October 2017
clinical initiatives, research and current updates in treatment
Treatment of Chemotherapy Extravasation Patrick Cullen, Pharmacy Practice Unit Extravasation is the escape of fluid into the extravascular space, either by leakage from a blood vessel or direct infiltration.1,2 The term usually refers to intravenous (IV) medication infiltrating the tissue around a blood vessel, which can cause injury ranging from mild skin reaction to severe necrosis.3 Extravasation is of particular concern with antineoplastic agents, as the basis for their mechanism of action usually depends on causing deliberate cellular toxicity. The incidence of chemotherapy extravasation is unclear. Estimated rates of extravasation of chemotherapy range from 0.01% to >5% per patient treated.4,5 Some data suggests that the incidence is decreasing, most likely due to increased awareness, and improved infusion guidelines and techniques.6,7 A number of factors may contribute to the risk of extravasation. These can be classified into mechanical factors relating to catheter insertion and placement, physiological factors relating to vascular problems, and the pharmacologic characteristics of the infused drug.8 Some of these factors are listed in Table 1. Patients receiving chemotherapy often have
one or more risk factors for extravasation. For example they tend to be older, meaning they are more likely to have fragile, thin and/or mobile veins.3 Chemotherapy extravasation can cause a wide range of symptoms, which vary according to the amount or concentration, and nature of the extravasated drug. Agents are separated into three broad categories on the basis of their mechanisms of cellular damage and potential to cause tissue injury: vesicants, irritants, and non-vesicants.6,8 Refer to Table 2. Note that some irritants may act like vesicants if a large volume or high concentration is extravasated. Non-vesicants rarely produce a reaction, but for other agents initial symptoms occur immediately after extravasation. There is usually acute pain (from mild to intense), and, within hours, this is usually followed by erythema and oedema surrounding the injection site. Initial symptoms are usually similar no matter the causative agent, however the progression beyond these initial symptoms differs greatly between irritants and vesicants.6,10,11 Irritants usually cause only a mild inflammatory reaction as described above.
Symptoms are usually of short duration and long-term effects are rare. Vesicants, on the other hand, have the potential to cause severe and lasting injury. Tissue destruction may be progressive and slow, taking weeks to manifest. This can progress to ulceration and even necrosis, which may damage underlying structures such as nerves, muscles and joints. Occasionally the damage may be so severe that function cannot be recovered in the affected area.6,8,10 Of the vesicants, anthracyclines have the greatest potential for injury. This is due to their mechanism of action. Drugs that bind nucleic acids in DNA (e.g. anthracyclines) cause cell death and lysis, which allows the drug to affect surrounding cells. This repetitive process can result in progressive and chronic tissue injury. Drugs which don’t bind to DNA can potentially be metabolised and cleared, limiting tissue injury. Because of the extent of injury which they can cause, and because they are in widespread use, anthracyclines are one of the most important chemotherapy agents to consider with regards to extravasation. Continued on page 4.
Table 2. Examples of common chemotherapeutic agents and classification.6
Table 1. Some key risk factors for extravasation.8,9 Mechanical
Pharmacological
Physiological
Vesicants
Irritants
Non-Vesicants
Small/fragile/ mobile veins
Vasoconstrictive potential
Impaired circulation
Anthracyclines (e.g. doxorubicin, epirubicin)
Etoposide, Bortezomib, Gemcitabine Platinum salts (carboplatin, cisplatin, oxaliplatin) Irinotecan, Fluorouracil Taxanes (e.g. docetaxel, paclitaxel)
Bleomycin
Poor cannulation site Untrained/inexperienced staff Bolus injection
High flow pressure
pH & osmolarity (further from physiologic levels increases the risk)
Decreased sensation (e.g. neuropathy)
Pre-existing conditions (e.g. diabetes)
Vinka alkaloids (e.g. vincristine, vinblastine) Mitomycin
Cytarabine Pemetrexed Monoclonal antibodies
Medicine Name Changes: The Practical Implications for Patient Safety and Clinical Practice Chris Giles, Pharmacy Practice Unit As covered in CIRCUIT last year, the Therapeutic Goods Administration (TGA) announced in April 2016 that it had updated over 200 active ingredient names used in Australia to align with those used internationally. Whilst some changes are minor, e.g. phonetic changes and/or changes to names of esters/salts of medicines (not the medicine name itself), others are much more significant changes to medicine names, resulting in substantial or complete name changes. ¬¬ Refer to Table 1 for some common examples ¬¬ Full details are on the TGA website: tga.gov.au/updating-medicineingredient-names TGA have allowed a 4 year transition period (ending April 2020), during which time the following changes are expected to occur: Different manufacturers of the same medicine are implementing the name change on packages, labels, product information (PI) and consumer medicines information (CMI) at different points in time. To date, very few products have been updated. Unfortunately, advance communication from manufacturers regarding name changes to affected products is inconsistent and there is no TGA mechanism available to monitor and advise health professionals when the manufacturers make the name changes on medicine packaging and PI/CMIs.2 So it is anticipated that a number of changes to the medicinal products themselves will not be known until those products reach health services and pharmacies. Updates to affected medicine names in pharmacy systems (dispensing and imprest), prescribing systems, electronic medicines management systems, and other clinical resources (e.g. AusDI, MIMS, Therapeutic Guidelines, PBS Online, etc.) will occur gradually as per software vendors’ own timeframes. For many such clinical information systems, it is not just a “simple matter” of updating to match the TGA list. Considerations of character limits in software database fields are important to ensure the safe on-screen displays and printed information (e.g. dispensing and storage labels, prescriptions), particularly for dual labelled medicines, e.g. “lidocaine
(lignocaine) with adrenaline (epinephrine)”. TGA acknowledge these challenges for the clinical software vendors and that the required name changes for medicines packaging and documents may not be able to be applied identically from the TGA list into such clinical applications.² However there is no standard list or business rules for how the name changes may be safely truncated to be accommodated in such clinical systems. During this transition period, manufacturers packaging, PI’s, CMI’s may therefore not match the drug names on dispensing labels, drug storage locations (dispensary and clinical areas) and/or prescriptions/medication orders. This poses a number of risks to patient safety. Confusion due to different medication names may result in: 1. Unnecessary delays or dose omissions: ¬¬ Handwritten medication order does not match the dispensing label and/or product packaging, leading to delays/ omissions in dosing. ¬¬ Pharmacy/nursing staff cannot locate medication as it is located in a different place on imprest or dispensary due to name change, e.g. thyroxine will be renamed as levothyroxine, eformoterol becomes formoterol. 2. Patients may be administered incorrect medication: ¬¬ Genuine product selection errors may not be detected prior to patient administration as an assumption is made that it is “just another TGA name change”. 3. Accidental overdose/duplicate dosing of the same drug with different names: ¬¬ Patients/carers confused about new medication names or mismatch in labelling and packaging information, and may consume medicines concurrently with old and new names. A number of mitigation strategies are recommended for implementation by health services during the transition period to minimise these risks: 1. Provide education and ongoing support for the clinical workforce regarding required changes in clinical practice (refer Table 2 on right for examples): ¬¬ Ensure ready access to the full list of medicine ingredient names that are changing in areas of clinical practice
(e.g. medication treatment rooms), and at the point of care (e.g. in folder with medication chart) ¬¬ Communicate information about the changes to all prescribers, including visiting medical officers, and table at Medical Advisory committees, and specialty medical practice committees/ craft groups. ¬¬ Include in medication related learning and development programs for nursing and pharmacy staff. 2. Include both the old and new name on shelf labels where medications are stored. Where a significant name change necessitates a change in the storage sequence, strategies should be to ensure that medicines can be easily located, e.g. implemented (e.g. “shelf talkers”, signs on/inside imprest cupboard doors. 3. Ensure universal application of new medicine names to embed throughout clinical practice: review all local policies, procedures, guidelines and resources, including documents provided to patients, containing medicine ingredient names that are changing and update them to include both the old and new name. 4. Ensure any applicable name changes are highlighted in medication counselling with patients and/or carers. Health services should conduct a local risk assessment of the impact of these name changes when deciding which are the most appropriate and effective risk mitigation strategies for their clinical environment and patient mix. Ongoing monitoring and evaluation of the effectiveness of these strategies by the appropriate clinical governance committee(s) should continue throughout the extended transition period. Any medication incidents/near misses arising from confusion due to these medicine name changes must be reported and investigated to determine if any further strategies are required to further improve patient safety. Over the next few years a sustained and consistent effort will not only be required by the health services in managing the risks outlined above, but also by health professionals in changing their practice to ensure the transition to the international medicine names is completed in the safest manner possible for patient care. References are available on request.
Table 1. Examples of medicines name changes likely to be encountered in clinical practice ¹ Significant name changes *shelf location will change
Minor spelling changes e.g. y → i, th → t, ph → f, ch → c, add → a, remove → o
Adrenaline and noradrenaline – permanently dual labelled
y→i
adrenaline
adrenaline (epinephrine)
noradrenaline
noradrenaline (norepinephrine)
amoxycillin
amoxicillin
cyclosporin
ciclosporin
th → t
Dual labelling (old and new name on the product label until 2023)
beclomethasone
beclometasone
benzhexol
trihexiphenidyl (benzhexol)*
flumethasone
flumetasone
dothiepin
dosulepin (dothiepin)
dimethicone 350
dimeticone 350
ethacrynic acid
etacrynic acid
eformoterol
formoterol (eformoterol)*
indomethacin
indometacin
frusemide
furosemide (frusemide)
ph → f
glycopyrrolate
glycopyrronium (glycopyrrolate)
cephalexin
cefalexin
cephalothin
cefalotin
cephazolin
cefazolin
hydroxyurea
hydroxycarbamide (hydroxyurea)
lignocaine
lidocaine (lignocaine)
clomiphene
clomifene
oxpentifylline
pentoxifylline (oxpentifylline)*
dexamphetamine
dexamfetamine
phenobarbitone
phenobarbital (phenobarbitone)
guaiphenesin
guaifenesin
procaine penicillin
procaine benzylpenicillin (procaine penicillin)
ch → c
trimeprazine
alimemazine (trimeprazine)*
cholestyramine
colestyramine
cholecalciferol
colecalciferol
Other significant changes
add → a
chlorpheniramine
chlorphenamine
benztropine
hexamine hippurate
methenamine hippurate*
remove → o
meglumine diatrizoate
amidotrizoate meglumine*
thyroxine sodium
levothyroxine sodium*
benzatropine
oestradiol
estradiol
oestrogens - conjugated
conjugated estrogens
oestriol
estriol
ethinyloestradiol
ethinylestradiol
Table 2. Impact on Clinical Practice: Clinical Workforce
Required Practice Change
Prescribers
• • • •
Handwrite prescriptions/medication orders using the new medicine names Select drugs by their new names in electronic prescribing systems Handwrite medicines using their new names: medication histories on admission Educating patients and/or carers
Pharmacy Staff
• • • •
Select drugs by their new names in electronic dispensing and drug distribution (imprest) systems Handwrite medicines using their new names: medication histories on admission Locate medicines in new storage locations (where applicable) Educating patients and/or carers
Nursing Staff
• • • •
Select drugs by their new names in electronic drug administration systems Locate medicines in new storage locations (where applicable) Handwrite medicines using their new names: medication histories on admission Educating patients and/or carers
Note: there are other practitioners in areas such as those in nuclear medicine and diagnostic imaging that are also affected by the name changes.
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What’s New Suvorexant Elizabeth Burgess, Epic Pharmacy Brisbane Private Hospital Suvorexant (Belsorma®) is indicated for the treatment of insomnia, characterised by difficulties with sleep onset and/ or sleep maintenance.1,2 It’s an orexin receptor antagonist and exerts its effects by blocking the binding of wake-promoting neuropeptides orexin A and orexin B, causing central nervous system (CNS) depression.3,4 Unlike other sleep inducing medications, suvorexant has no direct activity or binding affinity at acetylcholine, dopamine, gamma-aminobutyric (GABA), histamine, noradrenaline, opiate or serotonin receptors. Suvorexant is metabolised by CYP3A, therefore concomitant administration with
moderate or strong CYP3A inhibitors (e.g. clarithromycin, ciprofloxacin, “azole” antifungals, grapefruit juice) is not recommended, nor is combining it with alcohol or other CNS depressants, due to the risk of excessive sedation.4,5 Common adverse effects of suvorexant include: drowsiness, dizziness, upper respiratory tract infections, nausea, dry mouth and unusual dreams.4,5 The usual adult dose of suvorexant is 20mg for patients under 65 and 15mg for patients 65 and over.4 It may be taken with or without food, within 30 minutes of scheduled bedtime, ensuring at least 7 hours of sleep time remains. Suvorexant
should not be taken more than once per night due to its long half-life and increased risk of adverse effects at higher doses. There is no evidence available for its use in patients with either severe renal or hepatic impairment, pregnant or breastfeeding women, or children.6 Therapy should be reviewed following three months of regular use. Following cessation of recommended doses of suvorexant there is no evidence of physical dependence, rebound insomnia or effect on sleep onset or maintenance.4 References are available on request.
Treatment of Chemotherapy Extravasation Continued from page 1 The most important aspect of managing extravasation is prevention. Educating healthcare professionals on local protocols for preventing, identifying and managing extravasation is crucial. Medical staff should be aware of risk factors, signs and symptoms, and preventative measures and management. Education of patients is also an important preventative measure so that patients can immediately report any pain, discomfort or redness at the injection site, as these are the first signs to manifest. Appropriate infusion equipment is critical. One important consideration is the size of cannula used. The principle is to choose a needle that is least likely to dislodge while allowing blood to flow around it, which usually means using the smallest cannula in the largest vein. The choice of vein is equally important, and some general rules include avoiding small or fragile veins, limbs with lymphoedema or impaired circulation, or areas where functional damage could result e.g. hands or near joints. Other precautions to consider include ensuring
drugs are diluted to correct concentrations and infused at correct rates, flushing lines with normal saline before infusion and careful monitoring of the infusion site.9,11 If extravasation occurs, the acronym SLAP (Stop, Leave, Aspirate, Plan) should be followed. The infusion should be stopped immediately. The access device should be left in place, and as much drug aspirated as possible. Planning involves multiple steps as follows. The site should be marked and photographed (to determine if the affected area grows) and the event documented. The limb should be elevated to help reabsorption of the agent. Further treatment depends on the agent extravasated. If the drug is non-vesicant, a cold compress may suffice. Otherwise there are two strategies; localisation and neutralisation, or dispersion and dilution. The former is used for anthracyclines. A cool compress will cause vasoconstriction and restrict spread of the drug, and
the antidote dimethylsulfoxide (DMSO) should be applied topically. DMSO has free-radical scavenging properties and improves absorption of extravasate. For vinca alkaloids, warm compresses will cause vasodilation and increased blood flow which helps to dilute and disperse the extravasate. The antidote used is subcutaneously injected hyaluronidase (an enzyme that breaks down bonds in soft tissue) which helps the extravasate disperse, reducing its local concentration. If tissue damage persists despite these measures, surgery and skin grafting may be indicated to excise necrotic tissue.9,11 While chemotherapeutic extravasation is rare, the consequences can be severe and long-lasting. It is crucial that healthcare professionals are aware of the risks, and trained in the protocols for prevention and management. References are available on request.
If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: PharmacyPractice@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.
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