Epic Pharmacy Circuit October 2016

October 2016

clinical initiatives, research and current updates in treatment

Medicine name changes Sanja Mirkov, Pharmacy Practice Unit

The names of some medicines are changing to align with those used internationally. In line with this, medication labelling and packaging will change over the next four years.

During the changeover period, hospitals must review and update existing protocols, guidelines and consumer information. Medical, nursing and pharmacy software, as well as shelf / stock labels will also need to be updated. Medication charts should be annotated with old and new names and patients advised on medication name changes accordingly.

Type of changes to the medication names The official names for adrenaline and noradrenaline will remain the same and international names will be added in brackets. Some medicines will require dual labelling during the transition period, others will have minor spelling changes. Less significant changes include changes to suffixes: different salt names, added hydrates or swapping the word order so the drug name is before the salt.

The following table provides further examples of some medication name changes:

Name Change

Old

New

Official name not changing Overseas name in brackets

adrenaline

adrenaline (epinephrine)

noradrenaline

noradrenaline (norepinephrine)

Dual labelling To be displayed until 2023

colaspase

asparaginase (colaspase)

cysteamine

mercaptamine* (cysteamine)

dothiepin hydrochloride

dosulepin (dothiepin) hydrochloride

eformoterol

formoterol (eformoterol)

frusemide

furosemide (frusemide)

hydroxyurea

hydroxycarbamide (hydroxyurea)

lignocaine

lidocaine (lignocaine)

procaine penicillin

procaine benzylpenicillin (procaine penicillin)

hexamine hippurate

methenamine hippurate

maldison

malathion

amoxycillin

amoxicillin

Cephalosporins e.g.cephalexin

Cefalosporins e.g. cefalexin

cephalothin

cefalotin

cholecalciferol

colecalciferol

indomethacin

indometacin

oestradiol

estradiol

Other significant changes Minor spelling changes y–i ph – f th – t h – omitted oe – e

Not intended to be a comprehensive listing *NB mercaptamine (cysteamine) is NOT the same as the cytotoxic agent mercaptopurine. DO NOT confuse these two sound-alike drugs.

For a complete list of medicines affected, please visit the TGA website: https://www.tga.gov.au/updating-medicine-ingredient-names-list-affected-ingredients

Abstral® – Sublingual Fentanyl Tablet Bianca Vincent, Epic Pharmacy Murdoch

Abstral® is a fast-acting, sublingual tablet formulation of an opioid painkiller, fentanyl.1 It is indicated for the management of breakthrough cancer pain in adults who are already receiving maintenance opioid therapy for their chronic cancer pain.1 Abstral® is listed on the PBS as an authority required item for use in palliative care patients.3 Abstral® is available in six strengths; 100, 200, 300, 400, 600 and 800 microgram tablets.1 It has a rapid onset of action, as early as 10 minutes, and has been shown to maintain analgesia for 60 minutes.4 Due to considerable pharmacokinetic differences between Abstral® and other fentanyl products, patients should not be switched on a microgram per microgram (1:1) basis from other fentanyl products. Initial dose and dose adjustments are outlined in Figures 1 and 2.

The tablet should be placed under the tongue and should not be swallowed,

chewed or sucked.4 No food or drink should be consumed until the tablet has dissolved.4 Patients who have a dry mouth may take a sip of water beforehand to moisten their buccal mucosa.1 Nausea, constipation, headache and drowsiness are the most common side effects.1 Fatal respiratory depression has been reported following improper dosing and use in opioid non-tolerant patients.1 Like with other fentanyl formulations, Abstral® interacts with CYP3A4 inhibitors/ inducers, MAOI inhibitors, serotonergic drugs and CNS depressant drugs.1

Figure 1: Abstral® Practice Points1,4 Indication: Breakthrough pain in adult opioid-tolerant cancer patients Contradictions: Opioid-naïve patients, age <18 years, treatment of non-cancer pain, severe respiratory depression, severe obstructive lung conditions Dose: Start all patients on 100 micrograms; careful titration and monitoring is required. Maximum of two doses for a single episode of breakthrough pain. Allow at least two hours between treating breakthrough pain episodes. Maximum of four doses per day.

With approximately 65% of cancer patients experiencing breakthrough pain episodes, Abstral® is a valuable addition to the already available breakthrough cancer pain medications, however further studies are required to determine its comparative effectiveness.5

Warnings: Respiratory depression, Abstral® can be fatal to a child - keep out of reach of children

References available on request.

Figure 2: Dose Titration1 Is the patient opioid-tolerant? (taking at least 60mg of oral morphine daily or an equianalgesic dose of another opioid for a week or longer)6

No

Abstral® is contraindicated

Yes

Abstral® starting dose: 100 micrograms Assess pain relief at 30 minutes Adequate pain relief achieved?

Yes

Dose is effective for this patient Use this dose for subsequent breakthrough pain episodes Allow at least two hours between treating breakthrough episodes Maximum of four breakthrough episodes of Abstral® treatment per day

No

Administer a second tablet of Abstral® 30 minutes after the first dose if required First tablet strength (micrograms)

100

200

300

400

600

800

Second tablet strength (micrograms)

100

100

100

200

200

Not recommended

Note: Maximum of two doses for a single episode of breakthrough pain.

Rescue medication can be used if adequate analgesia is not achieved.

Increase the dose of the first tablet to the next higher strength tablet for the next breakthrough pain episode Allow at least two hours between treating breakthrough episodes Maximum of four breakthrough episodes of Abstral® treatment per day

What’s new EGFR Inhibitors in Lung and Colorectal Cancer Jihui Kang, Icon River City Pharmacy

Monoclonal antibodies act on extracellular binding site of EGFR and are administered intravenously. First generation mAbs, cetuximab and panitumumab, have shown benefit in KRAS wild type colorectal cancer.5,6 Recently, a second generation mAb, necitumumab, has been approved by the FDA for first-line therapy for metastatic squamous non-small cell lung cancer, in combination with gemcitabine and cisplatin.7 TKIs act on the intracellular binding site of EGFR and are administered orally. First generation TKIs, gefitinib and erlotinib, have been shown to be effective in advanced non-small cell lung cancer.8,9 Second and third generation agents, such as afatinib, osimertinib, rociletinib, have been developed for more potent inhibition of EGFR.10,11

In NSCLC, EGFR overexpression is associated with 50–80% of cancers and KRAS mutation ranges from 8–24%.1,15 TKIs, such as gefitinib, erlotinib and afatinib, have demonstrated efficacy in NSCLC when compared to chemotherapy. Gefitinib was found to be as effective as carboplatin/paclitaxel in EGFR mutation-positive Asian patients, with an improved patient quality of life (QOL).1,8,16 Additionally, gefitinib demonstrated non-inferior OS and PFS when compared to docetaxel in patients treated with previous platinum based chemotherapy.8 Erlotinib, as a first-line treatment, demonstrated comparable median OS with improved QOL and median PFS compared to chemotherapy arm.1,9 Afatanib, a second generation TKI, has shown a superior median OS and PFS when compared to pemetrexed /cisplatin in LUX-Lung 3 trial as a first-line therapy in patients with EGFR mutation-positive locally advanced or metastatic NSCLC.10 In Australia, both gefitinib and erlotinib are available on the PBS as monotherapy for initial and continuing treatment of locally advanced or

EREG

Activation

EGFR

EGFR P

EGFR

P

P

RAS

PI3K AKT

Proliferation

intracellular

PT

ERK

EN

RAF

Cell cycle activation and survival

Nucleus

Abbreviations: EGF- epidermal growth factor, AREGamphiregulin, EREG- epiregulin, EGFR- epidermal growth factor receptor, P- phosphor, RAS – rat sarcoma, ERKextracellular signal regulated kinase, PI3K – phosphatidyl inositol 3-kinase, PTEN- phosphatase and tensin homologue deleted on chromosome 10, AKT- protein kinase B, RAFrapidly accelerated fibrosarcoma

Figure 2. Mode of Action of EGFR Inhibitors3 EREG

EGF

Activation

AREG

Inhibition

EGFR

EGFR P

TKI P RAS

PI3K

Ab

Currently, there are two categories of EGFR inhibitors used in the treatment of cancer; monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs).

Figure 2 illustrates the mode of action of EGFR inhibitors.3

Non-Small Cell Lung Cancer (NSCLC)

EGF

Mo

KRAS is a type of RAS protein which relays signals from outside the cell to the cell’s nucleus via one of the EGFR signalling pathways.4 KRAS acts as molecular on/off switch in the pathway, however, when there is a mutation in the gene, there is a permanent activation leading to overexpression of downstream signalling, independent of EGFR activation or inhibition. As such, EGFR inhibitors may not be effective in KRAS mutation.3,4,12,15 A patient without KRAS mutation is referred to as being KRAS wild-type.

Cetuximab and panitumumab, both in combination with chemotherapy such as FOLFOX and FOLFIRI and as single agents, have been shown to be efficacious in the management of metastatic KRAS wild-type colorectal cancer in first-line, second-line and maintenance treatments. Studies have demonstrated that the addition of such drugs to chemotherapy significantly increased progression free survival (PFS) and improved median overall survival (OS).5–6 In Australia, both cetuximab and panitumumab are subsidised under the Pharmaceutical Benefits Scheme (PBS) for KRAS wild-type metastatic colorectal cancer both in the first-line setting and after failure of first-line therapy.5,6,12,13

AREG

EGFR

RAF EN

EGFR overexpression is detected in 65–75% of patients with colorectal cancer and is more predominant in advanced and metastatic cancer.3 Furthermore, a number of studies have found EGFR overexpression to be correlated with poor prognosis.5 KRAS mutation is present in approximately 30 to 50% of colorectal cancers.12

Ab

The epidermal growth factor receptor (EGFR) belongs to the tyrosine kinase receptor family, and is a cell-surface transmembrane protein.1–3 Ligand binding to the EGFR activates the downstream signalling pathways as demonstrated in Figure 1.3 In normal cells, this signalling promotes cell cycle activation, cell proliferation, cell survival and angiogenesis.1–3 However, EGFR gene mutation, overexpression of EGFR and/or overproduction of ligand can lead to over-activation of the signalling pathways, promoting the development of cancer.3 As such, EGFR activation is an attractive target in cancer therapy.2,3

Figure 1. EGFR Signalling Pathway3

ERK

AKT

P

PT

Colorectal Cancer

m

EGFR and KRAS in Cancer

intracellular Abbreviations: EGF- epidermal growth factor, AREGamphiregulin, EREG- epiregulin, EGFR- epidermal growth factor receptor, P- phosphor, mAb- monoclonal antiboidies, TKI –tyrosine kinase inhibitors, RAS – rat sarcoma, ERKextracellular signal regulated kinase, PI3K – phosphatidyl inositol 3-kinase, PTEN- phosphatase and tensin homologue deleted on chromosome 10, AKT- protein kinase B, RAFrapidly accelerated fibrosarcoma

metastatic NSCLC, in patients with an activating EGFR mutation.8,9,17,18 Afatinib is not yet available on the PBS.

Adverse Effects of EGFR Inhibitors EGFR is expressed in the epidermis, sweat glands and hair follicles of the skin hence cutaneous side effects are most common. These include rash, dry skin, mucous membrane alteration, ocular toxicities, hair changes, hair loss, nail changes and hand and foot reactions.2 Continued on page 4

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What’s New

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Palexia® IR: tapentadol 50mg immediate release, film-coated tablets Emma Rostas, Shannon Arenson, Epic Pharmacy Toowoomba Immediate-release (IR) tapentadol has recently become available in Australia, approved for use in moderate to severe chronic and acute pain that is unresponsive to non-opioid analgesics; an extension on the similar chronic pain indication for the extended-release formulation (Palexia® SR).1 Unlike Palexia®SR, the immediate release formulation is not subsidised by the Pharmaceutical Benefits Scheme(PBS).2

The most common adverse effects are typical of opioids: nausea, vomiting, dizziness, constipation, sedation and pruritis.4 Gastrointestinal side effects (nausea, vomiting, constipation) appear less common with tapentadol compared to oxycodone and tramadol.1,7,10 However tapentadol IR is potentially more sedating than oxycodone IR 7 and may have a slightly higher propensity than tramadol for causing dizziness.10

Tapentadol is a centrally-acting synthetic analgesic with combined mu opioid receptor activity and noradrenaline reuptake inhibition.1 Tapentadol is considered a potential alternative to oxycodone and the structurally related tramadol.3

Table 1: Comparison of IR Tapentadol, Tramadol and Oxycodone1,4,5

Tapentadol IR was studied in clinical trials mainly involving patients with post-operative pain, but also in patients suffering from acute lower back pain, and osteoarthritis-related pain prior to joint replacement surgery.1,7,9

EGFR Inhibitors in Lung and Colorectal Cancer Continued from page 3 Acneiform rash occurs in up to 85% of patients due to direct EGFR inhibition, and not as an allergic reaction to EGFR therapy.21 The majority of patients experience mild to moderate rash, which is more common with mAb treatment than oral TKIs.2,21 The rash usually appears about 1 week post EGFR inhibitor treatment and is generally located on the face and upper torso with up to 20% of patients requiring dose modification due to severe symptoms.

Pharmacological measures include topical and oral antibiotics, such as doxycycline, oral and topical steroids, as well as topical immunomodulatory agents. Patients are also recommended to avoid prolonged hot showers, and are encouraged to use moisturisers and sunscreens that are free of alcohol, fragrances and dyes.2

Tapentadol IR

As with other opioids, tapentadol has the potential for confusion with a similar named analgesic (in this case, tramadol) as well as confusion between the IR and SR formulations (both available as 50mg tablets), and should therefore be prescribed by both generic and brand name, and the formulation clearly specified.

References available on request.

Tramadol IR

Oxycodone IR

Approximate dose 75–100mg oral equivalence to morphine 10mg IM/SC

150mg oral

15–20mg oral

Onset of Action

20–40 minutes

60 minutes

30–60 minutes

Duration/Usual Dosing Interval

Every 4 to 6 hours

Analgesic Mechanism

Moderate-strong opioid, Noradrenaline reuptake inhibitor

Weak opioid, Serotonin & Noradrenaline reuptake inhibitor

Strong opioid

Possible Drug Interactions

Serotonergic medications

Serotonergic medications Cytochrome P450 (CYP2D6 & CYP3A4)

Serotonergic medications

EGFR inhibitors can also cause noncutaneous side effects. Diarrhoea, more common with oral TKIs, is a common side effect and is usually controllable with loperamide. Patients are also advised to avoid certain foods including greasy and/or spicy foods and dairy products and to keep up with adequate fluid intake. Other side effects include interstitial lung disease, electrolyte imbalances, such as hypomagnesaemia, hypophosphatemia, hypocalcaemia and hypokalaemia, and hepatotoxicity (particularly with TKIs).2,19 Furthermore, infusion reactions can occur with administration of mAbs.5,6,20 Incidence is higher with cetuximab than panitumumab, as cetuximab is a chimeric mAb, whereas panitumumab is a fully human mAb. Reactions may be managed by using prophylactic premedications such as antipyretics,

antihistamines and steroids prior to infusion. An infusion can be stopped with appropriate symptom management and it can also be re-challenged in most cases with re-administration of premedications followed by a slower infusion.20 In conclusion, several studies have confirmed that EGFR inhibitors have an important role in the treatment of cancers such as colorectal and lung cancers. Importantly, the effective management of EGFR inhibitor-induced adverse effects is paramount in order to avoid dose modifications or cessation of the EGFR inhibitors. Newer generation therapies with more potent inhibition are forthcoming and it will certainly be interesting to discover the clinical efficacy and practical implications of these newer agents.

References available on request.

If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.

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