Epic Pharmacy Circuit Newsletter September 2018

September 2018

clinical initiatives, research and current updates in treatment

Management of Neuropathic Pain Justine Forbes, Epic Pharmacy Hollywood

Neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” 1 Examples include: post-herpetic neuralgia, phantom limb pain, and diabetic neuropathy. This specific definition helps differentiate from cases of pain with either no known nervous system damage (e.g. fibromyalgia), or caused by musculoskeletal conditions. It also excludes nociceptive pain, such as inflammation and post-surgical pain.1,2 Diagnosis of neuropathic pain involves taking a detailed patient history and a clinical examination. History taking includes asking about pain descriptors (i.e. ‘shooting’, ‘trickling’, ‘ants crawling’), the distribution of pain, the severity, and impact on daily life.2 Examination includes sensory testing with tools (i.e. toothpick or cotton ball) to assess sensory loss or gain. If both the history and examination point to neuropathic pain, a diagnostic test such as an MRI, can be performed to help diagnosis.1,3 Early diagnosis is key for effective management, as neuropathic pain is associated with high levels of disability and psychological comorbidity.1 Treatment should begin with the underlying cause of pain. Tight glycemic control should be achieved where possible in diabetic neuropathy and antiviral therapy initiated within 72 hours of rash onset for postherpetic neuralgia and shingles.1 Other nonneuropathic pain should be managed, even with simple analgesia (e.g. paracetamol or nonsteroidal anti-inflammatories) to reduce pain burden.4 Neuropathic pain itself is usually refractory to simple analgesics, but they should always be trialed.2

Amitriptyline, a tricyclic antidepressant (TCA), helps to reduce pain by inhibiting noradrenaline and serotonin reuptake.

It also contributes anticholinergic and gamma-aminobutyric acid (GABA) activity. Amitriptyline’s analgesic effect is independent of its mood-altering (antidepressant) effect and lower doses are used to treat neuropathic pain compared to depression.1 Whilst it has been used for over 20 years to treat neuropathic pain, its adverse effects (weight gain, urinary retention) may deter some patients, and its use may not be appropriate in the elderly.

Other common adverse effects such as dry mouth and blurred vision generally wane over time. Encourage the patient to persist if adverse effects are minor. If amitriptyline is unsuitable, other TCAs may be trialed (e.g. nortriptyline or doxepin). 1,4,2 Pregabalin and gabapentin are antiepileptic medications that work on neuropathic pain by decreasing neuronal excitability in the spine and brain via the release of GABA.2 They have both shown efficacy in the treatment of neuropathic pain, with gabapentin appearing to have the safest adverse effect profile of the four first line agents. 1,5 In addition to treating neuropathic

pain, pregabalin is useful for improving sleep quality. Failure to respond to either gabapentin or pregabalin does not suggest the other drug will also fail, as the tolerability and efficacy of the two drugs can vary in individual patients.1 Duloxetine, a selective serotonin noradrenaline reuptake inhibitor (SNRI), inhibits pain transmission by inhibiting noradrenaline and serotonin reuptake.2 Adverse effects include: increased blood pressure, tremor and sexual dysfunction. These adverse effects may be unacceptable to the patient and cause discontinuation. It is for these reasons that amitriptyline is preferred to duloxetine for neuropathic pain.1,3 A significant number of patients with neuropathic pain will achieve only a partial response to one first-line agent, even at the maximum effective dose. Approximately 45% of neuropathic pain patients take at least two medications as treatment.1 Guidelines recommend tramadol, strong opioids like oxycodone, or lidocaine 5% patches as second line agents. Whilst opioids may be of some use in neuropathic pain, high doses are usually required, increasing the risk of adverse effects, tolerance and addiction.2 Third line options with limited evidence include capsaicin cream and botulinum toxin A.1,5,6,7 Non-pharmacological approaches should be an important part of treatment.

Patients often wish to be involved in the management of their neuropathic pain,

CAR T Cell Therapy – An innovative approach to treat cancer Linda Nguyen, Icon River City Pharmacy

CAR T cell therapy, an adoptive cell immunotherapy, is a personalised therapeutic approach whereby the patient’s T cells are removed from the patient’s blood, genetically modified, multiplied and reinfused back into the patient.1 CARs (also known as chimeric antigen receptors) are synthetic immunoreceptors that are attached to the T cells thus allowing it to more readily detect and destroy cancer cells within the body.2 Different cancer types have different antigens targets, thus CAR T cells are designed for a specific antigen in accordance with the cancer.

In 2017, the FDA approved 2 antiCD19 CAR T cell therapies.3 Kymriah® (tisagenlecleucel) is approved for the treatment of relapsed or refractory acute lymphoblastic leukaemia (ALL) (in patients <25 years old) and relapsed/refractory large B cell lymphoma in adults.4 Yescarta® (axicabtagene ciloleucel) is approved for relapsed/refractory large B cell lymphoma in adults.5 Clinical trials have demonstrated durable complete remission in these patients.6 83% of paediatric patients with relapsed/ refractory B-cell ALL achieved complete remission or complete remission with incomplete recovery of blood count within 3 months after Kymriah® infusion.4 In adult patients with relapsed/refractory large B cell lymphoma, 50% of patients responded to Kymriah® with 32% achieving complete remission.4 Likewise, 72% of patients responded to Yescarta® with 51% achieving complete remission.5

The CAR-T cell therapy process CAR T cell therapy involves various steps (Figure 1). Firstly, peripheral blood mononuclear cells, such as lymphocytes and monocytes, are collected from the patient’s blood by leukapheresis.7,8 The T cells are isolated and sent to the laboratory where they are activated by antibodies specific for CD3 and/or CD28 which induce T cell activation and proliferation. Using viral vectors, the CAR gene is introduced into T cells causing these cells to express the CARs on the cell surface.7,8 These cells are subsequently multiplied to achieve the required CAR T cell dose. The final product is cryopreserved and shipped to the clinical site. This process may take 1 to 2 weeks to complete.7

Approximately 1-2 weeks prior to CAR T cell administration, the patient may receive conditioning chemotherapy such as fludarabine and cyclophosphamide to reduce the number of lymphocytes within the body.2,4,7,8 This assists in improving CAR T cell uptake, proliferation and anti-tumour response.8 On the day of administration, the CAR T cells are thawed, premedications (such as antihistamines and paracetamol) are administered followed by intravenous infusion of the CAR T cells.4,5 Administration is usually a single dose or infusion, provided in the inpatient setting to allow for monitoring of adverse effects.8

Adverse effects and management The most common adverse effects with CD19 specific CAR T cell therapy include cytokine release syndrome, neurotoxicity and on-target-off-tumour toxicity.

Cytokine release syndrome (CRS) consists of influenza-like symptoms (fever, chills, myalgia), hypoxia and hypotension.1,6 Symptoms usually occur during the first two weeks after CAR T cell infusion.6 Patients with high tumour burden tend to experience more severe CRS.9 Severe CRS may be treated with tocilizumab (anti-interleukin-6 [IL-6]) as well as vasopressor and ventilator support if patient is haemodynamically unstable.6 Systemic corticosteroids may be used to rapidly reverse symptoms however prolonged use >14 days can ablate the CAR T cell population.4 Neurotoxicity includes encephalopathy, delirium, aphasia, seizures, cerebral oedema, confusion and tremor.1,6 Encephalopathy can occur in 40% of patients treated with CAR T cell therapy.6 The majority of cases are of mild to moderate severity. The mechanism is unknown, hence treatment is based on management of CRS (tocilizumab ± corticosteroids IV) and supportive care.6,7 Seizure prophylaxis (e.g. levetiracetam) may be used.5

On-target off-tumour toxicity (such as B cell aplasia and hypogammaglobulinaemia) occurs due to CAR T antigen expression in normal cells.7 Management includes infusion of gammaglobulin and antibiotics to prevent infectious complications.5 Prolonged B-cell aplasia due to the persisting effects of CAR T therapy can increase morbidity and mortality.7

Accessibility and cost Accessibility to CAR T cell therapy is influenced by cost and the availability of suitable manufacturing facilities for genetic engineering. An infusion can cost at least USD $373,000-$475,000.3 Potential hospitalisation costs due to treatment of adverse effects must also be considered.

In Australia, CAR T cell therapy is currently limited to clinical trial use at certain cancer centres.

Future development CAR T cell therapy is currently being investigated in other cancers including solid tumours. However, further research is required to identify suitable tumour antigen targets, especially due to the different biology of solid tumours compared to haematological malignancies.7 Other research areas include CAR T cells with additional functionality, novel CAR T dosing strategies, switch CAR T cells and combination therapy with checkpoint inhibitors or other targeted agents (e.g. ibrutinib).8

Summary CAR T cell therapy offers a unique therapeutic approach with remarkable results in relapsed/refractory paediatric B-cell ALL and adult large B cell lymphoma.

Further research and development will assist in understanding its use in other cancers, optimal target selection and minimisation of adverse effects.

References are available on request.

Figure 1: CAR-T cell therapy process10

Safe use of transdermal opioid patches Application of a transdermal patch is a noninvasive and effective method of administering medication across the layers of the skin and subcutaneous fatty tissue before redistribution into the blood stream to achieve a systemic effect.1 Drug movement occurs through diffusion across a concentration gradient, moving from the higher concentration in the patch to the lower concentration in the skin.

This process enables a constant concentration of the drug to be maintained in circulation.2 Advantages of using a patch to administer medication include: improved bioavailability (through avoidance of first pass metabolism), more uniform plasma drug concentrations and improved patient compliance.1 Clear labelling of the applied patch also enables rapid drug identification.

Accidental exposure is a risk associated with opioid patches and can happen at either home or at a health care facility. Unsafe patch application and disposal methods may result in the patch being left on clothes, in bed linen or dropped on the floor, inadvertently exposing non users.6 There have been several cases of opioid patches either being ingested or accidentally adhering to non-users. Chewing an opioid patch is particularly dangerous, as absorption through the buccal mucosa is up to 30 times higher than transdermal absorption.5 Early signs of opioid exposure are non-specific and difficult to identify, particularly in young children. Lethargy, which can easily be confused with fatigue, is one of the early signs.2 If an opioid patch adheres to a non-user, it should be removed immediately and medical assistance sought.

Buprenorphine and fentanyl are opioid analgesics available in transdermal patches.

Transdermal opioids have a slow onset and extended duration of action and are useful in the management of chronic pain. They are not recommended in the management of acute pain, inappropriate use of transdermal opioid patches for acute pain has been associated with a significant risk of respiratory depression which can be fatal.3 Buprenorphine patches are replaced every 7 days and fentanyl patches every 3 days. Buprenorphine, a partial opioid agonist, is the weaker of the two. A 20mcg/hour buprenorphine patch is approximately equivalent to 36mg of oral morphine daily.4 Fentanyl is a high potency opioid with a narrow therapeutic index.2 The lowest available transdermal strength of 12mcg/hour, is approximately equivalent to 45mg of oral morphine daily.4 Fentanyl patches are contraindicated in opioid naĂŻve patients, who are at risk of potentially lifethreatening respiratory depression.3 Due to the concentration gradient required for effective drug diffusion, fentanyl patches retain high residual levels of fentanyl (at least 30-50% of the original dose) after being removed.5

In Australia, the Therapeutic Goods Administration (TGA) have reported two occasions where children have been hospitalised following inadvertent exposure to a fentanyl patch.6 Both children suffered somnolence and loss of consciousness and were hospitalised as a result.6 In 2012 the United States Food and Drug Administration evaluated 26 cases of accidental exposure to fentanyl patches in children occurring over a 15 year period.6 The majority of the cases (16 out of 26) involved children aged 2 and under. In the 26 cases, there were 10 deaths and 12 hospitalisations.6 In one case, due to the unsafe disposal of a fentanyl patch at a nursing home, a 2 year old boy died after accidently ingesting the fentanyl patch.7

Anne Lewis & Jodie Wilson, Epic Pharmacy Greenslopes

Correct patch application and disposal reduces the risk of accidental exposure. The patch should be applied to clean, dry, intact and preferably hair free skin. It should then be pressed to the skin for 30 seconds ensuring the edges are adhering properly.8 Daily site checks are recommended to ensure the patch remains securely in place.8 Unsecure patches pose a risk to both users and non-users. There have been recorded cases of fentanyl patches transferring from the designated user to a non-user in instances of close contact i.e. sharing a bed.6 A partially detached patch can also easily transfer from an adult to an infant they are holding.2 Exposing the applied patch to heat can result in a temperature dependant increase in opioid transfer from the patch to the skin resulting in increased systemic absorption of the drug.8 All patch users should avoid exposing applied opioid patches to external heat sources such as electric blankets, heat packs, hot water bottles and even prolonged hot baths or saunas, as well as extremes of environmental heat e.g. during a heat wave.8 To ensure safe patch removal and disposal, once removed the patch should be folded together to ensure the medication is trapped within the adhesive surface. In a health care facility the folded patch should be disposed of in a sharps medical-waste disposal container.9 In a home setting the folded patch should be wrapped in paper or plastic and carefully disposed of in the rubbish bin, out of reach of children.2,5 References are available on request.

Correct disposal of opioid transdermal patches9 1.

Remove old patch. If removed by a non-user, wearing gloves can help avoid contact with the medication.

2.

Fold patch in half to ensure the adhesive sticks to itself and the medication remains trapped within the adhesive.

3.

Wrap in paper or plastic

4.

Dispose of used patch in the rubbish bin if at home (out of reach of children) OR Dispose of used patch in the sharps medical-waste disposal container in healthcare facilities

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What’s New Brexpiprazole (Rexulti®) tablets 1mg, 2mg, 3mg, 4mg Nandni Bhan, Epic Pharmacy Sandgate Brexpiprazole is an oral atypical antipsychotic used in the treatment of schizophrenia.1 It works by modulating dopamine, noradrenaline and serotonin in the brain. Brexpiprazole has greater receptor selectivity compared to other similar antipsychotics e.g. aripiprazole, resulting in improved efficacy and a reduced adverse effect profile.2,3

The recommended starting dose for brexpiprazole is 1mg daily. The dose is then titrated according to clinical response and tolerability, to the recommended daily dose of 2 to 4mg daily. In patients with moderate to severe hepatic or renal impairment, the recommended daily dose is 3mg daily.2,4 Brexpiprazole can be taken with or without food.

Common adverse effects include: sedation, extrapyramidal effects such as akathisia or tremor, weight gain and metabolic syndrome.2,3 Establishing baseline weight, body mass index, waist measurement, lipid levels, blood pressure and blood glucose levels are recommended and may assist in assessing the effects of metabolic syndrome.2 Routine full blood counts and liver function are also advised. Brexpiprazole is not approved for use in the elderly for the treatment of psychosis associated with dementia due to an increased mortality risk. 1,2

Brexpiprazole is predominately metabolised by cytochrome P450 (CYP) 3A4 and CYP2D6.

The serum concentration of brexpiprazole is increased by strong CYP3A4 inhibitors e.g. clarithromycin, and decreased by inducers e.g. carbamazepine, therefore, dose adjustment of brexpiprazole may be required with concomitant administration.2,4 References are available on request.

Management of Neuropathic Pain Continued from page 1 pain and should be counselled appropriately on realistic treatment expectations on diagnosis. While a ‘cure’ from neuropathic pain is unlikely, partial relief is usually considered a good result. If management encompasses a biopsychosocial approach, the patient is more likely to experience

positive results.6,8 Use of psychologists and physiotherapists have been shown to benefit patients, improving physical function and reducing stress. In rare scenarios (e.g. nerve entrapment) surgical intervention may be of some benefit.1

A holistic approach to neuropathic pain management is ideal, and patient education plays a significant role in this. All health care professionals can help improve patient outcomes in the management of neuropathic pain.

Common doses and adverse effects of the four first line agents3 Amitriptyline

Pregabalin

Gabapentin

Duloxetine

Starting dose

10-25mg nocte

25-75mg nocte

100-300mg nocte

30mg daily

Up-titration

By 10-25mg every 7 days

Increase to twice daily after 2 or 3 days, then increase strength slowly

Increase frequency and strength every 4 days

By 30mg every 7 days

Effective maintenance dose

10-100mg nocte

150-300mg twice a day

400mg-800mg up to three times a day

60mg once to twice daily

Adverse effects

Sedation, dry mouth, constipation, blurred vision, weight gain, urinary retention

Dizziness, diplopia, confusion, peripheral oedema, weight gain, dry mouth

Sedation, dizziness, peripheral oedema, weight gain

Nausea, dry mouth, constipation, sweating, dizziness, sexual dysfunction, tremor

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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