Knowledge Type: Clinical Articles

Around two thirds of Australian adults are living with overweight or obesity, and around a third are obese. Obesity presents a significant clinical challenge in the safe use of medicines.

Physiological changes associated with increased body mass can include:

• Altered cardiac output
• Increased adipose tissue
• Altered plasma protein binding
• Modified renal and hepatic function.

These physiological changes can all influence how drugs are absorbed, distributed, metabolised, and eliminated. Therefore, there is the potential for underdosing (which may lead to treatment failure) or overdosing (which may cause toxicity) if standard dosing strategies are used.

Pharmacokinetic changes in obesity:

• Absorption
  • Gastrointestinal transit time is typically accelerated, which can reduce the solubilisation and absorption of some orally administered drugs. However, absorption is not significantly affected for most oral drugs.
  • Absorption following subcutaneous, intramuscular, and transdermal administration may be less predictable. The increased amount of subcutaneous adipose tissue with its reduced blood flow could affect bioavailability.
  • Consideration of needle size is required to avoid administration errors for drugs administered intramuscularly. In some cases, standard needles may be too short and result in administration to the subcutaneous space.
• Distribution
  • Lipophilic drugs generally have a large volume of distribution as they readily distribute into adipose tissue. In patients with obesity, accumulation in adipose tissue may slow the elimination of the drug. This prolongs the drug half-life, increasing the risk of accumulation during chronic dosing. Examples of highly lipophilic drugs are phenytoin, diazepam, midazolam, propranolol, and verapamil.
  • Hydrophilic drugs are more likely to remain in the extracellular fluid, giving them a lower volume of distribution which more readily correlates with lean body mass. Examples of highly hydrophilic drugs are aminoglycosides, lithium, aciclovir, glycopeptides, beta-lactams, low-molecular-weight heparins
  • Plasma protein binding may be altered.
• Metabolism
  • Liver size and blood flow may increase, potentially enhancing the metabolism of some drugs.
  • Fatty liver disease may impair hepatic metabolism in some patients.
  • Some evidence suggests that glucuronidation reactions are significantly increased in obesity. Drugs metabolised via this pathway include paracetamol, some opioids (e.g. codeine, morphine), benzodiazepines (e.g. lorazepam, oxazepam, temazepam), and lamotrigine.
• Elimination
  • Kidney size and renal blood flow may increase which can enhance renal elimination of drugs. However, obesity is a risk factor for chronic kidney disease (CKD), which can lead to significantly reduced drug clearance.
  • Estimating renal function can be more challenging in obesity as standard equations can be inaccurate. The Cockcroft-Gault equation may overestimate clearance if total body weight is used; using adjusted body weight may improve accuracy.

Weight metrics

There are many weight metrics available, including:

• Total body weight (TBW): actual weight
  • Using TBW to dose drugs in patients who are obese makes the assumption that the pharmacokinetics of the drug are linearly scalable regardless of body weight. Relying on TBW may lead to significant overdosing.
• Ideal body weight (IBW): based on height
• Adjusted body weight (ABW): used when TBW significantly exceeds IBW
• Lean body weight (LBW): reflects metabolically active tissue.
  • This is often a useful metric to use when dosing drugs in obesity. Calculators are available in the Therapeutic Guidelines which simplifies the use of this metric.

The most appropriate metric will depend on the pharmacokinetic profile of the drug being dosed.

Medications that may require dose adjustments

1. Antimicrobials

• Vancomycin – dosed using TBW, requires therapeutic drug monitoring
• Aminoglycosides (e.g. gentamicin) – expert advice is recommended for dosing and monitoring of aminoglycosides in obesity. The volume of distribution is difficult to predict. Methods used to calculate doses include LBW, ABW, and dosing nomograms. Prompt plasma concentration monitoring is recommended as initial doses can vary significantly depending on the method used, particularly for patients at the higher end of the weight range.
• Beta-lactams – may require higher or more frequent dosing due to increased volume of distribution and clearance. For example, studies show that a 2g dose of cefazolin for surgical antibiotic prophylaxis is associated with a higher rate of postoperative infections in obese patients. The Therapeutic Guidelines now recommend a cefazolin dose of 3 g for surgical prophylaxis for patients who weigh more than 120 kg (with a GFR > 40 mL/min).
• Linezolid – standard dosing may be insufficient in obesity.

2. Anticoagulants

• Low molecular weight heparins (e.g. enoxaparin) – often dosed by TBW, but requires caution in obesity. Dose adjustment may be required for patients with a body weight > 150kg or a BMI > 40kg/m².
• Unfractionated heparin – weight-based dosing, but monitoring is essential.
• Direct oral anticoagulants (DOACs) – limited data in morbid obesity.

3. Sedatives and anaesthetics

• Propofol – induction dosing often based on LBW, maintenance may use TBW.
• Midazolam – increased volume of distribution; prolonged effects possible.
• Opioids – lipophilic; dose adjustment may be required to avoid accumulation.

4. Chemotherapy

• Historically underdosed due to toxicity concerns.
• Current evidence supports using TBW for most agents to avoid compromising efficacy.

5. Cardiovascular drugs

• Beta-blockers and calcium channel blockers – variable effects; lipophilic agents may accumulate.
• Digoxin – IBW may be used due to limited distribution into adipose tissue.

Medications that typically do not require dose adjustments

1. Medications with a wide therapeutic index

• This includes many penicillins as well as some cephalosporins. Standard dosing is often sufficient unless severe obesity is present.

2. Hydrophilic drugs with limited distribution

• Drugs that primarily remain in the plasma or extracellular fluid may not require dose adjustment. Ideal body weight may be used for these agents. An example would be atenolol.

3. Antidepressants

• Selective serotonin reuptake inhibitors (SSRIs) typically do not require dose adjustment, although clinical response should guide therapy.

Special considerations

Therapeutic drug monitoring (TDM) is important for drugs with a narrow therapeutic index, e.g. vancomycin, aminoglycosides. It is also important to remember that evidence is limited at extremes of body weight, i.e. BMI ≥ 40 kg/m². Individualised dosing and monitoring is essential.

Practical considerations:

• Identify drug characteristics (i.e. lipophilicity, therapeutic index)
• Choose appropriate weight scalar (e.g. TBW, IBW, etc.)
• Initiate therapy with recommended obesity-specific dosing, if available
• Monitor clinical response and drug levels where appropriate
• Adjust dose based on efficacy and toxicity.

Conclusion

Drug dosing in obese patients requires careful consideration as pharmacokinetics and pharmacodynamics may be altered. While some medications can be safely administered using standard dosing, others require individualised dosing to avoid toxicity or therapeutic failure. Evidence-based guidelines and therapeutic monitoring should be utilised to optimise outcomes.

As the prevalence of obesity continues to rise, refining dosing strategies for this population is an important aspect of safe and effective clinical care.

Patient safety is a shared responsibility across the healthcare team. Healthcare professionals often work within complex systems where high workloads, time pressures, communication challenges, and human factors can increase the risk of incidents. Incident reporting, including the reporting of near misses, is a cornerstone of clinical governance and continuous quality improvement. When used effectively, it supports learning, strengthens systems, and reduces the risk of patient harm.

What Is Incident Reporting?

The Australian Commission on Safety and Quality in Healthcare (the Commission) defines clinical incidents as “an event or circumstance that resulted, or could have resulted, in unintended or unnecessary harm to a patient or consumer; or a complaint, loss or damage.” Examples of clinical incidents include:

• Medication errors (prescribing, dispensing, administration, or monitoring);
• Patient falls or pressure injuries;
• Delays or failures in diagnosis or treatment;
• Documentation or handover errors;
• Procedural errors;
• Equipment or system failures; and
• Inappropriate treatment.

The most serious patient incidents are classified as sentinel events. Sentinel events are those that are completely avoidable and result in serious harm or death of a patient.

In Australian hospitals, incidents are reported through local electronic reporting systems and managed within organisational clinical governance frameworks. Incident reporting aligns with the National Safety and Quality Health Service (NSQHS) Standards, particularly the Clinical Governance, Medication Safety, Communicating for Safety, and Comprehensive Care standards.

Near Misses

A near miss is an incident that did not cause harm. This may be because it was identified and corrected in time, or because circumstances prevented harm. Examples of near misses include:

• A pharmacist identifying an incorrect dose before dispensing;
• A nurse detecting a mismatch between a medication order and the patient;
• A doctor identifying a prescribing error during chart review; and
• A clinician recognising incorrect equipment settings before use.

Near misses are just as important to report as incidents causing harm. The root cause of near misses and adverse clinical incidents are likely similar. Therefore, reporting near misses can identify vulnerabilities in systems and processes and provide an opportunity to improve safety before a patient is affected.

A further consideration for reporting near misses is that only a small proportion of incidents lead to adverse events. Therefore, only reporting events that led to serious outcomes provides insufficient data for analysis.

The Commission encourages the reporting of near misses, emphasising that they should be viewed as opportunities for improvement.

Why Reporting Matters

Reporting incidents and near misses is important to:

• Improve patient safety and care quality.
  • Incident and near miss reports allow organisations to identify patterns, trends, and high‑risk areas. This information supports system-level improvements, e.g. changes to policies, workflows, or electronic systems, and the implementation of education programs.
• Support a just and learning culture.
  • Australian healthcare organisations promote a just culture, where staff are encouraged to report incidents without fear of blame or punishment. The focus is on understanding what went wrong and why, rather than who was involved.
• Facilitate learning across disciplines.
  • Many incidents involve multiple points in the care pathway. Reporting enables shared learning across medical, nursing, pharmacy and other allied health teams.
• Meet professional and regulatory expectations.
  • All healthcare professionals have ethical and professional obligations to promote patient safety.
  • Incident reporting supports compliance with NSQHS Standards and organisational risk management processes.

Common Barriers to Reporting

Underreporting of clinical events remains a problem, particularly for near misses. One study found that only 13% of medication events are reported.

Barriers to reporting may include:

• Fear of blame, disciplinary action, or reputational impact;
• Time pressures and competing clinical priorities;
• Belief that the incident was minor;
• Uncertainty about what should be reported; and
• Lack of feedback on submitted reports.

In one Australian study, lack of feedback was the most commonly stated barrier for reporting (57.7% for doctors and 61.8% for nurses). Providing feedback to healthcare professionals in the form of newsletters and discussions at departmental meetings has been found to increase reporting rates. Timely and meaningful feedback should also be provided to patients and carers, as appropriate.

Responsibilities

Frontline clinicians have a number of important roles and responsibilities in incident management, including:

1. Recognising reportable events

• All clinicians should report
  • Incidents that resulted in patient harm;

• • Near misses with the potential for harm;
  • Recurrent unsafe conditions or system issues; and
  • Errors intercepted at any stage of care.

2. Contributing to high-quality reports

• Effective incident reports should be:
  • Objective and factual – describe what happened, while avoiding assumptions or judgments;

• • Clear and specific – include relevant details such as timing, location, and contributing factors; and
  • Timely – submitted as soon as practicable after the event.
• Reports should focus on system factors (e.g. communication gaps, workload, design of charts or electronic systems) rather than individual performance.

3. Escalating Immediate Risks

• If an incident presents an ongoing or immediate risk to patient safety, concerns should be promptly escalated through clinical and managerial pathways, in addition to completing an incident report.

 

4. Learning from near misses

• Near misses are powerful learning tools as they can reveal system weaknesses without patient harm.
• Learning from near misses involves:
  • Reviewing reports to identify recurring themes or trends;

• • Analysing contributing factors such as interruptions, unclear documentation, or handover issues;
  • Implementing targeted improvements (e.g. standardised processes, decision support, double-checks); and
  • Sharing lessons learned with clinical teams to prevent recurrence.
• Feedback to staff about changes resulting from these reviews is critical. When clinicians can see that reporting leads to real improvements, engagement and reporting rates increase.

5. Building a strong reporting culture

• Clinicians can contribute to a strong reporting culture by supporting colleagues, discussing safety concerns openly, and reinforcing the fact that reporting is a professional responsibility and a positive action.
• Healthcare organisations and leaders can also support effective incident reporting by:
  • Promoting psychological safety and a just culture;
  • Providing education on incident and near miss reporting;
  • Ensuring reporting systems are easy to access and use;
  • Communicating outcomes and improvements arising from reports; and
  • Encouraging multidisciplinary review and learning.

Conclusion

Incident reporting and learning from near misses are essential to the provision of safe, high‑quality care. Nurses, doctors, and pharmacists each bring unique perspectives to identifying risks and improving systems. By reporting incidents and near misses, clinicians contribute to shared learning, stronger systems, and better outcomes for patients.

Every incident report, regardless of harm, has the potential to prevent future incidents and improve care.

Further information on incident management, including specific resources published by states and territories, are available from the Commission.

 

The product information for pegylated liposomal doxorubicin (Caelyx®) has been updated. The adverse effects section now includes advice that renal-limited thrombotic microangiopathy (TMA) has been reported in association with high cumulative exposure.

Pegylated liposomal doxorubicin (PLD) is a specialised formulation of the anthracycline chemotherapeutic, doxorubicin. Encapsulation of doxorubicin in polyethylene-glycol (PEG)-coated liposomes prolongs its circulation time, enhances tumour targeting, and may reduce key toxicities such as cardiotoxicity and myelosuppression. These properties have made PLD a valuable option in the treatment of a range of malignancies, including Kaposi sarcoma, ovarian cancer, and breast cancer.

While pegylation reduces some toxicities, this formulation is associated with higher rates of palmar-plantar erythrodysesthesia. More recently, rare reports have emerged of renal-limited TMA.

What is renal-limited thrombotic microangiopathy?

Thrombotic microangiopathy refers to a group of conditions characterised by:

• Endothelial injury in microvessels;
• Microvascular thrombosis; and
• Organ dysfunction.

The condition is often drug-induced, although other causes include autoimmune diseases, malignant hypertension, and infections.

When TMA affects the kidneys without systemic haemolysis or thrombocytopaenia, it is classified as renal-limited TMA. While not a common finding, renal-limited TMA has a poor prognosis. One recent study demonstrated that 30% of these patients will progress to end-stage kidney disease.

Case reports

Renal‑limited TMA has previously been reported in association with PLD, although many early cases involved patients also taking other medications known to cause TMA. More recently, the American Journal of Kidney Diseases published a case report of two patients who developed this condition in association with PLD without exposure to other TMA-causing drugs.

Case details include:

• High cumulative PLD doses (760mg/m² and 1240mg/m²)
• Proteinuria and rising serum creatinine
• Kidney biopsy consistent with chronic TMA
• No exposure to other drugs known to cause TMA
• Stabilisation or improvement occurred once PLD was ceased. Neither patient required dialysis.

Additional clinical reports:

• Renal-limited TMA was reported in an 80-year old man after extended PLD monotherapy for metastatic Kaposi sarcoma. Acute kidney injury resulted and the patient required haemodialysis. The patient’s clinical history, laboratory, and kidney biopsy data all support PLD as the primary aetiologic factor.
• A case was reported in a kidney transplant recipient with Kaposi sarcoma in remission following treatment with PLD. This patient developed a slowly progressive renal-limited TMA that was proven on biopsy. Kidney function improved following discontinuation of PLD. The patient presented with Kaposi sarcoma recurrence and, due to poor tolerance to alternative therapies, was restarted on PLD. Kidney function started to deteriorate again three months after resuming PLD therapy.

Across case reports, high cumulative PLD exposure (often >700-800mg/m²) is a common factor. However, one report occurred at a lower cumulative dose (~300mg/m²) in a patient with preexisting chronic kidney disease (CKD) and hypertension. This highlights the potential for patient-specific susceptibilities.

Clinical features

Renal-limited TMA linked to PLD tends to present with:

• Gradual rise in serum creatinine;
• Proteinuria;
• Hypertension; and
• Little or no evidence of systemic haemolysis or thrombocytopaenia.

The mechanism for how PLD may cause this condition is not understood. However, processes implicated in other drug-induced cases of TMA include:

• Endothelial cell injury due to oxidative stress;
• Platelet aggregation triggered by damaged microvascular endothelium; and
• Impaired microcirculatory blood flow in glomeruli.

Management and monitoring

Early recognition is critical to minimise renal impairment. Increases in creatinine, new proteinuria or hypertension in patients on PLD may warrant evaluation for renal-limited TMA. Renal biopsy is required for definitive diagnosis.

Management of renal-limited TMA includes removal of the causative agent along with supportive care. Cessation of the causative agent often stabilises or improves kidney function if implemented early.

A wide range of medications have been associated with drug‑induced TMA, with chemotherapeutics and quinine most commonly implicated. However, establishing causal relationships with drugs is challenging and the condition is thought to be under-recognised. Some medications linked with TMA are shown in Table 1.

Table 1. Drugs associated with TMA (adapted from Mazzierli 2023)

Chemotherapeutic drugs	Targeted cancer drugs	Immunosuppressants	Antimicrobials	Other drugs
Docetaxel	Alemtuzumab	Certolizumab pegol	Levofloxacin	Valproic acid
Gemcitabine	Imatinib	Cyclosporin	Ciprofloxacin	Quetiapine
Mitomycin C	Lenvatinib	Tacrolimus	Metronidazole	Quinine
Oxaliplatin	Nintedanib	Interferon	Penicillins	Cocaine
Pentostatin	Palbociclib	Leflunomide	Rifampicin	Oxycodone hydrochloride SR (drug misuse)*
Vincristine	Regorafenib	Sirolimus	Trimethoprim-sulfamethoxazole	Clopidogrel
Lomustine	Sunitinib	Everolimus	Famciclovir	Bupropion
Bortezomib	Bevacizumab	Adalimumab	Valaciclovir	Estrogen/ Progesterone
Carfilzomib	Ramucirumab			Hydroxychloroquine
Ixazomib	Pazopanib			Simvastatin
Daunorubicin
Tamoxifen
Trastuzumab

*Cases of TMA secondary to the intravenous use of the sustained-release product intended for oral use. This is suspected to be related to the polyethylene oxide coating on these tablets which may be directly toxic to endothelial cells. Other excipients may also play a role.    

Conclusion

Pegylated liposomal doxorubicin has some potential advantages over conventional doxorubicin in terms of reduced cardiotoxicity and enhanced pharmacokinetics. However, it may be associated with renal-limited TMA. While this adverse event is rare, the clinical outcome is often poor.

Awareness of this association, along with active monitoring of renal function and early investigation of kidney injury are vital. These steps can prevent irreversible kidney damage and preserve renal function in affected patients.

Infusion reactions are unexpected adverse responses that occur during or shortly after the infusion of a medication. These reactions can be allergic or non-allergic and may affect any organ system. Many reactions are mild, but severe and even life-threatening reactions can occur. Therefore, early recognition and prompt intervention is essential.

There is a wide spectrum of signs and symptoms associated with infusion reactions, including:

• Flushing;
• Itching;
• Urticaria;
• Fever or chills;
• Dyspnoea or chest tightness;
• Hypotension or hypertension;
• Back or abdominal pain; and
• Gastrointestinal effects (e.g. nausea, vomiting).

Infusion reactions can have a significant impact on patients and the healthcare system. They may necessitate prolonged infusion times, dose reductions or delays, discontinuation of therapy, or hospitalisation.

The onset and severity of these reactions can also differ widely which impacts their management:

• Mild to moderate infusion reactions
  • Often non-allergic and related to cytokine release.
  • Typical features include flushing, mild dyspnoea, fever, pruritus
• Severe infusion reactions
  • May involve airway compromise
  • Typical features include bronchospasm, angioedema, severe hypotension.
• Delayed reactions
  • May occur hours to days after administration. These reactions are less common and may present with symptoms such as fever, fatigue, joint pain, and muscle aches.
  • Drugs associated with delayed infusion reactions include monoclonal antibodies, parenteral iron, and enzyme replacement therapies.

Clinically, it is often difficult to distinguish allergic from non‑allergic infusion reactions. Anaphylaxis is the most severe presentation of an allergic reaction. This is characterised by rapidly developing and life-threatening problems affecting the airway, breathing and circulation which is often accompanied by skin or mucosal changes. This is a medical emergency requiring prompt intervention.

Anaphylactoid reactions mimic the signs and symptoms of anaphylaxis. However, these reactions are not IgE-mediated and can occur upon first exposure to an agent. The immediate management of these two conditions is the same.

Risk factors

Infusion reactions can occur with a wide range of medicines. Drug classes that are more commonly implicated include:

• Monoclonal antibodies;
• Taxanes;
• Platinum-based chemotherapy;
• Pegylated liposomal doxorubicin; and
• Asparaginase.

Non-allergic infusion reactions are typically more likely to occur with the first or second exposure to a drug. The rate of infusion is a significant factor, and concomitant medications may also have an impact. The formulation may be important to consider as some excipients may contribute to these reactions (e.g. polysorbate 80).

Infusion reactions can occur with subcutaneous administration, although the incidence is much lower than intravenous. When a medication is administered subcutaneously, serum levels rise more slowly than when the same medication is administered intravenously. This results in later and lower peak serum concentrations (C_max). It is thought that a faster and higher C_max is associated with a more rapid release of cytokines. Therefore, subcutaneous administration may reduce the risk of cytokine-mediated reactions. However, this is often at the expense of an increase in local injection site reactions.

Monoclonal antibodies

Many monoclonal antibodies are associated with infusion reactions. Studies suggest that the origin of the drug (i.e. human, chimeric, or mouse) does not correlate with the risk of reaction. This supports the understanding that most of these reactions are caused by cytokine release, rather than an IgE-mediated allergy. However, anaphylaxis has also been reported with monoclonal antibodies.

Rituximab is known to have a particularly high incidence of infusion reactions. In clinical trials of lymphoma patients, the incidence was as high as 77% for the first infusion, reducing to 30% for the fourth infusion. Most of these reactions could be classified as mild to moderate, with severe reactions reported in around 10% of patients. The incidence of infusion reactions when rituximab is used for non-cancer indications appears to be significantly lower.

These reactions are typically non-allergic and can be reduced with premedication and adherence to a slower infusion rate for the first dose (refer to the product information and/or clinical guidelines for recommendations). Particular care is required in patients with a high tumour burden or a high number of circulating malignant cells as they may be at greater risk of severe infusion reactions.

Platinum agents

Carboplatin, cisplatin, and oxaliplatin are all associated with infusion reactions. In most cases these reactions are IgE-mediated, and their incidence tends to increase with each treatment cycle. For oxaliplatin, cycles 9-10 are reported to be the average time of infusion reactions to first occur. For carboplatin, they tend to occur around cycle 5-6.

Vancomycin

Rapid administration of vancomycin can cause non-allergic infusion reactions. Symptoms can include hypotension, flushing, erythema, urticaria, pruritus, and pain or muscle spasms of the chest and back. Recovery is typically rapid with discontinuation of the infusion. Other potential causes of the reaction (e.g. anaphylaxis) must be ruled out.

Depending on the severity of the reaction, it may be appropriate to restart the infusion at a lower rate once the symptoms have resolved. In these cases, the patients should be closely monitored in case of further reaction.

Response

Infusion reactions should be managed according to local policies. The following is a general overview of how a reaction may be managed, although strategies may differ for specific drugs.

1. Stop the infusion
2. Assess the patient
   • Check airway, breathing, circulation, vital signs, and symptom severity
3. Maintain IV access
4. Notify the prescriber
   • Drug, dose, and timing
   • Symptoms and vital signs
   • Any interventions already performed
5. Administer emergency medication as ordered. Depending on the severity, this may include
   • Antihistamines
   • Corticosteroids
   • Bronchodilators
   • Adrenaline for anaphylaxis
6. Supportive care as appropriate
   • g. oxygen, fluids, continuous monitoring
7. Document
   • Comprehensively document details of reaction, including onset, symptoms, interventions, patient response.
   • Thorough documentation can help to distinguish between allergic and non-allergic reactions. E.g. anaphylactic reactions typically occur within the first few minutes of the infusion, while reactions related to cytokine release usually begin within 30-120 minutes of beginning the infusion.
8. Prepare for rechallenge (if appropriate)
   • Some therapies may be restarted at a slower rate once symptoms resolve, depending on prescriber directions and local policy.
   • Patients who experience mild to moderate infusion reactions are more likely to tolerate re-challenge (with a slower infusion rate and appropriate premedication) compared to patients who experience severe reactions.

Immediate escalation is required for patients who show any of the following signs or symptoms:

• Airway compromise
• Respiratory distress
• Hypotension
• Altered consciousness
• Rapidly progressing symptoms.

The presence of these symptoms may indicate anaphylaxis or a severe reaction requiring an emergency response.

Prevention strategies

There are many strategies to reduce the risk of infusion-related reactions.

Pre-medication protocols

Many high-risk drugs have pre-medication protocols to reduce the risk of reactions. These protocols may include the administration of an antihistamine, steroid, and/or antipyretic prior to the infusion.

Slow initial infusion rates

Gradual titration reduces the risk of cytokine-mediated reactions. For some medications, a reduced dose may also be recommended for the first infusion.

Close monitoring

Close monitoring is particularly important during the first 15-30 minutes of the infusion and during dose escalations.

Patient education

Encourage patients to report early symptoms such as itching, throat tightness, or dizziness. Patients should also be educated on the potential for delayed reactions following discharge and should understand what symptoms require prompt reporting to their healthcare professional.

Conclusion

Infusion reactions are unpredictable but can be managed with careful observation, rapid assessment and prompt intervention. Adherence to the recommended infusion rate and any premedication requirements may minimise patient risk. Recognising early symptoms and following clear escalation pathways further improves patient safety. Comprehensive documentation may also assist in differentiating non-allergic reactions from true allergies. This may avoid the inappropriate discontinuation of first-line therapies.

The decision to restart an infusion will depend upon the nature of the infusion reaction. In the case of mild and moderate infusion reactions, rechallenge can often be considered. Factors that will influence this decision include the drug in question, the type of reaction, treatment goals, and the preferences of the patient and prescriber. If rechallenge is attempted, premedication and a reduced infusion rate may be implemented.

While most infusion-related reactions are mild to moderate, severe reactions can occur. It is important that healthcare professionals recognise these reactions and act quickly to ensure optimal outcomes.

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.