The introduction of biosimilar medicines encourages competition in our Australian market. This will lead to a reduction in the cost of medicines, resulting in savings to the health care system. These lower prices improve affordability of, and access to new treatments for seriously ill patients. Biosimilar medicines are tested in Australia. They are checked for safety and to confirm they provide the same health outcomes as the reference biological medicine.

As part of the 2017 budget process, the Government agreed to continue its investment in educating prescribers, pharmacists and consumers on the benefits of using biosimilar medicines through supporting the GBMA (Generic and Biosimilar Medicines Association) with a grant to undertake activities to further promote the appropriate prescribing, dispensing and use of biosimilar medicines.

Biosimilars are biological agents that are a highly similar version of the active substance of their originator or reference product (biologic). However, they cannot be proven to be 100% identical due to the inherent variability in all biologic medicines.

Other Forms of Biologics:

• Biobetter – an improved version of originator; and
• Non-comparable biologics – not similar to the original medicinal product.

Biological medicines, including biosimilar medicines, are used to treat serious diseases such as:

• Rheumatoid arthritis;
• Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease;
• Cancer;
• Diabetes;
• Multiple sclerosis;
• Kidney disease; and
• Severe psoriasis.

Biosimilars Approved in Australia:

Some of the biosimilar medicines approved by the Therapeutic Goods Administration are shown in Table 1.

Table 1. Biosimilar medications registered in Australia

Active ingredient	Reference brand (Sponsor)	Biosimilar brand (Sponsor)	Date Biosimilar listed on the ARTG*
Filgrastim	Neupogen® (Amgen)	Nivestim®  (Pfizer)	16/09/2010
		Tevagrastim® (Teva Pharma Australia)	29/08/2011
		Zarzio®(Sandoz)	07/05/2013
Pegfilgrastim	Neulasta® (Amgen) Also registered under the brand name Tezmota®, Ristempa®	Fulphila® (Alphapharm)	17/08/2018
Rituximab	MabThera® (Roche) Also registered under the brand name Ristova®	Riximyo® (Sandoz) Also registered under the brand names Rixonfya® , Rixvyda®	30/11/2017
		Truxima® (Celltrion), Also registered under the brand name Ritemvia®, Rituzena®, Tuxella®	16/04/2018
Trastuzumab	Herceptin® (Roche) Also registered under the brand name Herclon®	Simabtra® (Celltrion) Also registered under the brand names Herzuma® , Hertuzu®	17/07/2018
		Ogivri® (Alphapharm)	11/12/2018
		Ontruzant® (Samsung Bioepis)	9/01/2019

*Australian Register of Therapeutic Goods (ARTG); Data correct at 1 March 2019 per Therapeutic Goods Administration publication of the ARTG.

Substitution:

The difference between biosimilar and generics is extremely important to understand. Generic, or small molecule drugs, are identical copies of their reference products and produced via chemical synthesis. As biological medicines are derived from living cells or organisms, no two batches are ever exactly the same. However, for an agent to be approved as a biosimilar, it must have been assessed to be therapeutically equivalent with no clinically meaningful differences.

Table 2 shows the main differences between chemical medicines and biological (including biosimilar) medicines.

Table 2. Differences between chemical medicines and biological and biosimilar medicines

	Chemical medicines	Biological and biosimilar medicines
Molecular structure	Small, simple structure For example, the size of an aspirin molecule is 21 atoms	Medium to very large, complex structure For example, the average size of a human growth hormone is around 3,000 atoms. The average size of an antibody is more than 20,000 atoms
Manufacture	Produced by a simple chemical process using chemical compounds	Produced by a biological process using living cells or organisms
Copying	All batches are exactly the same	Batches may be slightly different
Availability	Usually prescribed by general practitioners or specialists, or can be bought over the counter	Usually prescribed by specialists
Administration	Often swallowed in tablet or capsule form	Usually administered by injection or infusion

Introduction

The BRAF V600E mutation is found in approximately 8% to 15% of patients with metastatic colorectal cancer (mCRC) and is a marker of poor prognosis. Patients with this particular mutation have typically been treated with standard first-line therapy regimens for RAS wild-type mCRC, which even with intensified regimens, still produce poor results. After failure of initial therapy, subsequent treatment with second and third-line therapy provides limited benefits, with reported overall response rates (ORRs) of less than 10%, median progression-free survival (PFS) times of approximately two months and median overall survival (OS) times ranging from four to six months.

Unlike in other tumour histologies with BRAF V600E mutations such as melanoma and non-small cell lung cancer, inhibition of BRAF alone in BRAF V600E-mutant mCRC produces minimal clinical response. This is due to the rapid feedback activation of epidermal growth factor receptor (EGFR) which allows prolonged MAPK (mitogen-activated protein kinase) activation and continued cell proliferation. However, when combined with targeted inhibition of EGFR, inhibition of BRAF results in synergistic inhibition of tumour growth in BRAF V600E-mutant CRC xenograft models. Additionally, even more profound inhibition of the MAPK signalling pathway and greater anti-tumour activity could be achieved with the addition of a MEK inhibitor, as has been clinically validated.

Triplet Therapy of BRAF, MEK and EGFR-inhibitors

The BEACON CRC open-label phase III clinical trial aims to clinically evaluate the triplet combination of encorafenib (Braftovi®, a BRAF inhibitor), binimetinib (Mektovi®, a MEK inhibitor) and cetuximab (Erbitux®, an EGFR-targeted monoclonal antibody) in patients with BRAF V600E–mutated mCRC who had disease progression after one or two previous regimens. 665 patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan, or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group).

The doses used in the clinical trial, as part of a 28-day cycle, are as follows:

1. Encorafenib 300mg orally daily
2. Binimetinib 45mg orally twice daily
3. Cetuximab 400mg/m² initially then followed by 250mg/m² intravenously weekly

The results of the study were very promising, as the median OS was 9.0 months in the triplet-therapy group (95% CI = 8.0 – 11.4 months) compared to 5.4 months (95% CI = 4.8 – 6.6 months) in the control group. The objective ORR was 26% (95% CI = 18 – 35) in the triplet-therapy group and 2% (95% CI = 0 – 7) in the control group (P<0.001). The median OS in the doublet-therapy group was 8.4 months. Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.

The most frequently reported adverse effects included predominantly gastrointestinal and skin toxicities such as diarrhoea and dermatitis acneiform, as well as fatigue and nausea. Higher grade (grade 3 or 4) skin toxicities were rare and were less common than the 12% rate of grade 3 or 4 rash reported for cetuximab monotherapy. This suggests that BRAF inhibition may ameliorate this cetuximab-related adverse effect. Some patients experienced known MEK inhibitor class-related adverse effects such as serous retinopathy (also referred to as retinal pigment epithelial detachment), increased creatine phosphokinase, and reduced left ventricular ejection fraction. However, these are generally reversible and manageable with dose interruption, with or without subsequent dose reduction. The triplet combination regimen appeared to be well tolerated and the safety profile manageable.

Administration and Pharmacokinetic Properties of Braftovi® + Mektovi®

Both encorafenib and binimetinib should be swallowed whole with water. Both drugs are mainly cleared by the liver. Encorafenib has many potential drug interactions as its metabolism involves cytochrome P450 (CYP) 2C19, 2D6 and 3A4. Strong inhibitors of CYP3A4 such as clarithromycin and itraconazole, and grapefruit juice should be avoided. Liver disease will increase the concentrations of both drugs. A reduced encorafenib dose is advised in mild hepatic impairment (Child-Pugh Class A) and the combination should not be used in patients with greater impairment. The terminal half-life is about nine hours for binimetinib and six hours for encorafenib. Little active drug is excreted in the urine. Dose reductions are not required in mild to moderate renal impairment. However, there is no data regarding use of the combination in severe impairment. Animal studies have shown foetal toxicity. Therefore, the combination should not be used in pregnancy. Women of child-bearing potential should use effective contraception during treatment and for at least one month afterwards.

Conclusion

In conclusion, a combination of encorafenib, binimetinib, and cetuximab targeted therapy regimen resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation, and may soon become a new standard of care. To maximise the potential for benefit to patients, additional investigation of this regimen in the first-line and potentially the adjuvant settings is warranted. A clinical trial to investigate the triplet therapy regimen in the first-line setting (ANCHOR-CRC [Encorafenib, Binimetinib, and Cetuximab in Subjects With Previously Untreated BRAF-Mutant Colorectal Cancer]) was recently initiated.

The term neuroendocrine tumours (NETs) is used to describe a heterogeneous group of rare, typically slow-growing neoplasms originating from specialised cells in the neuroendocrine system. These cells are capable of releasing hormone-like substances into the blood in response to signals from the nervous system. NETs can develop anywhere in the body, but they most commonly occur in the gastrointestinal tract (stomach, small and large intestine, appendix), followed by lungs, pancreas, and to a lesser extent in the gonads (ovaries and testes), liver, and the biliary tract. This extensive diversity means that NETs display different behavioural patterns depending on the cell of origin and site of the tumours.

Clinical manifestations of NETs do not only depend on the tumour’s type, size, and location, but also whether it is functional (produces excess hormones to cause symptoms), and has metastasised. NETs also frequently demonstrate elevation of one or more biochemical markers. Serum chromogranin A (CgA) is the most established one, and may be useful in making diagnosis, estimating prognosis, and measuring response to therapy. Pathological evaluation of the disease extent involves both anatomical imaging and functional nuclear imaging with radiolabelled somatostatin analogues (e.g. ¹¹¹Indium-labelled pentetreotide, OctreoScan®), which help determine the TNM (Tumour-Node-Metastasis) classification of the tumour. All of the aforementioned factors, along with mitotic count or Ki-67 index (as a marker of cell proliferation), will affect how NETs are classified and graded, and ultimately influence the management options.

Surgical resection of the primary tumour and as much of the metastatic disease as possible is the mainstay of curative therapy, and will increase the efficacy of subsequent medical therapy. However, in patients where surgery is not feasible, selective hepatic embolisation techniques such as trans-catheter arterial chemo-embolisation (TACE) or selective internal radiation therapy (SIRT) may be used to treat liver metastases regardless of the origin of the primary tumour. Depending on the tumour grade, effective management strategies may also include cytotoxic chemotherapy, which is more beneficial in refractory, high grade or poorly differentiated tumours. On the other hand, somatostatin analogues (SSAs) and targeted therapies such as tyrosine kinase inhibitors and anti-angiogenics are preferable as early treatment for well differentiated disease. Patients with tumours expressing somatostatin receptors, as indicated by the degree of radionuclide uptake in somatostatin receptor scintigraphy, will benefit the most from peptide receptor radionuclide therapy (PRRT) as well as SSAs.

The Somatostatin Analogues

Somatostatin is a neurotransmitter peptide that generally serves to inhibit cellular secretion. In the body, it controls the release of several other hormones such as insulin and glucagon. Synthetic somatostatin analogues arise from the pharmacological reconfiguration of endogenous somatostatin, which substantially prolongs the half-life of the peptide and hence improves its efficacy.

The characteristic of gastroenteropancreatic (GEP) NETs presents a major challenge to its management due to the varying neuroendocrine cell types involved and the subsequent diversity of the secretory spectrum of neuropeptides and amines produced (which may include serotonin, catecholamines, dopamine, histamine, gastrin, glucagon, and prostaglandins, among others). The clinical manifestation is a collection of non-specific symptoms commonly referred to as carcinoid syndrome, such as diarrhoea, cutaneous flushing, bronchoconstriction, and cardiac disease – more specifically right-sided heart failure; as well as sweating, intermittent abdominal pain, and gastrointestinal bleeding.

Somatostatin analogues that are currently available in the market, Sandostatin® LAR® (octreotide) and Somatuline® Autogel (lanreotide) display high affinity binding for somatostatin receptors. As NET cells often express high density of somatostatin receptors, this effectively induces biochemical responses that result in the inhibition of hormone secretion and provides symptom relief for patients with GEP NETs.

Some of the approved indications of SSA therapy are:

1. Treatment of patients with symptomatic carcinoid syndrome
2. Prevention or treatment of carcinoid crisis as part of the perioperative management of patients with GEP NETs, and for at risk patients prior to commencing PRRT or chemotherapy
3. Treatment of progressing well-differentiated metastatic GEP NETs regardless of the presence or absence of carcinoid syndrome
4. Treatment of symptomatic vasoactive intestinal peptide secreting tumours

The SSAs are generally well tolerated, although side effects such as mild gastrointestinal upset (bloating, abdominal pain and nausea), hyperglycaemia, hypothyroidism, and development of gallstones (cholelithiasis) with long-term treatment may occur. The recommended starting doses when used as anti-proliferative treatment are octreotide LAR 30 mg (IM injection) or lanreotide autogel 120 mg (deep SC injection) given every four weeks. The long-lasting depot formulation allows the drugs to be administered monthly, which largely eliminates the need for once daily injections. However, it may be useful to initially commence patients on a short-acting SSA to assess treatment tolerability before converting to a long-acting preparation.

The role of SSAs in the management of GEP NETs is well established. It not only ameliorates symptoms of the carcinoid syndrome from functional GEP NETs but also demonstrates considerable anti-proliferative activity, which prolongs patients’ progression-free survival.  Therefore the general consensus favours treating both functional and non-functional NETs with SSAs, regardless of whether or not the tumours produce a distinct clinical syndrome.

Chronic pain is a common condition thought to affect at least one in five Australians. While opioids have been increasingly used in this population, there is a lack of evidence to support their long-term efficacy.

A recent meta-analysis of 96 randomised clinical trials on opioid use in chronic non-cancer pain demonstrated no clinically important improvements in pain or function. Compared to placebo, opioid use was associated with a statistically significant improvement of pain (-0.69cm on a 10cm visual analogue scale) and improved physical functioning (2.04 of 100 points). However, these improvements were marginal and did not meet the minimally important differences (i.e. the smallest amount of improvement that a patient would recognise as being significant).

While the evidence for long-term efficacy is limited, there is substantial evidence to demonstrate a dose-dependent risk of serious harms. These harms may include overdose, abuse, and an increased risk of fractures, myocardial infarction, cognitive impairment, and problems affecting the endocrine and digestive systems. These opioid-related risks translate into an average of almost 150 hospitalisations and three deaths in Australia each day.

In an effort to reduce the harms associated with prescription opioids, the Therapeutic Goods Administration (TGA) has announced the following measures:

• Immediate-release opioids will be available in smaller size packets. This will facilitate the dispensing of appropriate quantities to patients and avoid concerns related to the storage of leftover opioids. This change is particularly important when opioids are prescribed for the treatment of minor, self-limiting pain states. OxyNorm® is already available in packets of 10 capsules in addition to the larger packs containing 20 and 60 capsules;
• The product information (PI) documents for all prescription opioids will be updated to include a boxed warning and class statements regarding their potential for harmful and hazardous use;
• Consumer medicines information (CMI) leaflets will be updated for all prescription opioids to include prominent and consistent safety information and warnings for consumers;
• The indications listed in the PI will reinforce the requirement to reserve opioids for when other analgesics have proven ineffective;
• The indication for fentanyl patches will be updated to state that they should only be used to treat patients with cancer, in palliative care, or under exceptional circumstances. Fentanyl is a high potency opioid, and the misuse of fentanyl patches has been identified as a potential emerging issue in Australia. An increasing number of fentanyl-associated deaths have been reported, most of which involved the extraction and injection of the contents of fentanyl patches; and
• An educational campaign will run to communicate these changes to consumers and healthcare professionals.

Smaller pack sizes and updated fentanyl indications are expected in the first half of 2020; the other changes will be phased in. These measures add to other recent changes such as the upscheduling of codeine and the progression of real-time prescription monitoring.

All of these actions are intended to support the objectives of the National Strategic Action Plan for Pain Management. As the overarching goal of this plan is to improve the quality of life for people living with pain, regulatory changes are not intended to limit appropriate access to opioids for patients in need. Instead, the national action plan advocates for the safe and effective use of pain medication in conjunction with non-pharmacological measures where appropriate.

There have been increasing reports of a class of oral anti-diabetic medications causing serious complications in patients undergoing routine surgical procedures.

The class of medications is called sodium-glucose co-transporter-2 (SGLT2) inhibitors or ‘flozins’. They are known as ‘flozins’ because of the suffix the medications in this class share. The nine flozin-containing products currently registered for use in Australia include:

• Forxiga® (dapagliflozin)
• Xigduo® (dapagliflozin + metformin)
• Qtern® (dapagliflozin + saxagliptin)
• Jardiance® (empagliflozin)
• Jardiamet® (empagliflozin + metformin)
• Glyxambi® (empagliflozin + linagliptin)
• Steglatro® (ertugliflozin)
• Steglujan® (ertugliflozin + sitagliptin)
• Segluromet® (ertugliflozin + metformin)

Under the Pharmaceutical Benefits Scheme (PBS), these medications are indicated for use in patients with type 2 diabetes mellitus and can be given in combination with other anti-diabetic medications such as metformin, sulfonylureas, and dipeptidyl peptidase-4 (DPP4) inhibitors (‘gliptins’).

Flozins work to lower blood glucose levels by reducing the amount of glucose reabsorbed in the kidneys, and therefore increasing the amount of glucose passed in the urine.
This often results in sweet-smelling urine and an increased risk of urinary tract infections.

In rare situations, in which a patient is taking a flozin prior to admission and throughout the peri-operative period, the patient may develop a serious complication called diabetic ketoacidosis (DKA). DKA is characterised by hyperglycaemia, very low insulin levels and metabolic acidosis. DKA can occur when the insulin levels in the body are insufficient to meet the body’s basic metabolic requirements. This causes the body to metabolise fatty acids for energy instead of glucose. A by-product of the metabolism of free fatty acids are ketones. If this cycle is not broken by increasing the amount of insulin available to the body, ketosis results which can lead to metabolic acidosis which requires emergency medical treatment.

The signs and symptoms of DKA include the symptoms of hyperglycaemia such as urinary frequency, polyuria (passage of large volumes of urine) and polydipsia (excessive thirst), with the addition of nausea and vomiting. Treatment requires correction of dehydration with IV 0.9% saline, correction of any electrolyte imbalances, insulin therapy and pH correction if required.

When a patient develops DKA associated with the use of a flozin, it often presents with a normal or only slightly elevated, blood glucose level (euglycaemic DKA, or euDKA). This makes identification and diagnosis of euDKA difficult and increases the likelihood of the complication going unnoticed until it becomes serious.

Recommendations for Practice

• All patients who were taking a ‘flozin’ prior to admission should have this medication withheld two days prior to any surgical procedure. This may require adjustment or addition of other glucose-lowering therapies.
• Consider delaying non-urgent surgeries if a ‘flozin’ has not been withheld in the two days prior.
• Consider withholding ‘flozins’ in patients who are acutely unwell, for example with active infection.
• Blood ketone levels should be routinely monitored in the peri-operative period to screen for DKA.
• ‘Flozins’ should only be restarted when the patient is eating and drinking normally. This may also require adjustment or addition of other glucose-lowering therapies.

Lamotrigine is a broad-spectrum antiepileptic agent indicated for the treatment of both focal and generalised seizures. It is also approved for the prevention of depressive episodes in people with bipolar disorder. While many studies demonstrate the safety and efficacy of lamotrigine, the product information contains a boxed warning. This warning states that lamotrigine has been associated with severe and potentially life-threatening rashes, particularly when used in children.

These skin reactions typically occur within the first eight weeks of therapy. While the majority of skin reactions are mild and self-limiting, serious events including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. As it is not possible to reliably predict which rashes will become life-threatening, lamotrigine should be ceased in any patient who develops a rash unless the rash is clearly not drug-related. In patients who present with SJS, TEN, or DRESS with the use of lamotrigine, the medication should be ceased immediately and not restarted at any time.

While SJS and TEN were once thought to be distinct conditions, they are now considered part of a disease spectrum with SJS at the less severe end. The condition typically begins with influenza-like symptoms before widespread mucocutaneous exfoliation develops with or without blisters. In SJS, over 10% of the body surface area is affected, while over 30% is affected in TEN. Blisters then merge to form sheets that detach to expose the dermis which appears red and oozing. The mucous membranes may also become involved to produce severe conjunctivitis, difficulty breathing and swallowing, genital pain, difficulty urinating, and diarrhoea. While these conditions are rare, the mortality rate is high at up to 12% for SJS and around 30% for TEN. Patients who recover may experience long-term complications including pigmented and scarred skin, damaged nails and joints, and vision loss.

Drug rash with eosinophilia and systemic symptoms is a serious form of T-cell-mediated drug allergy. The symptoms of DRESS are highly variable as multiple organ systems can be affected. However, it often initially presents with a generalised influenza-like syndrome and progresses to include morbilliform eruption, haematological abnormalities (e.g. eosinophilia, atypical lymphocytes, thrombocytopenia, anaemia), and lymphadenopathy. Early manifestations of DRESS can present with fever and lymphadenopathy and patients should be reviewed even if a rash is not present. The mortality rate from DRESS is around 10% but can be considerably higher if organ failure occurs.

The incidence of skin rashes with lamotrigine has been reported to be as high as 9.98% in prospective studies and as low as 2.09% from post-marketing studies. However, the incidence of serious skin reactions is much lower, affecting around one in 500 patients. Children appear to be at greater risk, with up to one in 100 children taking lamotrigine for epilepsy hospitalised for skin reactions.

The overall risk of rash is thought to be highly associated with the initial dose. Actions that may reduce the risk of serious skin reactions include:

• Adhering to initial dosing recommendations;
• Following the recommended guide for dose escalation; and
• Consideration of drug interactions.

The product information should be consulted for advice on initial dosing and subsequent dose escalation. This may also be relevant for patients who have temporarily discontinued lamotrigine. When lamotrigine has been discontinued for a period exceeding five half-lives, it is recommended that the initial dose-escalation schedule is followed.

In healthy volunteers taking no other medications, the mean elimination half-life of lamotrigine is 25.4 after multiple doses. However, the half-life of lamotrigine is highly variable and affected by a number of medications that induce or inhibit its metabolism. Lamotrigine is predominantly metabolised by glucuronidation. Valproate significantly inhibits this metabolism and can almost double the mean half-life of lamotrigine. This may increase the risk of serious skin reactions and demands a lower lamotrigine dose. For patients already taking valproate, lamotrigine is recommended to be initiated at 50% of the usual dose. This is usually administered as the usual dose given on alternate days for the first two weeks of therapy. Conversely, medications such as phenytoin, carbamazepine, phenobarbitone, and primidone may induce the glucuronidaiton of lamotrigine and reduce its half-life. Antiepileptic medications known not to significantly affect the metabolism of lamotrigine include gabapentin, levetiracetam, pregabalin, topiramate, and zonisamide. If the effect of other drugs on lamotrigine metabolism is unknown, it is safest to use the reduced dosing regimen recommended for patients taking valproate.

Lamotrigine has the potential to cause serious skin reactions. To reduce the incidence of these reactions, it is recommended that therapy is initiated at low doses and escalation not exceed what is advised in the product information. While most serious skin reactions are expected to occur within the first eight weeks of therapy, case reports exist of serious skin reactions developing much later. Therefore, any rash that appears during lamotrigine therapy requires immediate evaluation. Discontinuation of lamotrigine should be considered if an alternative aetiology of the rash cannot be established.

Wilson disease is a rare disorder of copper metabolism. People with this condition have a genetic defect that reduces biliary copper secretion, allowing this trace element to accumulate in various organs including the liver, brain, kidneys, and cornea. The genetic defect that alters copper transport also impairs the incorporation of copper into cerulosplasmin, a protein that stores and transports copper around the body.

The clinical presentation of Wilson disease can be highly variable. Signs and symptoms may include:

• Hepatic fibrosis;
• Hepatic cirrhosis;
• Marked hyperbilirubinaemia
• Haemolytic anaemia;
• Kayser-Fleischer rings (dark rings encircling the iris due to copper deposition);
• Low serum ceruloplasmin concentration;
• Menstrual irregularity or amenorrhea;
• Repeated miscarriages;
• Infertility;
• Haematuria;
• Motor deficits (e.g. tremors, dystonia, dysarthria, dysphagia); and
• Cognitive or psychiatric abnormalities.

Some patients exhibit only minor hepatic or neurological symptoms while others may develop acute or chronic liver failure. Serious neurological impairment is not commonly seen in children and is typically associated with more advanced disease due to delayed diagnosis, poor treatment compliance, or treatment failure. The prognosis is usually good for patients who present early and begin appropriate therapy. Treatment must be continued lifelong, even if the patient is asymptomatic. Untreated, Wilson disease may be fatal.

Although Wilson disease cannot be managed by diet alone, it is often recommended to reduce copper intake during the initial phases of treatment. Copper may be ingested in the form of drinking water, vitamin supplements, and foods. Foods particularly high in copper include organ meats, shellfish, chocolate, nuts, and mushrooms. Medications are essential in the treatment of Wilson disease and include chelating agents and zinc.

Chelating agents

Two chelating agents used in the treatment of Wilson disease are D-penicillamine and trientine. These agents chelate with copper to form a stable, soluble complex that can be excreted by the kidneys.

Studies demonstrate that both chelating agents are equally and highly effective in controlling the hepatic symptoms of Wilson disease. A retrospective cohort study of treatment-naïve patients demonstrated improvements in hepatic symptoms in 90.7% of patients taking D-penicillamine and 92.6% of patients taking trientine. However, chelation therapy appears to be less effective for the management of neurological symptoms, with improvement observed in 67.5% of the D-penicillamine group and 55% of the trientine group.

While D-penicillamine and trientine are structurally unrelated compounds, they have similar administration requirements. Each drug must be administered on an empty stomach at least one hour before meals, two hours after meals, and at least one hour apart from any other drug, food or milk. This prevents inactivation of the chelating agent in the gastrointestinal tract due to metal binding.

Neurological worsening is perhaps the most concerning adverse effect of chelating therapy. It is thought to occur soon after initiation of therapy in around 10% of patients, although some studies suggest a higher incidence. While the mechanism is unclear, it is postulated that treatment leads to a sudden mobilisation of copper from the liver, into the bloodstream, and finally to the brain. This may result in free radical-induced tissue injury. A temporary dose reduction resolves most cases of neurological worsening, although the symptoms are irreversible in up to 3% of patients. Initiating therapy at low doses with close clinical monitoring has been suggested to avoid this issue.

In addition to chelating copper, D-penicillamine and trientine also bind to iron and may lead to iron deficiency. If iron supplements are required, they should be taken at least two hours away from the chelating agent to ensure adequate absorption. This is particularly important for trientine as it forms a toxic complex with iron.

Trientine is considered a second-line option and currently holds orphan drug designation with the Therapeutic Goods Administration (TGA). It is recommended to be reserved for patients who are intolerant of D-penicillamine. Discontinuation of D-penicillamine due to adverse effects is relatively common, occurring in up to 30% of patients. Some of its more serious adverse effects are bone marrow toxicity and nephrotoxicity. While clinical experience with trientine is less than D-penicillamine, trientine is associated with fewer adverse effects.

Zinc

Zinc can also reduce copper levels in Wilson disease. It achieves this by increasing the expression of enterocyte metallothioneins, a family of proteins that bind various metal ions. Zinc is a potent inducer of metallothioneins that then bind preferentially to copper. The bound copper is then sequestered within the enterocyte, preventing its absorption into the bloodstream. This copper can then be removed from the body via the faeces due to the normal and rapid turnover of the small intestinal epithelia.

Zinc therapy leads to a reduction in the absorption of dietary copper and also a reduction in the reabsorption of copper that is endogenously secreted in digestive fluids. Unlike chelating agents, zinc may not reduce the copper content in the liver. Deterioration of liver function has been reported during zinc therapy, including in previously asymptomatic patients. Some studies suggest that zinc may be more beneficial for the treatment of neurological impairment compared to hepatic impairment. However, like chelating agents, neurological deterioration has also been reported on zinc therapy.

One advantage of zinc over chelating agents is its very low level of toxicity. The main adverse effect of zinc therapy is gastrointestinal irritation. As food reduces the absorption of zinc, it should be given on an empty stomach. However, if gastric upset is troublesome, the treating physician may consider the following options:

• Administration with a small protein meal;
• Giving the first dose of the day mid-morning rather than before breakfast;
• Giving the daily dose in three divided doses rather than two; or
• Switching to an alternative zinc salt (the acetate and gluconate salts are generally better tolerated than sulfate salts; limited data suggests that all salt forms of oral zinc are effective).

Other therapies

Combination therapy with a chelator and zinc has been suggested due to their different mechanisms of action. However, if administered together, chelating agents will chelate zinc and result in reduced absorption of both agents. Therefore, doses of zinc and chelating agents should be given at least one hour apart from each other. As both agents also need to be given in divided doses spaced from food, the resulting dosing schedule is likely to be complicated which may significantly affect compliance. A systematic review also suggests that combination therapy is associated with a higher mortality rate (12.7%) compared to monotherapy (6.6%).

As copper accumulation causes oxidative stress-related damage, antioxidant supplementation has been suggested as an adjunctive therapy. Some studies have found that patients with Wilson disease often have low levels of vitamin E. Although there is a lack of high-quality data to support the use of antioxidants in Wilson disease, vitamin E or N-acetylcysteine may be considered.

Physiotherapy and occupational therapy may be indicated to improve independence and quality of life. In order to avoid additional hepatic injury, patients should be advised to avoid alcohol and ensure they are vaccinated against hepatitis A and B. Patients with hepatic involvement require management appropriate to their level of liver disease.

Parkinson’s disease is a progressive neurological disorder estimated to affect over 110,000 Australians. While the presentation of Parkinson’s disease can be quite varied, the condition is characterised by bradykinesia plus either muscle rigidity, rest tremor, or both.

Hospitalisation is common among people with a diagnosis of Parkinson’s disease. Each year, around a third of patients with Parkinson’s disease visit an emergency department or are admitted to hospital, with half of these patients going on to have a repeat encounter. Admission to a healthcare facility can be risky for people with Parkinson’s disease. Evidence suggests that these patients have a longer length of stay, more complications, and worse outcomes compared to patients without a diagnosis of Parkinson’s disease. The following factors may contribute to these results:

• Delayed or varied dosing of anti-Parkinson medications;
• Administration of medications contraindicated in Parkinson’s disease; and
• Administration of medications that interact with anti-Parkinson medications.

Dosing schedule

Levodopa and dopamine agonists are the main medications used to improve motor function in patients with Parkinson’s disease. Anticholinergics, catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase type B (MAO‑B) inhibitors, and amantadine may also be used. Adherence to prescribed therapy regimens is important as significant deterioration in function can develop when variations from the usual dosing schedule occur.

Levodopa has a relatively short half-life of around 90 minutes. Patients in the early stages of the disease often enjoy a prolonged clinical effect from twice-daily doses which may be due to preserved levodopa storage capacity of presynaptic neurones. However, as the disease progresses, there is a continued loss of these neurones and a reduced duration of levodopa’s clinical effect. It is these patients who are particularly vulnerable to deterioration if doses are delayed or missed. Parkinson’s NSW advises that a delay of just 15 minutes can cause clinical deterioration.

Admission to a healthcare facility may increase the risk of missing or delayed doses for a variety of reasons. The patient may not have brought their own medications in with them, or there may be confusion regarding the patient’s dosing schedule leading to delays in completing the medication chart. One retrospective study found that 76% of patients prescribed medications for Parkinson’s disease had at least one missed dose documented, corresponding to 0.7 missed doses per patient per day. The most common documented reasons for dose omissions were ‘unable to swallow’ (14%), ‘out of stock’ (12%), ‘nil by mouth’ (8%), ‘refused’ (4%), and ‘in theatre’ (4%). However, the majority of omissions had no documented reason.

Acute deterioration can occur when doses are missed. The patient may experience a worsening of tremors, increased rigidity, loss of balance, confusion, agitation, impaired bowel motility, and difficulty swallowing and communicating. This can lead to complications related to falls, aspiration pneumonia, and bowel obstruction as well as causing significant distress for the patient and their family. Parkinsonism-hyperpyrexia syndrome is another potential complication associated with the sudden cessation or reduction in dose of anti-Parkinson medications. This potentially fatal syndrome is characterised by pyrexia, muscle rigidity, reduced consciousness, and autonomic instability. While this condition is rare, the mortality rate is reported to be up to 4% with an additional one-third of patients left with permanent sequelae. Management relies on prompt diagnosis and resumption of anti-Parkinson medications.

Strategies that may reduce the incidence of inadvertent dosing variances include:

• Educate patients prior to an elective admission to bring their own medications, in the original containers, with them to the hospital;
• Educate patients to bring a current medication schedule with them to the hospital;
• Conduct a best possible medication history with each patient as soon as possible after presentation to hospital;
• Ensure medication orders are written for the times the patient normally takes their medications, rather than standard administration times;
• Institute a system to easily identify patients who have Parkinson’s disease; and
• Consider reviewing the availability of common anti-Parkinson medications in imprest and emergency cupboards.

Alternatively, medications may have been deliberately withheld while the patient is nil by mouth e.g. prior to surgery. The Therapeutic Guidelines: Neurology advise that patients with good control of their Parkinson’s disease can miss up to three doses of oral anti-Parkinson therapy if necessary. However, patients with fragile disease control or those expected to miss more than two or three oral doses should receive their anti-Parkinson medication by a non-oral route.

One option that could be considered in a patient who is nil by mouth is the transdermally administered dopamine agonist, rotigotine. An appropriate starting dose can be calculated using the concept of levodopa equivalent doses (LEDs). An LED is the dose of anti-Parkinson medication that provides an equivalent level of symptom control as 100mg of immediate-release levodopa plus a dopa-decarboxylase inhibitor. Another option is to administer the medication via an enteral feeding tube, although not all levodopa formulations are suitable for this route of administration. Any alteration to a patient’s usual medication regimen is ideally supervised by a physician experienced in the management of Parkinson’s disease, especially if the patient has fragile disease control.

It may also be prudent to consider the timing of interventions to minimise interruption to the medication routine. For example, a patient who is nil by mouth prior to surgery can still take prescribed oral medication with a small amount of clear fluid up to two hours before elective surgery. Therefore, placing patients with Parkinson’s disease at the beginning of operating lists and resuming medications as soon as possible after surgery may improve clinical outcomes.

Inappropriate medications

Another issue that can arise during hospitalisation is the administration of medications that are contraindicated in Parkinson’s disease or interact with medications used in the treatment of Parkinson’s disease.

Due to the underlying pathology of Parkinson’s disease, medications that antagonise the effects of dopamine should be avoided as they will impair symptom control. Many medications can reduce the effects of dopamine; some examples are shown in Table 1.

Table 1. Medications to avoid in all patients with Parkinson’s disease

Medication class	Examples	Mechanism of interaction
Typical antipsychotics	Chlorpromazine Flupenthixol Fluphenazine Haloperidol Pericyazine Trifluoperazine Zuclopenthixol	Blocks D2 receptors in the brain
Atypical antipsychotics	Amisulpride Aripiprazole Asenapine Brexpiprazole Clozapine* Olanzapine Paliperidone Quetiapine* Risperidone Ziprasidone	Blocks D2 receptors in the brain (effect is less pronounced than with typical agents)
Anti-emetics	Metoclopramide Droperidol Prochlorperazine	Blocks D2 receptors in the brain (domperidone preferred as it does not cross the blood-brain barrier)
Antihistamines	Promethazine Alimenazine (trimeprazine)	Weak D2 blocking effect
Tetrabenazine	Tetrabenazine	Reduces dopamine stores
Antihypertensive	Methyldopa	Inhibits dopa decarboxylase to reduce conversion of l-dopa to dopamine

*If an antipsychotic is required for a patient with Parkinson’s disease, quetiapine or clozapine are less likely to worsen Parkinson’s symptoms

Care is also required to avoid or minimise interactions with anti-Parkinson medications. Drug interactions, such as those shown in Table 2, may result in worsening of symptoms or produce severe adverse effects.

Table 2. Interactions with medications used to treat Parkinson’s disease

Anti-Parkinson Medication	Interacting medications	Effect
MAO-B inhibitors (rasagiline, selegiline, safinamide)	Pethidine	Risk of serotonin syndrome
	Tramadol
	Dextromethorphan
	Selective serotonin reuptake inhibitors (SSRIs)
	Tricyclic antidepressants (TCAs)
	St John’s Wort
	MAO inhibitors (phenelzine, tranylcypromine)	Non-selective MAO inhibition may lead to hypertensive crisis
	Moclobemide	Increased risk of hypertensive episodes
Apomorphine	Ondansetron	Severe hypotension, loss of consciousness, bradycardia and seizure activity may result
Amantadine	Anticholinergic agents	Additive anticholinergic adverse effects
Levodopa	Antihypertensives	Additive hypotension

Conclusion:

While it is important for all medications to be administered as prescribed, it is particularly crucial to minimise variations to medications used to treat Parkinson’s disease. Medication regimens for the management of Parkinson’s disease are highly individualised, and the patient’s original dosing schedule should be closely followed during admission. Minimising dosing delays and therapy interruptions may help to improve clinical outcomes by preventing acute deterioration and prolonged length of stay.

What are clinical trials?

The World Health Organization defines clinical trials as:

‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Clinical trials may also be referred to as interventional trials. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc.’

How important are clinical trials?

Clinical trials are important to allow new interventions to become available and improve health outcomes. Clinical trials are designed and conducted in a group of human subjects in order to develop new interventions to show the benefits and identify any possible adverse effects related to the interventions.

How clinical trials work

Before a clinical trial is initiated, researchers may first test new interventions in laboratory and animal studies. When the results are promising, the next step is conducting clinical trials in humans, which will help to collect more information about the effectiveness and safety of a new intervention.

Clinical trials in Australia are governed by national ethics guidelines in the National Statement on Ethical Conduct in Human Research and codes of conduct in the Australian Code for Responsible Conduct of Research. Clinical trials of any unapproved substances and devices must also comply with the Therapeutic Goods Administration. Any participants in a clinical trial must give informed consent. They must be fully informed of the objectives, risk and benefits of the study.

All clinical trials are conducted according to trial protocols. A protocol consists of a list of measures for clinical trials teams to follow to ensure the study is performed correctly and participants’ safety. The protocol includes the type of subjects who are eligible to take part in the study; the study objectives; the study design, tests and procedures; number of subjects and length of study; preparation and administration of the investigational product; etc. Control groups are used in clinical trials to compare against a new intervention that is being assessed. A control group can be an existing treatment or a placebo. Randomisation is one of the ways used to avoid bias in a study. A computer system is normally used in this process to allocate human subjects to a control group or to a group using the new intervention. Blinding is another way to eliminate bias in a clinical trial. A single-blinded study means the clinical trial team knows which treatment is assigned to which participants. In this type of study, the human subjects in the trial do not know if they are receiving control drug or investigational drug. In a double-blinded study, both the clinical trial team and the participants do not know if a control drug or investigational treatment is given to which participant. In some situations where certain criteria outlined in the study protocol are met, a participant may need to be unblinded. This may occur if a patient experiences severe adverse effects and the practitioner needs to know the actual type of treatment given to the patient.

Phases of clinical trials:

Clinical trials are commonly conducted through four to five phases:

Phase 0 clinical trial or pilot study

In this phase, small doses of the experimental drug are given once or for a short time to a very limited number of humans (about 10 to 15 people) to test how a drug is processed in the body and how the body responds to the drug.

Phase I clinical trial

The main purpose of a Phase I trial is to test the safety and tolerability of an intervention at the best dose with the fewest side effects. The lowest dose is given and increased until side effects become too severe or the desired effect is seen. The number of human subjects usually ranges between 20 to 80 people and the study is normally conducted over several months. The information gathered in this phase is used to design Phase II trials.

Phase II clinical trial

Phase II studies aim to assess whether an intervention works and to provide additional safety data. The information gathered in this phase is used to develop research methods and design Phase III study protocols. Phase II clinical trials involve up to several hundred human subjects and may take several months to two years.

Phase III clinical trial

Phase III clinical trials involve several hundred to several thousands of human subjects, and the length of the study may take one to four years. As it involves a larger population and longer duration, the results of the studies will show long-term or rare side effects, and treatment benefits of the intervention studied.

Phase IV clinical trial

Phase IV trials are conducted after an intervention has been marketed. Several thousands of human subjects are recruited in the study for a longer duration. The study is designed to monitor the effectiveness of the approved intervention. The studies are also used to gather information about any adverse effects related to the approved intervention. It may also assist in investigating the potential use of the intervention in a different condition or in combinations with other therapies.

Over the past decade, the rate of opioid-related deaths and hospitalisations has increased in Australia. Pharmaceuticals are a significant contributing factor, responsible for 65% of opioid-induced deaths in 2016.

It is estimated that between 3% and 10% of opioid naïve patients become chronic users following the prescription of opioids in the post-operative period. Evidence suggests that it is the duration of opioid use, rather than the dose, that is the strongest predictor of misuse. One study found that a single repeat prescription increases the risk of misuse by more than 40%. In contrast, for patients that do not become chronic users, up to 80% of their prescribed opioids remain unused. This represents a considerable financial cost to the consumer and the healthcare system. However, the potential costs associated with diversion, misuse, and accidental ingestion are likely much greater if these unused medicines are not stored and disposed of thoughtfully. It is, therefore, imperative that the duration of opioid therapy is carefully considered to allow adequate pain relief while preventing the supply of excessive quantities.

OxyNorm® 5mg is now available in packets of ten capsules making it the only short-course oxycodone pack in Australia. All existing pack sizes of OxyNorm® will continue to be available. The reduced pack size of OxyNorm® 5mg capsules aligns with the options currently under review by the Therapeutic Goods Administration (TGA) to increase the regulatory control of strong opioids. While this change only affects the 5mg strength of OxyNorm®, prescribers are encouraged to limit the prescribed quantity of all opioids to what is clinically appropriate for the individual patient.