Knowledge Type: Clinical Articles

A new presentation of abiraterone has been added to the Pharmaceutical Benefits Scheme (PBS). Abiraterone is available in several formulations that differ in strength, bioavailability, and administration instructions.

Abiraterone is an antiandrogen used in the treatment of prostate cancer. It selectively inhibits the CYP17 enzyme (17α hydroxylase/C17,20-lyase). This enzyme is involved in androgen biosynthesis in the testes, adrenal glands, and prostate tumour tissue. Blocking this enzyme significantly reduces the production of testosterone and other androgens, leading to suppression of tumour growth.

The CYP17 enzyme also plays a role in glucocorticoid production. When this enzyme is inhibited, there is a reduction in cortisol production which reduces negative feedback on adrenocorticotropic hormone (ACTH). As ACTH levels rise, there is an excess production of mineralocorticoids.

Some patients may experience symptoms of mineralocorticoid excess. This can include hypertension, hypokalaemia and fluid retention. Co-administration with a corticosteroid suppresses ACTH release. This reduces the incidence and severity of adverse effects associated with mineralocorticoid excess.

There are many brands of abiraterone available, as well as two products that also contain a corticosteroid, as shown in Table 1.

	Zytiga®*	Andriga®	Yonsa Mpred™
Abiraterone content	250mg	500mg	125mg
	500mg
Formulation	Standard	Standard	Fine particle
Corticosteroid included	Nil	Prednisolone 5mg	Methylprednisolone 4mg
Typical abiraterone dose**	1,000mg daily	1,000mg daily	500mg daily
Administration instructions	Take on empty stomach	Take on empty stomach	Swallow whole without regard to food

*Multiple generic brands available

**Dose may be reduced in response to toxicity

Andriga®

Andriga® is a composite pack containing 500mg abiraterone tablets and 5mg prednisolone tablets. It is marketed as Andriga-5® and Andriga-10® with both products containing the same strength and quantity of abiraterone. Andriga-5® is intended to provide 5mg per day of prednisolone while Andriga-10® provides 10mg per day of prednisolone.

The absorption of abiraterone is highly affected by food. Depending on the fat content of a meal, taking the tablet with food can increase systemic exposure up to 17 times compared to administration in a fasted state. As meals typically vary in composition, the manufacturer advises that the abiraterone tablets must be taken on an empty stomach, i.e. at least two hours after food and at least one hour before food.

The usual daily dose is abiraterone 1,000mg plus prednisolone 5mg (for hormone sensitive prostate cancer) or prednisolone 10mg (for metastatic castration-resistant prostate cancer).

Yonsa Mpred™

Yonsa Mpred™ is a composite pack containing 125mg abiraterone tablets and 4mg methylprednisolone tablets.

The abiraterone in this product is formulated as a fine particle which is intended to improve its bioavailability and reduce pharmacokinetic variability. Randomised studies found that 500mg fine particle abiraterone is bioequivalent to 1000mg in healthy subjects under fasted conditions. The effect of food on this formulation is not considered to be significant. Therefore, patients may take these tablets without regard to meals.

Therapeutic equivalence has also been demonstrated between 500mg fine particle abiraterone and 1000mg standard abiraterone in a study in men with progressive metastatic castration-resistant prostate cancer. Testosterone levels and prostate-specific antigen (PSA) were monitored after treatment with either 500mg fine particle abiraterone or 1000mg standard abiraterone. The study found comparable testosterone suppression, and a similar proportion of patients achieved at least 50% reduction in PSA from baseline.

The other key difference with Yonsa Mpred™ is the choice of glucocorticoid. Yonsa Mpred™ contains methylprednisolone instead of prednisolone. Methylprednisolone is a more potent corticosteroid, with 0.8mg methylprednisolone being approximately equivalent to 1mg of prednisolone.

The usual dose is abiraterone 500mg daily plus 4mg methylprednisolone (taken daily for metastatic hormone sensitive prostate cancer or twice daily for metastatic castration resistant prostate cancer).

Summary

Abiraterone is available in several presentations, and it is important to understand their differences. Standard abiraterone tablets must be taken on an empty stomach to reduce variations in drug exposure. Fine particle abiraterone (i.e. Yonsa Mpred™) has greater bioavailability and may be taken without regard to food. The two presentations are not interchangeable.

The current criteria for PBS subsidy is shown in Table 2.

Medication	PBS criteria
Abiraterone 250mg	Castration resistant metastatic carcinoma of the prostate
Abiraterone 500mg
Yonsa Mpred®	Metastatic castration sensitive carcinoma of the prostate
	Castration resistant metastatic carcinoma of the prostate
Andriga-5®	N/A
Andriga-10®	Castration resistant metastatic carcinoma of the prostate

 

Hereditary fructose intolerance (HFI) is a rare genetic disorder where individuals lack aldolase B, an enzyme required for the metabolism of fructose-1-phosphate. When an individual with HFI is exposed to fructose, fructose 1-phosphate accumulates in the liver and kidney. Symptoms of acute toxicity may include nausea, vomiting, abdominal pain, and hypoglycaemia. Chronic symptoms can include failure to thrive, fatigue, persistent abdominal pain, jaundice, and severe liver and kidney damage.

Fructose is primarily derived from the diet. It is found in its free form in honey, fruits, and some vegetables. Fructose can also be derived from the ingestion of sucrose and sorbitol. Sucrose is a disaccharide containing one glucose and one fructose molecule joined together, while sorbitol is converted to fructose in the liver.

When exclusively breastfed, infants with HFI are asymptomatic with normal growth and development. Symptoms typically become apparent when solid foods are introduced. However, symptoms can occur earlier when infant formula containing these sugars is used.

If this condition is identified and managed before organ damage occurs, quality of life and life expectancy are normal. Management requires the dietary restriction of fructose, sucrose, and sorbitol.

Hereditary fructose intolerance should not be confused with fructose malabsorption. Fructose malabsorption is a common condition where individuals cannot absorb fructose properly. The ingestion of fructose can produce gastrointestinal issues such as diarrhoea and bloating in these individuals. In contrast, HFI is a metabolic disorder that can lead to serious and life-threatening reactions upon exposure to fructose.

Sugars in medicines

Many medications and nutritional supplements contain sugars that must be avoided in HFI. Sorbitol is found in many medicines for oral use, particularly oral liquid medicines (e.g. analgesics, antibiotics). However, some capsules and tablets also contain this sugar.

The risk of harm is significantly higher when fructose or sorbitol is administered parenterally, particularly when the intravenous route is used. Fatal outcomes have been reported in adults with HFI following the intravenous administration of 25g of sorbitol. These reactions involve hepatorenal failure associated with bleeding.

Sorbitol is used as an excipient in some products for parenteral use. It can be used to adjust tonicity or as a stabilising agent for proteins and peptides. Products containing sorbitol include some monoclonal antibodies, immunoglobulins, growth factors, and vaccines. However, the amount can vary significantly. For example, Flebogamma® (human normal immunoglobulin) contains sorbitol 50mg/ml, while Stamaril® (yellow fever vaccine) contains only 8mg/dose of sorbitol.

The ingestion of large quantities of fructose can be particularly problematic for infants. Life-threatening events can occur when young children with HFI receive medicines containing fructose intravenously. As young children with this condition may not yet be diagnosed, it recommended to avoid the use of intravenous medicines containing fructose in children under two years unless there is an overwhelming need and no appropriate alternative.

Some vaccines routinely recommended for use in children under two years do contain sorbitol or sucrose as excipients (e.g. MMR and varicella zoster vaccines). However, the amounts are low and absorption slower due to their administration via the subcutaneous or intramuscular routes. Severe events due to HFI have not been reported with these vaccines.

Some examples of medicines containing sugars of concern in HFI are shown in Table 1.

Table 1. Medications containing fructose, sucrose, or sorbitol.

Medication	Sugar	Comment
Oral medications
Rotarix®	Sucrose	Infants with severe adverse reactions (e.g. hypoglycaemia, pallor, hypotonia) should be investigated for HFI.
Melatonin (Voquily® oral solution)	Sorbitol	Contains 140mg/mL sorbitol. Should not be used in HFI.
Icosapent ethyl (Vazkepa®)	Sorbitol	Contains 83mg sorbitol per capsule. Should not be used in HFI.
Lopinavir/ ritonavir (Kaltera®)	Fructose	Kaletra® oral liquid contains fructose; tablets are fructose-free.
Injectable medications
Anidulafungin (eraxis®)	Fructose	Contains 120mg fructose per 100mg vial. Avoid in HFI
Lipegfilgrastim (Lonquex®)	Sorbitol	Avoid in HFI. Each pre-filled syringe contains 30mg sorbitol.
Filgrastim (Nivestim®, Zarzio®)	Sorbitol	Avoid in HFI.
Pegfilgrastim (Pelgraz®, Ziextenzo®)	Sorbitol	Avoid in HFI. Each pre-filled syringe contains 30mg sorbitol.
Immunoglobulin solutions	Sorbitol	Some products use sorbitol as a stabiliser. E.g. Flebogamma® contains sorbitol 50mg/mL and is contraindicated in HFI.
Other
Micolette enema	Sorbitol	Contains sorbitol 625 mg/mL

The polysorbate content of medicines should also be considered as these agents are derived from sorbitol. Polysorbates may be used as a surfactant to improve the dissolution of poorly water-soluble drugs (e.g. docetaxel, amiodarone) or to stabilise protein-based medicines (e.g. some monoclonal antibodies).

Summary

There is currently no established and generally accepted safe dose of fructose for patients with HFI. Some reports consider amounts up to 40mg/kg/day (up to 1.5g) safe. However, evidence suggests that inadequate restriction of fructose can cause growth deficiency even in patients who are clinically asymptomatic.

Maintaining a low fructose diet can be challenging due to the widespread presence of fructose in foods. Support groups can assist with practical dietary strategies.

During hospitalisation, additional care is required to avoid the administration of medicines and fluids containing fructose, sucrose, or sorbitol to patients with HFI.

Inadequate adherence to antipsychotic therapies is one of the main barriers to optimal symptom control in schizophrenia. Discontinuation of antipsychotics is associated with an increased risk of disease relapse, hospitalisation, suicide, and reduced social functioning. While reported adherence for oral antipsychotics varies widely depending on the study and method used, adherence rates are consistently low for people with schizophrenia.

Factors associated with a higher rate of discontinuation include:

• Male gender
• Early phases of disease
• Poor education
• Intellectual disability
• Unemployment
• Low insight into disease
• More severe negative symptoms
• High number of previous psychiatric hospital admissions

Long-acting injectable (LAI) antipsychotics play an important role in the management of psychiatric disorders. They are most useful for improving compliance in patients who forget to take their doses or who have poor insight into their condition.

Other factors that may favour the use of LAI include:

• Where early warning of non-adherence is vital (e.g. patients who experience severe consequences when stopping antipsychotics, such as violence, self-harm, loss of employment/housing, etc.);
• Patients who respond well to a specific oral antipsychotic but have dose-dependent side effects. The more consistent blood levels provided by an LAI may be beneficial by avoiding the higher daily peaks often seen with oral therapy;
• Patients with poor or unpredictable absorption with oral therapies; and
• Patient preference. Some patients may prefer LAIs rather than taking oral medication each day.

While LAI antipsychotics can improve patient outcomes, they are high-risk medications that are prone to errors.

General considerations

Long-acting antipsychotics are administered intramuscularly (IM) and release the active ingredient slowly over time. This provides sustained therapeutic blood levels.

Ideally, the patient should be stabilised on an oral formulation of the same antipsychotic before an LAI is used. This is important to ensure the patient tolerates the medication before a long-acting form is used. However, this may not always be possible. For example, flupentixol is available as an LAI but has no oral formulation.

In addition, many orally administered antipsychotics do not have a LAI formulation. For patients taking one of these agents, it is recommended that they be switched to an oral agent that is available as an LAI and stabilised on that prior to initiation of the injectable form.

Table 1 shows the various antipsychotic formulations available.

Table 1. Antipsychotic formulations available (adapted from AMH)

Antipsychotic	Oral	Injection
Amisulpride	Tablet, oral liquid (Solian®)
Aripiprazole	Tablet (Abilify®)	Long-acting: ·       Once-monthly (Abilify Maintena®) ·       2-monthly (Abilify Asimtufii®)
Asenapine	Wafer (Saphris®)
Brexpiprazole	Tablet (Rexulti®)
Cariprazine	Capsule (Reagila®)
Chlorpromazine	Tablet, oral liquid (Largactil®)	Short-acting (Largactil®)
Clozapine	Tablet, oral liquid (Clopine®)
Droperidol		Short-acting (Droleptan®)
Flupentixol		Long-acting (Fluanxol® Depot, Fluanxol® Concentrated Depot)
Haloperidol	Tablet, oral liquid (Serenace®)	Short-acting (Serenace®) Long-acting (Haldol®)
Lurasidone	Tablet (Lavione®)
Olanzapine	Tablet, orally disintegrating tablet, wafer (Zyprexa®)	Short-acting (Zyprexa® IM) Long-acting (Zyprexa® Relprevv)
Paliperidone	Tablet (Invega®)	Long-acting: ·       Once-monthly (Invega Sustenna) ·       3‑monthly (Invega Trinza) ·       6‑monthly (Invega Hafyera)
Periciazine	Tablet (Neulactil®)
Quetiapine	Tablet (Seroquel®)
Risperidone	Tablet, oral liquid (Risperdal®)	Long-acting: ·       Fortnightly (Risperdal Consta) ·       Monthly (Risvan)
Ziprasidone	Capsule (Zeldox®)	Short-acting (Zeldox®)
Zuclopenthixol	Tablet (Clopixol®)	Intermediate-acting (Clopixol® Acuphase), Long-acting (Clopixol® Depot)

Adverse effects associated with LAIs are typically similar to the corresponding oral agent. However, there may be some differences.

Injection site reactions such as pain, redness, swelling, or induration are unique to the injectable formulations. Older antipsychotics (e.g. flupentixol, haloperidol, zuclopenthixol) are formulated in oily vehicles which may result in a higher incidence of injection site reactions. Frequent large volume administration of these oily injections may also be associated with the development of muscle fibrosis and granulomas.

For all LAI antipsychotics, the injection site should be rotated to mininise injection site reactions. In all cases, care must be taken to avoid inadvertent intravenous administration.

As shown in Table 1, there are many antipsychotics formulations available. The presence of such a large range of products, some with similar names, increases the potential for medication selection errors. Therefore, great care is required when selecting and administering these products.

The following provides a summary of the LAI antipsychotics available.

Long-acting formulations

Aripiprazole

Aripiprazole has two modified-release injectable products:

• Abilify Maintena^® (monthly)
• Abilify Asimtufii^® (every two months).

Flupentixol

Flupentixol is available in two LAI formulations:

• Fluanxol Depot^® – 20 mg/mL
• Fluanxol Concentrated Depot^® – 100 mg/mL

The concentrated depot is preferred where volumes greater than 2-3mL of the lower strength product are required or where the patient complains of discomfort from a large injection volume.

Haloperidol

There are two brands of injectable haloperidol:

• Serenace^® (short-acting)
• Haldol^® (long-acting).

The haloperidol present in Haldol^® is the long-acting form, haloperidol decanoate. When given IM, haloperidol decanoate is hydrolysed by esterases in the blood and tissues to slowly release haloperidol into the systemic circulation. Plasma levels rise slowly, typically peaking 3-9 days after injection, with an apparent half-life of around 3 weeks. Steady state plasma levels are achieved in 2-4 months when given monthly.

Olanzapine

Olanzapine is available in two injectable forms:

• Zyprexa IM^® (short-acting)
• Zyprexa Relprevv^® (long-acting).

Zyprexa Relprevv^® contains olanzapine pamoate monohydrate, a crystalline salt that is insoluble in water and has very low solubility in muscle. When injected into the gluteal muscle, the salt slowly dissolves to allow a sustained release of olanzapine into the bloodstream over the dosing period. Following administration, plasma levels typically peak within the first week.

Post-injection syndrome has been reported to occur in 1.85% of patients. This syndrome most commonly presents with symptoms of sedation or delirium and can appear similar to alcohol intoxication. Other symptoms may also occur such as extrapyramidal symptoms, aggression, hypertension, or convulsions. This typically occurs within an hour of injection, although rare cases have occurred two hours or more after the injection. Full recovery was reported within 24-72 hours after injection in all cases. However, the potential for post-injection syndrome does necessitate additional monitoring. Following each injection of Zyprexa Relprevv, patients should be observed for at least two hours and actively monitored for alertness every 30 minutes. Patients should be educated about this potential effect and advised to abstain from activities that may be dangerous (e.g. operating machinery) the day after injection.

Paliperidone

There are three LAI forms of paliperidone, each with a different dosing interval:

• Invega Sustenna^® (monthly)
• Invega Trinza^® (3-monthly)
• Invega Hafyera^® (6-monthly)

These three LAI formulations all contain paliperidone palmitate. The palmitate salt has extremely low water solubility which allows for the extended dosing period. Following IM injection, paliperidone palmitate dissolves slowly before being hydrolysed to paliperidone and absorbed into the systemic circulation.

Paliperidone is the major active metabolite of risperidone. Tolerability should be established with oral paliperidone or oral risperidone prior to initiating a LAI form of paliperidone.

Risperidone

There are two LAI forms of risperidone:

• Risperdal Consta^® (every 2 weeks)
• Risvan^® (every 4 weeks)

Zuclopenthixol

Zuclopenthixol is available in two injectable formulations:

• Clopixol Acuphase^®
• Clopixol Depot^®

These products are not interchangeable. Clopixol Acuphase contains the acetate ester which is slowly released from the oil and then rapidly hydrolysed to zuclopenthixol. Maximum serum levels are reached within around 24-36 hours. Conversely, Clopixol Depot contains the decanoate ester which provides a slower release of zuclopenthixol from the oil depot. Maximum serum levels are reached within 3-7 days.

Clopixol Acuphase is only intended for short-term treatment (up to two weeks). The manufacturer recommends that the maximum accumulated dosage in a course should not exceed 400 mg, and the total number of injections should not exceed four. This is considered an intermediate-acting product and dose intervals are usually two to three days, although an additional injection may be required 24-48 hours after the first injection. One or two injections is usually sufficient to reduce symptoms prior to initiation of zuclopenthixol maintenance treatment (oral or depot).

Clopixol Depot is the LAI form of zuclopenthixol and is administered at intervals of two to four weeks. This product is intended for maintenance therapy.

Incorrect use of the intermediate-acting Clopixol Acuphase instead of the long-acting Clopixol Depot can result in severe adverse effects as the active ingredient is released much faster.

Medication errors

While LAI antipsychotics have demonstrated improvements in adherence and may improve clinical outcomes, they are not without their challenges.

Medication errors may occur with LAI antipsychotics for many reasons, including:

• Patients with mental health issues may transfer between facilities frequently
  • Inadequate medication reconciliation and communication between facilities can lead to missed or delayed doses, additional unnecessary doses, and confusion between formulations;
• Use of one-time orders instead of continuous orders may increase the risk of errors; and
• Availability of multiple formulations with different strengths, dosing intervals, and administration requirements
  • Many of these products fit the definition of look-alike sound-alike (LASA) medications.
  • For example, the name risperidone can be confused for paliperidone. It would also be very easy to confuse the brand names of Abilify, Abilify Maintena, and Abilify Asimtufii.
  • The outer packaging appears very similar for many of these LAI products.

The consequences of medication errors may be more significant for LAIs as their effects are long-lasting and administration via the incorrect route is associated with significant harm.

Strategies that may be considered to minimise selection errors include:

• Storage considerations
  • Physically separate look-alike products
  • Physically separate different strengths and formulations
  • Always keep medications in their original packaging
  • Do not store medication in a way that impairs recognition
• Verification
  • Query any order that seems ambiguous
  • Identify medicines by name and strength
  • Check appropriateness of therapy
• Minimise interruptions
• Report errors and near misses.

Summary

Long-acting injectable antipsychotics play an important role in the management of psychiatric conditions. They may improve compliance, particularly for patients who find it difficult to remember daily dosing.

There are many formulations available which may increase the risk of medication errors. Careful selection of products is required to ensure these medications are used safely and effectively.

The product information should be referred to as each product has unique instructions. For most LAI antipsychotics, the deltoid or gluteal sites are used (ventrogluteal site typically preferred for gluteal administration). A summary of LAI antipsychotics is shown in Table 2.

Table 2. Summary of LAI antipsychotic administration

Antipsychotic	Product	Administration site	Usual dosing interval
Aripiprazole	Abilify Maintena	Deltoid or gluteal	Monthly
	Abilify Asimtufii	Gluteal	2-monthly
Flupentixol	Fluanxol Depot	Gluteal	2-4 weeks
	Fluanxol Concentrated Depot	Gluteal
Haloperidol	Haldol	Gluteal	Monthly
Olanzapine	Zyprexa Relprevv	Gluteal	2-4 weeks
Paliperidone	Invega Sustenna	Deltoid or gluteal	Monthly
	Invega Trinza	Deltoid or gluteal	3-monthly
	Invega Hafyera	Gluteal	6-monthly
Risperidone	Risperdal Consta	Deltoid or gluteal	2 weeks
	Risvan	Deltoid or gluteal	Monthly
Zuclopenthixol	Clopixol Depot	Large muscle	2 weeks

 

While smoking rates have declined significantly over the past few decades, smoking continues to be an important contributor to disease burden in Australia.

Smoking cessation is associated with significant health benefits, including rapid improvements in lung function and cardiovascular health. However, changes in smoking status can affect the plasma levels and efficacy of certain medications. These effects occur through pharmacokinetic and pharmacodynamic interactions and should be considered when someone starts or stops smoking, or changes how much they smoke.

Pharmacokinetic interactions

Pharmacokinetic interactions occur due to chemical compounds found in tobacco smoke, known as polycyclic aromatic hydrocarbons. These chemicals can affect cytochrome (CYP) P450 isoenzymes, key enzymes involved in the metabolism of many drugs. While various isoforms may be affected, CYP 1A2 is the most clinically relevant.

Smoking can induce CYP 1A2, resulting in increased metabolism of medications that are substrates of this enzyme. This enzyme induction can result in lower blood levels of these medicines. Therefore, people who smoke may have require higher doses to achieve therapeutic effect. When these individuals stop smoking, this effect is removed, and blood levels of affected medications may rise significantly.

Examples of medications that are substrates of CYP 1A2 include amitriptyline,

clozapine, and warfarin. Dose adjustment may be required when patients stop smoking to reduce the risk of adverse effects, particularly for drugs with a narrow therapeutic index.

While there is some variation between individuals, the median half-life of CYP 1A2 is around 39 hours. Therefore, normalisation of CYP1A2 activity can occur rapidly when patients stop smoking. If dose adjustment is required, it should be done within two to three days of smoking cessation. As many factors are involved, predicting the most appropriate dose adjustment can be challenging.

An interesting example of the potentially complex effects of smoking can be seen with clopidogrel. Clopidogrel is a prodrug that is converted to its active metabolite via oxidative metabolism involving several CYP450 enzymes. Smoking can increase this conversion, leading to a greater antiplatelet effect. Major randomised trials have found a substantial reduction in cardiovascular events in patients taking clopidogrel who smoke compared to non-smokers. This effect has been dubbed “the smoker’s paradox”. Other P2Y₁₂ antagonists, such as prasugrel and ticagrelor, have demonstrated more consistent antiplatelet effects within both smoking and non-smoking populations.

As this enzyme induction is mediated by compounds found in tobacco smoke and not the nicotine, these interactions typically do not occur with smokeless nicotine delivery methods (e.g. vapes, nicotine pouches). Patients switching from cigarettes to smokeless nicotine products may experience similar changes in drug levels as those who quit smoking entirely.

Pharmacodynamic interactions

Pharmacodynamic interactions from smoking may occur due to nicotine. Unlike the pharmacokinetic interactions, these effects can also occur from the use of smokeless nicotine products, including nicotine-replacement therapy.

These interactions are often related to the stimulant effects of nicotine. For example, smokers may require higher doses of benzodiazepines as nicotine can oppose their sedative effects. However, the clinical relevance of this is likely to be low.

Some further examples of interactions to consider when patients stop smoking are shown in Table 1.

Table 1. Drugs affected by smoking cessation

Drug	Effect of smoking cessation	Dose adjustment
Antipsychotics
Chlorpromazine	Increased serum levels	May need dose reduction
Clozapine	Serum levels rise significant	Major effect: ~50% dose reduction may be required
Olanzapine	Serum levels rise significant	Major effect: ~30% dose reduction may be required
Cardiovascular
Clopidogrel	Reduced efficacy	Prasugrel or ticagrelor may be better options – more consistent effects.
Warfarin	Serum levels increase by 15% on average	May require lower dose. Monitor INR
Beta blockers	Serum levels may increase	Dose reduction may be required
Other
Insulin	Increased subcutaneous absorption due to removal of nicotine’s vasoconstrictive effect	Dose reduction may be required. Insulin sensitivity may also slowly increase following smoking cessation.
Benzodiazepines	Increased sedation due to loss of stimulatory effect of nicotine	Minor effect: may require lower benzodiazepine dose
Methadone	Serum levels may rise	May need dose reduction
Theophylline	Serum levels may rise	May need dose reduction
Caffeine	Caffeine levels rise	Reduce caffeine intake

Relevance

While the benefits of smoking cessation cannot be overstated, its potential effects on an individual’s medication regime may need to be considered. This is true for patients who are intending to quit smoking for good as well as patients who may be obliged to temporarily abstain (e.g. during hospitalisation). It may also be relevant for patients who choose to transition from smoking to a smokeless form of nicotine.

Patients should be encouraged to discuss their smoking status and any intended changes to their smoking with their doctor. Dose modification may be considered for some prescribed therapies when there is a significant change in a patient’s smoking status.

The Therapeutic Goods Administration (TGA) has finalised its decision regarding the scheduling of vitamin B6. Vitamin B6 is a general term used to describe the compounds, pyridoxine, pyridoxal, and pyridoxamine, and their respective phosphate esters.

Table 1 shows the updates that will occur to the Poisons Standard for oral products containing vitamin B6. Products are classified according to the recommended daily dose (RDD).

Table 1. Scheduling changes for oral preparations of vitamin B6 for human therapeutic use

RDD	Existing status	Updated status
≤ 50mg	Unscheduled
50mg to ≤ 200mg	Unscheduled	Schedule 3
> 200mg	Schedule 4 – prescription only

A new Schedule 3 entry will be created for products containing 50-200mg of vitamin B6 per RDD. These products will no longer be available in supermarkets and health food stores and will require pharmacist consultation prior to purchase.

The implementation date for these changes has been set at 1 June 2027.

Reasons for Decision

Vitamin B6 is a water-soluble vitamin involved in over 100 enzymatic reactions, primarily those involved in protein metabolism. This vitamin is naturally present in a range of foods, is added to some foodstuffs, and is available in many supplements.

While vitamin B6 is water-soluble, it can accumulate in the body. Pyridoxine has a relatively long elimination half-life of around 15 to 30 days. This means that even small daily doses can accumulate over time, potentially leading to toxicity.

Signs and symptoms of vitamin B6 toxicity include paraesthesia, hyperaesthesia, weakness, atrophy, reduced reflexes, fasciculation, numbness, and pain. While both small and large-fibre neuropathies can occur, small-fibre dysfunction is thought to be the most common presentation. These are often more difficult to diagnose and may lead to underreporting.

As of October 2025, the TGA had received 250 reports of peripheral neuropathy, peripheral sensorimotor neuropathy, small fibre neuropathy, polyneuropathy or chronic polyneuropathy for products containing vitamin B6. An additional 162 reports of ‘Hypervitaminosis B6’ or ‘Vitamin B6 increased’ were received with less specific reaction terms that may be indicative of neuropathies (e.g. paraesthesia, burning sensation, etc.).

While it has been traditionally thought that nerve damage is only seen with chronic ingestion of high doses of vitamin B6, evidence suggests that toxicity is possible even at relatively low doses. Research findings also indicate significant inter-individual variation may exist in the metabolism of vitamin B6.

Where symptoms of excessive vitamin B6 occur, improvements are often achieved when supplementation is ceased or reduced. However, long-lasting or permanent nerve damage has been reported.

The TGA requires all vitamin B6-containing listed medications with a recommended daily dose exceeding 10 mg to include a paraesthesia warning.

Recommended intake for vitamin B6

The Australian recommended dietary intake (RDI) for vitamin B6 ranges from 0.1 mg/day for infants 0–6 months to 1.7 mg/day for men over 50 years, and as high as 1.9 mg/day during pregnancy and 2.0 mg/day during breastfeeding.

As vitamin B6 is found in a wide range of foods and has high bioavailability, deficiency is considered rare in Australia. Signs and symptoms of deficiency include seborrhoeic dermatitis, convulsions, microcytic anaemia, depression, and confusion. Populations that may be more likely to experience deficiency include the elderly, and those with alcohol dependence, malabsorption syndromes, or certain kidney, liver and autoimmune conditions. Some medications, such as isoniazid, penicillamine, and hydralazine, may also increase vitamin B6 requirements.

The upper level of intake (UL) can be defined as the highest average daily nutrient intake level likely to pose no adverse health effects for almost all individuals in the general population. Increasing intake above the UL increases the potential risk of adverse effects. In Australia, the UL for vitamin B6 (as pyridoxine) ranges from 15mg/day for young children up to 50mg/day in adults. However, it is worth noting that the European Food Safety Authority (EFSA) recently reduced its adult UL to 12.5mg/day. This decision was made following a review that found evidence that nerve damage may occur at lower doses than previously thought.

The Australian National Health and Medical Research Council (NHMRC) is reviewing the UL of vitamin B6. The TGA advises that the limits set in their final decision will be re-evaluated if the NHMRC implement any changes.

Products containing vitamin B6

Complementary products containing vitamin B6 include products with a range of marketed indications, including:

• Vitamin B6 or B-complex supplements;
• Multivitamin and mineral formulas;
• Mental function;
• Women’s health;
• Hair, skin and nails support;
• Weight-loss and sports performance;
• Muscle cramps;
• Migraine; and
• Gout.

Many products currently available over-the-counter exceed the UL for vitamin B6 when taken on their own as directed. It also may not be obvious from the front label that these products contain a significant amount of vitamin B6. The risk here is that people may unknowingly take multiple products containing vitamin B6, putting themselves at risk of high cumulative exposure and potential nerve damage.

The new scheduling for higher dose products (50mg to ≤ 200mg RDD) means that these medicines will no longer be available for self-selection. It is anticipated that the creation of this Schedule 3 listing will reduce the risk of individuals inadvertently taking high doses of vitamin B6. Consumers will receive advice from a healthcare professional rather than having to rely on reading and interpreting the fine print on labels themselves.

Uses for High Dose Vitamin B6

There is evidence to support the use of high doses of vitamin B6 for a limited number of indications, although these patients would be managed by a medical professional.

Isoniazid poisoning

Isoniazid induces a state of functional pyridoxine deficiency by at least two mechanisms:

1. Metabolites of isoniazid directly attach to and inactivate pyridoxine species.
2. Inhibition of pyridoxine phosphokinase, the enzyme responsible for activating pyridoxine to pyridoxal 5′ phosphate.

Pyridoxine supplementation (e.g. 25mg with each isoniazid dose) is regularly used with isoniazid therapy to reduce the risk of peripheral neuropathy. Higher pyridoxine doses are used in cases of isoniazid poisoning.

In acute isoniazid poisoning complicated by seizures or metabolic acidosis, up to 5g of pyridoxine may be given as a single dose. A repeat dose may be warranted if signs and symptoms do not resolve after 30 minutes. Intravenous administration is preferred in these cases. However, a parenteral formulation is not currently registered in Australia. If intravenous pyridoxine is not available or the supply is inadequate, the Therapeutic Guidelines advise that oral pyridoxine can be used. Care is required if administered orally with activated charcoal as this significantly reduces pyridoxine bioavailability.

Pyridoxine-dependent epilepsy

This is a rare condition that usually presents with seizures during infancy. These seizures can be controlled with large doses of pyridoxine, and this must be continued for life. The Therapeutic Guidelines recommend daily doses of 50 to 100mg. Doses may be doubled during acute febrile illness to prevent exacerbation of seizures.

Nausea and vomiting during pregnancy

The Therapeutic Guidelines provides advice on the use of pyridoxine to manage nausea and vomiting during pregnancy. For this purpose, pyridoxine may be administered as a 12.5mg dose in the morning and at midday, followed by a 25mg dose at night.

Summary

Vitamin B6 toxicity can cause neurological injury, particularly when intake occurs over long periods or where the daily dose exceeds 200 mg. However, peripheral neuropathy has been reported with daily doses under 50 mg.

Many supplements and complementary medicines contain sufficient vitamin B6 to cause toxicity when taken as directed. Many of these products are not marketed as a vitamin B6 supplement. Therefore, there is the real risk that consumers may unintentionally take more than one product with significant amounts of vitamin B6. This highlights the importance of specifically asking patients about their use of complementary medicines when taking a medication history.

The upcoming scheduling changes are intended to make it easier for consumers to recognise when a product contains vitamin B6. It will also reduce the risk of people accessing high amounts of vitamin B6 without consultation with a healthcare professional.

New guidelines have been published to support safe deprescribing. The University of Western Australia-led guidelines were developed by more than 70 experts and patient representatives. They integrate existing best-practice recommendations and general principles for safe deprescribing.

These guidelines are designed to translate research into practical steps for reducing or stopping inappropriate medicines in older adults.

Background:

Data suggests that medicine-related harm is responsible for at least 250,000 hospital admissions each year in Australia, with an annual cost of around $1.4 billion. Two-thirds of these admissions are potentially preventable.

The World Health Organization (WHO) Medication Without Harm initiatives highlight that unsafe medication practices and medication errors are a leading cause of injury and avoidable harm around the world. The Australian response aimed to reduce avoidable medication errors, adverse drug events and medication-related hospital admissions by 50% over the period to 2025. The three main areas focussed on in this response are:

• Monitoring polypharmacy and responding to inappropriate polypharmacy
• Reducing harm from high-risk medicines; and
• Improving medication safety at transitions of care.

Polypharmacy is a significant issue in Australia, particularly in older adults. The definition of polypharmacy used by Australian Commission on Safety and Quality in Health Care (the Commission) is five or more medicines taken at the same time. This includes prescription, over-the-counter and complementary medicines. The Commission reports that over 40% of people aged 50 years or older take five or more medicines, and over 10% take ten or more medicines.

Polypharmacy in older people is associated with an increased risk of:

• Hospitalisation;
• Functional impairment;
• Geriatric syndromes (e.g. confusion, falls, incontinence, and frailty); and
• Mortality.

While multiple medicines may be clinically indicated, ongoing assessment of a patient’s risk and benefit can identify medicines that are no longer appropriate.

Deprescribing

Deprescribing can improve health outcomes, reduce treatment burden, and enhance quality of life. However, the process can be challenging as many factors must be taken into consideration. This includes the patient’s overall health, quality of life, goals, preferences, affordability, pill burden, health literacy, and medication adherence.

The new clinical practice guideline aims to simplify the deprescribing process by bridging the gap between research and practice. The guideline provides clear and actionable recommendations and strategies to minimise potential risks. The guidelines are intended to be used by health professionals across various settings, including primary care, hospitals, and residential care. The focus is on people 65 years of age and older, with special considerations for Aboriginal and Torres Strait Islander peoples and other disproportionately affected groups.

The guidelines provide deprescribing advice for key drug classes. Some examples are shown below:

Urinary anticholinergics

Overactive bladder is a common condition affecting older adults which can significantly affect quality of life. Urinary anticholinergics can provide symptomatic relief. While their efficacy is often modest, this medication class is associated with significant adverse effects.

Anticholinergic effects include dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment. It is important to remember that these effects are additive, and many medications have anticholinergic properties, even if that is not their primary mechanism of action.

A high cumulative anticholinergic burden in older people is associated with an increased risk of falls, cognitive decline, and higher all-cause mortality.

Consideration of deprescribing is recommend in the following cases:

• Patients with cognitive impairment, delirium, dementia, or a high risk of falls. The risk of adverse cognitive outcomes and sedation may outweigh the benefits of ongoing use in these patients, particularly for those with a high anticholinergic burden;
• Where no clear indication exists or no identifiable benefit; or
• For drug-induced symptoms where the original drug can be suitably reduced, discontinued, or replaced by another drug.

A comprehensive medication review is also highly recommended for all older people receiving multiple medications with anticholinergic properties.

Proton pump inhibitors (PPIs):

While PPIs are effective for the management of many gastric conditions, they are often continued for prolonged periods without an appropriate indication. Underprescribing in people requiring gastroprotection has also been reported, particularly in older patients and those with polypharmacy.

As a class, PPIs are relatively safe when used in accordance with guideline recommendations. However, long-term use has been associated with many adverse effects ranging from nutritional deficiencies to infections and even gastric cancer. Therefore, the guidelines recommend considering deprescribing long-term PPIs when originally used for a short-term condition or where no clear indication exists for ongoing use.

Benzodiazepines

Sleep disturbances are common in older adults and may be compounded by comorbidities such as chronic pain and depression. Non-pharmacological strategies, along with interventions that address any contributing factors, are first-line options. However, sedatives are commonly prescribed and are often continued for longer than recommended.

Chronic use of benzodiazepines is associated with significant harms, including falls, cognitive impairment, and an increased risk of osteoporotic fractures.

The guidelines suggest deprescribing be considered in older people taking a benzodiazepine for more than four weeks for the treatment of insomnia. The risk of harm with long-term use is noted to generally outweigh any potential benefits (except special cases, such as palliative care). If ongoing treatment is considered appropriate, on-demand or intermittent use at the lowest effective dose is preferable.

The guidelines also provide guidance in withdrawal schedules. The evidence supports tapering the dose by 25% every one to four weeks, while monitoring for withdrawal symptoms and sleep quality. Slower tapering strategies may be appropriate for people at higher risk of withdrawal effects, e.g. patients with prolonged duration or high doses of benzodiazepines and those with a history of withdrawal difficulties.

General

The above examples offer targeted approaches to deprescribing specific drug classes. In addition to this, regular medication review is recommended for older people taking multiple long-term medicines. While there is a lack of direct evidence to quantify the benefits and potential harms associated with general deprescribing, consensus-based recommendations have been developed to guide the process.

The guidelines recommend considering deprescribing medicines that meet one of the following categories:

• No clear indication or an obvious contraindication exists, or if there is an inappropriate prescribing cascade;
• Adverse effects or interactions outweigh the potential benefits;
• Used for symptomatic relief, where the symptoms are resolved and unlikely to recur; or
• Used for prevention, when the potential benefits are uncertain or unlikely to be realised.

When medication review identifies a medicine as being suitable for deprescribing, an individualised deprescribing plan should be developed in collaboration with the patient and/or their carer, where appropriate.

Summary

Both prescribing and deprescribing should be collaborative processes involving healthcare professionals, patients, and their families or carers where appropriate. Deprescribing aims to optimise medication regimens by discontinuing unnecessary or harmful medicines and simplifying treatment plans. It acknowledges that a person’s physiology, preferences, and goals change over time.

The deprescribing process requires shared decision-making, agreed actions, clear communication, and ongoing monitoring for benefits and risks. Deprescribing may lead to drug discontinuation, dose reduction, or switching to a new medication that better aligns with the patient’s goals and evidence-based care. Dose tapering is often more acceptable to patients compared to abrupt cessation. Tapering also offers a practical way to determine the lowest effective dose where complete discontinuation is not possible or appropriate.

The new guidelines can be accessed here.

Background clinical information:

Iron deficiency (ID) is a broad term referring to low iron stores and is only classified as iron deficiency anaemia (IDA) when haemoglobin levels fall below certain cut-off values. The World Health Organization (WHO) has set these at 130 g/L in males, 120 g/L in non-pregnant females and 110g/L in pregnant females. (Al-Naseem, Sallam et al. 2021)

It is important to note that whilst iron deficiency anaemia is the most frequent presentation of iron deficiency, the two terms are neither synonymous nor interchangeable. Iron deficiency is a umbrella term referring to low iron stores that do not meet the body’s iron requirements, regardless of whether anaemia is present or not. (Al-Naseem, Sallam et al. 2021)

Importantly, the two conditions are diagnosed differently. Iron deficiency  is measured by a low ferritin, which is an intracellular iron storage protein responsible for ‘stock piling’ surplus iron once all cellular needs are met, and in presence of an acute demand, releases the stored iron.  (Kotla, Dutta et al. 2022).

In contrast, iron deficiency anaemia shows a low haemoglobin level.  (Patel 2025)  It is a more severe form of iron deficiency and sufferers can present with shortness of breath, syncope, and reduced exercise tolerance.

In clinical practice, when ferritin levels dip below 30 μg/L, an absolute iron deficiency exists. Aside from being an iron storage facility, ferritin is an acute-phase reactant that is increased in serum during chronic inflammation. Cut-off values for ferritin in iron deficiency  are increased to 100 μg/L in states of chronic inflammation. (Soppi 2018)

Generally, iron deficiency can be due to insufficient iron intake such as poor nutrition (Lucas and Garg 2024), decreased absorption, frequent blood donations, blood loss and chronic inflammation whilst iron deficiency anaemia is most often from blood loss, especially in older patients but is also seen in pregnancy, and in celiac disease. In short, iron deficiency anaemia is a late and more severe form of iron deficiency (Soppi 2018) (Al-Naseem, Sallam et al. 2021)

In Australia around 12 per cent of women, eight per cent of pre-school-aged children, and 20 per cent of people over 85 years are anaemic.

Treatment options:

Contemporary formulations of iron include ferric carboxymaltose (Ferinject®) and ferric derisomaltose (Monofer®). In these preparations, iron is bound within a large, complex carbohydrate shell which allows for a slow release of iron and permits large single doses to be given.

In contrast, the lack of popularity of iron sucrose (Venofer®) is due to the relative instability of the sucrose (carbohydrate) shell allowing only for a low infusion dose of 100mg. (Lucas and Garg 2024)

Dosing:

To replenish the iron stores the Ganzoni formula is used:

Total iron dose required (mg iron) = body weight (kg) X (target Hb – actual Hb- g/L) x 0.24 + 500mg (if ≥ 35kg).

NB: If the body weight is < 35kg, then add on 15mg/kg, not 500mg.

Iron sucrose (Venofer®) is TGA registered only as a single 100mg infusion due to its relative instability and is only for chronic haemodialysis patients receiving erythropoietin stimulating agents.

Ferinject® can be given as a rapid infusion of up to 1g of iron over 15 minutes and has a very low rate of infusion reaction of 0.2-1.7%, and anaphylaxis at < 1.0%. (Patel 2025) Monofer®, abbreviated to FDI (ferric derisomaltose) can be administered up to 1500mg over 30 minutes as a single infusion, hence it may only require one medical intervention. The incidence of adverse reactions for Monofer® is reported to be 0.54%.(Sivakumar, Jubb et al. 2019)

Benefits:

Ferinject®, abbreviated to FCM (ferric carboxymaltose), is profitably used in inflammatory bowel disease, upper gastrointestinal bleeding, chronic kidney disease (CKD), malignancy, perioperative bleed, perinatal iron deficiency anaemia and heavy uterine bleeding. It is superior to iron sucrose for improving Hb, ferritin, and transferrin saturation. The Hb rises by 20-30g/L inside eight weeks.  (Lyseng-Williamson and Keating 2009, Patel 2025). The dose can be given over 15 minutes for 1g. (Lucas and Garg 2024)

If a dose of Ferinject® greater then 1000mg is required, a seven-day interval is required. (Lucas and Garg 2024) (Patel, Thanvi et al. 2025).

Monofer® has a superior matrix structure which allows for higher single doses, hence causing a more rapid restoration of iron levels. 1g can be given over 20 minutes and 1500mg over 30 minutes as a single infusion. (Lucas and Garg 2024) The TGA has listed it as indicated when oral iron preparations are ineffective or cannot be used, or when there is a clinical need for the rapid delivery of iron. The diagnosis must be based on laboratory tests.

Irrespective of the form of IV iron chosen, substantial benefit has been shown in CKD, IBD and heart failure because elevated levels of hepcidin in these conditions prevent the beneficial absorption of oral iron. (Kaitha, Bashir et al. 2015, Gutiérrez 2021, Loncar, Obradovic et al. 2021)

Contraindications for Ferinject:

• Hypersensitivity to ferric carboxymaltose complex, to Ferinject or to any of its excipients
• Anaemia not attributed to iron deficiency, e.g. other microcytic anaemia
• Evidence of iron overload or disturbances in utilisation of iron.

Contraindications for Monofer:

• Hypersensitivity to the active substance, to Monofer or any of the excipients.
• Non-iron deficiency anaemia (e.g. haemolytic anaemia).
• Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis).

Safety:

Of the two commonly used formulations, hypersensitivity reactions (HSRs) have been reported by Mulder, van den Hoek et al. (2019) to be 75% lower for Ferinject  compared to Monofer (RR = 0.248, CI: 0.145-0.426, P < 0.0001). Irrespective of the IV iron used, the presence of comorbidities raised the risk of HSRs by a factor of 3.6.

Moderate to severe hypersensitivity reactions occur at a rate of 0.2-1.7%. Mild reactions include urticaria, itching, rash, nausea and tachycardia. A slower rate of infusion and an antihistamine and/or corticosteroid treatment may allow the infusion to occur. True anaphylaxis to the aforementioned 3 products is estimated from clinical trials to be < 1%.

The more stable the carbohydrate which binds the iron core, the less likely minor infusion reactions will occur. (Gómez-Ramírez, Shander et al. 2019)

Around 1 in 100 people have a Fishbane reaction with Monofer, which can cause a flushed feeling. This is not an allergic reaction.

Research shows that the risk of hypophosphatemia differs between the two formulations of iron with the risk with ferric carboxymaltose (FCM) ranging from 47-57% whilst for ferric derisomaltose (FDI) the range is 4-8%. (Boots and Quax 2022)

Skin staining from IV iron, known as extravasation, can be permanent. In clinical trials it occurred at a rate of 1.3% (Lucas and Garg 2024)

Given that both formulations demonstrate rapid increases in haemoglobin, serum ferritin, and transferrin saturation, a decision as to which to use will be based on whether a dose more than 1000mg is needed, any prior history of hypophosphatemia, and cost (if any) to the patient and/or the health institution, be it a GP practice or hospital.

Conclusions:

• Monofer® causes less hypophosphatemia than Ferinject® but has a higher of ADRs.
• A higher iron dose of Monofer® can be given compared to Ferinject® because Monofer® is a more stable carbohydrate-based iron-embedded molecule.
• Iron deficiency anaemia is the most severe presentation of iron deficiency, but the two terms are neither synonymous nor interchangeable.

The Australian Commission on Safety and Quality in Health Care (the Commission) has released four new resources to address gaps and inconsistencies in care coordination and post-sepsis support for survivors, families, and carers.

Sepsis is a life-threatening condition triggered by an abnormal and extreme response to infection. This complex clinical syndrome involves organ dysfunction as a result of this overwhelming, systemic inflammatory response. Patients can quickly progress to septic shock with profound circulatory and metabolic abnormalities. The mortality rate is high for both conditions, although it is particularly high for septic shock compared to sepsis.

The rapid initiation of appropriate antibiotic therapy, organ support and resuscitation reduces mortality. Therefore, early recognition of sepsis is key.

Australian data

Data from the 2025 National Sepsis Program Extension Epidemiology Report* demonstrates the impact of sepsis in Australia:

• Over 84,000 people hospitalised with sepsis in 2022–23.
• More than 12,000 of these cases resulted in death (around 1 in 7)
• Direct hospital cost estimated to be $700 million per year.
• Indirect costs thought to exceed $4 billion per year.

*This report only contains data from publicly funded admitted care.

National Sepsis Program

The new resources introduced by the Commission include:

• Model of Care Framework– outlines essential elements for effective sepsis care and follow-up support. The framework is intended to guide health services in the implementation of the Sepsis Clinical Care Standard. It focuses on providing high-value healthcare across all stages of the sepsis journey with an emphasis on transitions of care.
• Business case – supports investment in coordinated care and post-sepsis services.
• Coordination of care and post-sepsis support – interactive PDF – illustrates the Model of Care Framework to support local conversations about the sepsis patient journey and the opportunities for quality and safety improvements across transitions of care.
• Coordination of care and post-sepsis support – Supporting evidence and implementation ideas – offers practical steps for applying the framework in different healthcare settings.

These resources form part of the National Sepsis Program, a program designed to improve the awareness, recognition and support for people at risk of or diagnosed with sepsis in Australia.

Other key components of the program include:

1. Sepsis Clinical Care Standard

The goal of the Sepsis Clinical Care Standard is to ensure that any patient presenting with signs and symptoms of sepsis is recognised early and receives coordinated, best-practice care to reduce the risk of death or ongoing morbidity. It does this by providing national guidance on early recognition, treatment, outcomes, and post-discharge support.

2. Public Awareness Campaigns

Public awareness campaigns are run each year: Sepsis Awareness Month (September) and World Sepsis Day (13 September). These campaigns aim to increase community understanding of the signs of sepsis to promote early action.

3. Education and Resources

The Commission, in partnership with the George Institute for Global Health, Sepsis Australia and Medcast, has developed a free online education module for primary health professionals. This one-hour (CPD accredited) course supports health professionals in recognising and responding to sepsis and post-sepsis syndrome.

Challenges

While progress has been made in the management of sepsis, ongoing challenges include:

• Rates of readmission within 30 days remain high at around 22%.
• Health inequities persist
  • Aboriginal and Torres Strait Islander people experience double the sepsis hospitalisation rates of non-Indigenous Australians.
  • Patients living in rural settings and those at greater socio-economic disadvantage have a higher risk of readmission within 30 days.
• Rising costs (estimated average cost per sepsis separation increased by 50% in the 10 years to 2022-23).
• Access to coordinated and comprehensive follow-up care.

When looking at sepsis survivors, up to 50% experience post-sepsis syndrome (PSS). This is a complex condition with long-term physical, cognitive, and psychological impacts. Extreme fatigue, muscle and joint pain, and memory issues are common. Patients may also experience anxiety, depression, and symptoms of post-traumatic stress disorder. While the symptoms of PSS may be different for each patient, the condition often has a significant impact on quality of life.

Future Directions

Australian data shows that 28.7% of sepsis cases in admitted care occurred in patients with diabetes, 15.8% in patients with renal disease, and 13.4% in patients with cancer. Partnerships with chronic disease associations has been suggested to more efficiently deliver information to people at greatest risk.

Potential partners include Diabetes Australia, Kidney Health Australia, and Cancer Australia.

Other priorities include:

• Enhancing data collection and surveillance
• Expanding culturally safe care models
• Strengthening community-based follow-up care.

Summary:

Sepsis is a medical emergency requiring rapid recognition and treatment to minimise organ damage and prevent death. While mortality is significant, survivors often face long-term impacts from PSS.

The National Sepsis Program provides resources to improve care coordination and outcomes for patients and their families. Health services are encouraged to adopt the new resources and integrate the Sepsis Clinical Care Standard into practice to improve patient outcomes.

Further resources:  Sepsis in primary care online learning module.

Parkinson’s disease is a progressive disorder characterised by bradykinesia, resting tremor, rigidity, and postural instability. Dopaminergic medications, such as levodopa and dopamine agonists, are standard treatments for the motor symptoms of Parkinson’s disease.

Parkinson’s disease is associated with many complications. Dopamine dysregulation syndrome (DDS) is one such condition that can arise during the long-term treatment of Parkinson’s disease. This condition is characterised by an addictive pattern toward the use of dopaminergic medicines. Patients may take doses far in excess of what has been prescribed and beyond what is required to manage their motor symptoms.

This excessive use of dopaminergic medicines can lead to dyskinesias and psychiatric adverse effects, such as mania and psychosis. Withdrawal symptoms can also occur which may present with dysphoria and anxiety. However, even when severe drug-induced adverse effects occur, patients with DDS are typically unwilling to reduce their use of these medicines.

The pathogenesis of DDS is poorly understood. One theory is that it may be related to stimulation of the mesolimbic pathway, a central part of the brain’s reward system. In susceptible individuals, stimulation of this pathway by dopaminergic medications may lead to addictive disorders such as DDS.

Behavioural disturbances associated with DDS

Studies suggest that two thirds of patients with DDS have impulse control disorder (ICD). Common ICDs in Parkinson’s disease include pathological gambling, hypersexuality, compulsive shopping, and compulsive eating.

Punding is another behavioural disturbance often associated with DDS. Punding is a complex stereotyped behaviour typified by repetitive, non-goal-oriented activities. Examples could include compulsively assembling and disassembling objects or sorting and re-sorting collections. While people may be aware of the disruptive and unproductive nature of their behaviour, they often exhibit intense fascination with their activity and become frustrated if interrupted.

The prevalence of punding in patients with Parkinson’s disease has been reported to be between 1.4% and 14%. This wide range reflects the different populations used in various studies. The lower prevalence rate was reported in a large study of unselected Parkinson’s patients, while the higher rate was found in a study specifically looking at patients taking high doses of dopaminergic medicines. However, this behaviour is likely to be underreported due to a lack of awareness and a reluctance of patients to discuss the issue.

Risk factors

The most important risk factor for DDS appears to be chronic high doses of dopaminergic medications. Other potential risk factors were highlighted in a retrospective longitudinal study of patients with Parkinson’s disease. This study suggest the following factors may be associated with a higher risk of DDS:

• Younger age of Parkinson’s disease onset;
• A personal history of depression;
• A personal or family history of substance abuse;
• A positive family history of Parkinson’s disease in a first-degree relative; and
• Greater change in motor performance between ‘Off’ and ‘On’ states.

Contrary to some earlier studies which found a higher prevalence in males, this study did not find any gender differences in the prevalence of DDS.

A greater understanding of risk factors is important as this could be used to identify patients predisposed to developing this disorder. Preventative strategies, such as supervision of medication use, have been suggested as a means of preventing DDS in high-risk patients.

Treatment

Dopamine dysregulation syndrome can cause significant functional impairment. Therefore, early identification and appropriate management are important. However, this condition is difficult to treat and likely to recur.

Optimisation of dopaminergic therapy is recommended as the first step in the management of DDS, although any changes to dopaminergic therapy should be managed by a specialist. Possible strategies that could be considered include reducing the dose of dopaminergic medicine and optimising adjunct therapies. Adjuncts include monoamine oxidase (MAO) B inhibitors (e.g. rasagiline) and catechol-O‑methyltransferase (COMT) inhibitors (e.g. entacapone). However, optimisation of oral dopaminergic medicines has only been shown to resolve DDS in less than 10% of cases, and may be associated with worsening motor symptoms and features of withdrawal.

When optimisation of oral therapy fails, more advanced treatment options could be considered. In one study, long-lasting resolution of DDS was achieved by 80% of patients switched to duodenal levodopa infusion and 57% of patients undergoing deep brain stimulation. However, sample sizes were small, and further research is required in this area. Case studies suggest that aripiprazole could have a potential place in the management of DDS. Aripiprazole is a partial agonist at dopamine D₂ receptors and also exhibits agonist activity at serotonin 5HT_1A receptors and antagonist activity at serotonin 5HT_2A receptors. This partial D₂ agonist activity has been trialled in other substance abuse disorders with some success, although further studies are required.

The support of family or carers has been found to be a significant factor in achieving optimal outcomes for these patients. Monitoring of compliance with dopaminergic therapy by caregivers is associated with long-lasting remission of DDS. This may include delivering medications directly to the patient and ensuring the patient does not have any hidden medications or additional healthcare providers.

Summary

Dopamine dysregulation syndrome is a complex condition that can significantly affect quality of life for people with Parkinson’s disease. Unfortunately, the condition remains poorly understood, and there is limited evidence to guide effective management. Existing studies have often yielded inconsistent results. This is likely due to variations in follow-up duration, assessment tools, and study populations. Effective supervision and support from caregivers should be encouraged in both the prevention and management of DDS.

Correct use of medicine is a crucial factor in effective patient self-care and hence positive outcomes in any chronic disease. Different concepts have evolved from the notion of correct use of medicine, such as compliance, adherence and concordance.  Compliance is defined as “the extent to which the patient follows the health professionals’ advice and takes the treatment”. This concept is being replaced by the term ‘adherence’, as compliance may imply a submissive, uninvolved patient in a paternalistic setting. Adherence is defined as “…the extent to which a person’s behaviour – taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health-care provider”. Concordance is a new concept which has evolved and is defined as “agreement between the patient and healthcare professional, reached after negotiation that respects the beliefs and wishes of the patient in determining whether, when and how their medicine is taken, and (in which) the primacy of the patient’s decision (is recognized)”. For the purposes of this article, the term ‘adherence’ will be used to discuss contributing factors and influences in  medicine-taking behaviour, consequences of poor adherence, and strategies to improve  medicine adherence, thereby demonstrating the shift towards the concept of concordance.

The literature shows that adherence is a complicated notion, the culmination of the interaction of a variety of aspects such as the features of the condition, social background, access, and patient beliefs and characteristics. Factors that can influence adherence to medicines include gender, age, ethnicity, education, social support, marital status, mood impairment or cognition, number of prescribing doctors and visiting more than one pharmacy; and it has been found that patients with a higher income and lower medicine expenses tend to be more adherent. There are several reasons cited for patients not adhering such as simply forgetting to take the medicine, affordability, concern about safety or effectiveness, fear of or experiencing adverse effects, confusion over the directions, no longer feeling unwell or not feeling any different, feeling that they cannot manage with the number of medicines they should take and how to coordinate them, having dexterity challenges, or being simply too unwell.

Adherence to medicines is a variable aspect of treatment, as daily influences impact upon everyday choices, and chronic illnesses involve symptoms, exacerbations, and future impacts, each of which are frequently changing. In a study by Elliott et al (2007) the team concluded that continuing communication with patients about their medicines is necessary, and requires collaboration across disciplines for patients with chronic conditions. In order to positively guide patient decision-making regarding medicine use, health professionals need to be informed of the patients’ current as well as previous choices, as they may place importance on different issues from the prescribers; and with each newly introduced drug the new decisions made by the patient may not always be shared with the prescriber. Hence, when new medicines are initiated, good practice would indicate that a health professional is available to discuss medicines with patients.

Adherence is an important area to consider, as patients are generally poorly adherent to medicines, particularly in chronic disease states. Lack of adherence can lead to medicine wastage, morbidity and hospitalisation. Rates of adherence for a number of chronic medicine regimens have been found to be between 40-50%, and non-adherence is linked to more frequent doctor consultations, and increased rates or duration of hospitalisation. Medicine non-adherence is reported in the literature at a rate of approximately 50% in developed nations, with around half of this proportion being deliberate and the remainder due to ignorance of not taking medicine as they should or due to a complicated regimen. In a study by Lewis (1997), it was found that sickness due to non-adherence to medicines in the United States costs approximately US$100 billion per year. The National Audit Office reported that returned medicines in England for 2007 approximate to £100M annually. Noens et al (2009) found that significantly more chronic myeloid leukaemia patients (CML) with an unsatisfactory response had not taken their imatinib (23.2%) compared those who achieved peak response (7.3% imatinib not taken). In addition, the team found there were significantly fewer missed tablets (9%) in patients who demonstrated a complete cytogenic response, in comparison to the 26% with an incomplete cytogenic response, in a patient group who underwent treatment for a minimum of 12 months with imatinib.

The fact that a disease may possibly be life-threatening does not appear to increase medicine adherence, and findings indicate that adherence can decrease over time. A study by von Mehren and Widmer (2011) found that the population of patients who adhered to imatinib for CML and gastrointestinal stromal tumours decreased from almost 100% during the first four months of treatment to 23% at the 14^th month. It was also reported that nearly 30% of patients ceased their medicines for 30 or more days during year one of treatment in patients prescribed imatinib for CML or gastrointestinal stromal tumours. In another study conducted by Partridge et al (2003), it was shown that long-term adherence to tamoxifen reduced from 83% in the first year of treatment to 50% when the fourth year milestone was reached.

Encouraging open and equal discussion about medicines can facilitate a more beneficial discussion for both the health professional and the patient, leading to improved prescribing practices and better patient adherence. Many studies demonstrate the intervention of a pharmacist enhances medicine adherence rates. Carter et al (2005) report that support networks, the active participation of patients, and advocating self-care are significant contributors to positive treatment outcomes. Furthermore, patients report an enhanced quality of life when they are contented with the level of information regarding their medicines that is provided to them, and Cassileth et al (1980) similarly mention that patient mechanisms for managing can be derived from the information they provide.

Concordance refers to a consultative procedure where a collaborative approach between doctor and patient leads to prescribing. Pharmacists can have a role in facilitating this process, thereby alleviating the doctor to focus on diagnosis and formulating a treatment plan. The concordance approach can lead to a more empowered patient as their feelings have been discussed and respected, an open forum encouraged to discuss any ensuing treatment challenges, and hence there is a greater likelihood of the patient following the prescribed treatment and therefore commit to a more transparent decision-making process within which they have played a role. The philosophy is founded upon delivery of information and viewpoints on the part of the prescriber, and in valuing patient autonomy in reaching decisions rather than imposing directions upon them without further discussion.

Optimising patient outcomes from taking medicine is a multi-faceted concept which relies on the interplay of many ever-changing factors. Ultimately, medicine adherence is founded in an open and trusting relationship between the patient and members of the healthcare team, and the establishment of a positive rapport to foster a team approach involving the patient at the centre. In order to establish a sincere collaboration, then a mindfulness of, and pledge to respecting patient autonomy and exercising competent communication skills are required to facilitate the interaction. Greater success in achieving patient adherence may occur by eliciting patient opinions, truly listening to them and assisting them to rationalise difficulties in order to complete the decision-making process, compared to simply dictating how patients should proceed.