,
Liposomal Doxorubicin
nausea & vomiting)
Hydrochloride to 20mg/m2 and/or
reduce dose of carboplatin to
AUC 4 provided toxicity has
resolved to ≤ Grade 1.
If further toxicity occurs, an
additional reduction may be
made after discussion with
consultant
Grade IV toxicity
Withhold treatment and discuss
(except alopecia,
with consultant
nausea & vomiting)
• If a delay of more than 3 weeks is required for recovery, or more than 2
dose reductions are necessary, the patient should discontinue
treatment.
Adverse effects – the
contents of the table indicate
the adverse effects that should
be documented on consent to
treatment forms
Rare or Serious Side Effects
Febrile neutropenia
Myelosuppression
Peripheral neuropathy
Convulsions
Thromboembolism
Secondary leukaemias
Optic neuritis
Acute Hypersensitivity reactions
(first infusion)
Cardiac toxicity
Pulmonary Fibrosis (very rare)
Frequently occurring Side Effects
Nausea and vomiting
Alopecia (reversible)
Possible diarrhoea or constipation
Fatigue / asthenia
Stomatitis and mucositis
Allergic reactions such as rash and
pruritus
Palmar-Plantar Erythrodyaesthesia
(PPE) / Hand-Foot Syndrome (HFS)
Discoloured urine
For full details of adverse effects and contraindications, see the Summary
of product characteristics (SPC) of each component of the regimen
Significant drug
interactions –
For full details consult product
literature/ reference texts
Controlled document
Carboplatin:
•
Warfarin/coumarin anticoagulants: increased or fluctuating
anticoagulant effects. Avoid if possible: in the first instance,
consider switching patient to a low molecular weight heparin during
treatment or if the patient continues taking an oral anticoagulant
monitor the INR at least once a week and adjust dose accordingly.
•
Aminoglycoside antibiotics: increased risk of nephrotoxicity and
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ototoxicity
• Clozapine: increased risk of agranulocytosis, avoid concomitant
use
• Diuretics: increased risk of nephrotoxicity and ototoxicity
• Nephrotoxic drugs: increased nephrotoxicity ; not recommended
• Phenytoin: reduced absorption of the antiepileptic
Pegylated Liposomal Doxorubicin Hydrochloride:
•
Comments
Cumulative Doses
Ciclosporin: giving doxorubicin with high doses of ciclosporin can lead
to neurotoxicity.
N/A
Use Pegylated Liposomal Doxorubicin Hydrochloride in caution at
cumulative doses in excess of 450mg/m2 (or equivalent antracycline
dosage). Consider previous anthracycline exposure.
References
•
•
•
•
National Institute for Health and Clinical Excellence. Technology Appraisal 91. Paclitaxel, pegylated
liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of
advanced ovarian cancer. [internet] accessed 09/12/2010, available at
http://www.nice.org.uk/nicemedia/live/11554/33024/33024.pdf
Pujade-Lauraine E, Uwe Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, et al.
Pegylated Liposomal Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for
Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse. J Clin Oncol 2010 28(20): 33233329.
Pujade-Lauraine E, Mahner S, Kaern J, Gebski V, Heywood M, Vasey P, et al. A randomized,
phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel
in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer
Intergroup (GCIG). J Clin Oncol 2009;27:18s: abstr LBA5509
Rose PG. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarain cancer. The
Oncologist. 2004;10 (3):205–14.
•
Sehouli J, Camara O, Schmidt M, Mahner S, Seipelt G, Otremba B, et al. North-Eastern German
Society of Gynecological Oncology. Pegylated liposomal doxorubicin (CAELYX®) in patients with
advanced ovarian cancer: results of a German multicenter observational study. Cancer Chemother
Pharmacol. 2009 64(3):585-91.
•
Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in hepatic impairment
[internet]. accessed 09/12/2010 available at http://www.bopawebsite.org/tikidownload_file.php?fileId=621
•
Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in renal impairment
[internet]. accessed 09/12/2010 available at http://www.bopawebsite.org/tikidownload_file.php?fileId=620
•
Summary of Product Characteristics Caelyx® (Pegylated Liposomal Doxorubicin Hydrochloride)
2mg/ml concentrate for solution for infusion (Schering-Plough) [internet], accessed 10/09/2010
available from http://www.medicines.org.uk/EMC/medicine/7017/SPC
•
Summary of Product Characteristics Carboplatin 10mg/ml Intravenous Infusion (Hospira)
[monograph on the Internet].accessed 09/12/2010 available from
http://www.medicines.org.uk/EMC/medicine/622/SPC
•
Baxter K, editor. Stockley’s Drug Interactions. Pharmaceutical Press; 2009. Accessed on line on
09/12/2010 available at https://www.medicinescomplete.com/mc/
•
Trissel LA. Handbook of Injectable Drugs, 15th edition. American Society for Health-Systems
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Pharmacists 2009. Accessed on line on 09/12/2010 available at
http://www.medicinescomplete.com/mc/hid/current/
•
Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4th ed. Radcliffe Medical Press.
2002.
Document title
®
Document number
Approval date
Written by
Pegylated Liposomal Doxorubicin Hydrochloride PLDH (Caelyx ) and Carboplatin chemotherapy
for ovarian cancer
ASWCS09 GYN009
11/12/2011
Digitally signed by Paul Cornes
Dr Paul Cornes, Consultant Clinical Oncologist, BHOC
DN: cn=Paul Cornes, o=BHOC,
ou=Consultant Oncologist, email=james.
Jarrod Dunn Cancer Services Pharmacist, TST
[email protected], c=GB
Checked by
James Carr, Network Pharmacist, ASWCS
Authorised by
Jeremy Braybooke, Chair, ASWCS Network
Chemotherapy Group
December 2013
Review date
Document reviewed by
Version number
Summary of changes
Controlled document
Paul Cornes
James Carr
Jeremy
Braybrooke
Date: 2011.12.15 17:03:40 Z
Digitally signed by James Carr
DN: cn=James Carr, o=ASWCS,
ou=Network Pharmacist, email=james.
[email protected], c=GB
Date: 2011.12.15 17:04:14 Z
Digitally signed by Jeremy Braybrooke
DN: cn=Jeremy Braybrooke, o, ou,
[email protected], c=GB
Date: 2011.12.15 17:04:43 Z
1.1.a
Version
Document No
Version Number
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1.1.a
Last printed 15/12/2011 17:02:00 *ONLY VALID ON DATE OF PRINTING*
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