Potentially Inappropriate Medicines in the Australian Setting

A list of potentially inappropriate medicines (PIMs) specific to the Australian setting has recently been published. Potentially inappropriate medicines can be defined as medications with risks that may outweigh their benefits in older adults. This includes medicines with a high risk of severe adverse effects and drug interactions, as well as an increased risk of falls.

The use of PIMs in older people should be avoided unless there is a clear therapeutic need and an absence of effective and lower-risk alternatives. Avoiding PIMs is an important part of the quality use of medicines, as demonstrated by the 2020 report Medicine Safety: Aged Care. This report showed that the use of PIMs is common, with over half of all people living in aged care facilities prescribed a PIM. Furthermore, one in five unplanned hospital admissions among this population is a result of taking a PIM. Admissions related to PIMs include falls, heart failure, confusion, constipation, and gastrointestinal bleeds. Studies suggest that PIMs also cause up to 39% of all cases of delirium.

Older patients may be more susceptible to medication-related harm due to physiological changes associated with the ageing process. A medicine’s pharmacokinetic and pharmacodynamic properties can be affected by changes in body composition and reductions in renal and hepatic function. Furthermore, older patients are more likely to have multiple comorbidities and polypharmacy, thereby increasing the risk of drug interactions.

The newly published list of Australian-specific PIMs is significant for two reasons. Firstly, it may be more relevant than international lists due to differences in medication availability and clinical practice guidelines in Australia. Secondly, this new list also includes recommendations for potentially safer alternatives.

Table 1 contains the medicines and medicine classes that achieved consensus agreement for inclusion in the Australian list of PIMs.

Table 1. PIMs and possible alternatives (adapted from Wang et al. 2024)

PIM or medicine class Avoid these drugs in older people Avoid this medicine or medicine class in older people with these conditions Alternatives that may be considered
Alpha-adrenoreceptor antagonists (prazosin) Prazosin
  • Risk of hypotension
  • Taking other antihypertensive
  • Frailty
  • Risk of falls
  • Initial dose adverse effects
  • ACE inhibitors
  • Sartans
  • Calcium channel blockers
  • Silodosin
  • Tamsulosin
Antiemetics – dopamine antagonist Chlorpromazine

Prochlorperazine

  • Parkinson disease
  • Polypharmacy
  • Lewy body dementia
  • Neurodegenerative diseases
  • Frailty
  • High risk of falls
  • Ondansetron
  • Domperidone
Antihypertensives, centrally acting (methyldopa, clonidine and moxonidine) Methyldopa
  • Risk of hypotension
  • Risk of falls
  • Taking other antihypertensive
  • Frailty
  • ACE inhibitors
  • Sartans
  • Thiazide diuretics
Antipsychotics (haloperidol, zuclopenthixol, trifluoperazine, thioridazine, periciazine and flupenthixol) Haloperidol

Zuclopenthixol

Trifluoperazine

Thioridazine

Periciazine

Flupenthixol

  • Risk of extrapyramidal reactions
  • Taking anticholinergic medications
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Cognitive impairment
  • Cardiovascular diseases
  • Cerebrovascular diseases
  • Risk of falls
  • Atypical antipsychotics (e.g. quetiapine)
  • Risperidone
  • Non-pharmacological strategies (e.g. yoga)
Antipsychotics (olanzapine, quetiapine, amisulpride, ziprasidone, lurasidone, risperidone, aripiprazole and paliperidone) Olanzapine
  • Cardiometabolic syndrome
  • Risk of falls
  • Polypharmacy
  • When a non-pharmacological option has not been adequately tried
  • Neurodegenerative diseases
  • Long-term use
  • Quetiapine
  • Risperidone
Benzodiazepine, long-acting (clobazam, clonazepam, diazepam, flunitrazepam and nitrazepam) Clonazepam

Flunitrazepam

  • Dependence
  • Other medications with sedative properties
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Cognitive impairment
  • Poor renal function
  • Long-term use
  • Risk of falls
  • Short-acting benzodiazepine
  • Melatonin (for indication of sleep)
  • Non-pharmacological strategies

 

Benzodiazepines, medium-acting (bromazepam and lorazepam) Bromazepam

Lorazepam

  • Falls
  • With other sedating medications
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Cognitive impairment
Benzodiazepines, short-acting (alprazolam, oxazepam and temazepam) Alprazolam
  • Falls
  • With other sedating medications
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Dependency
  • Renal impairment
  • Long-term use
  • Oxazepam
  • Temazepam
  • Melatonin (for indication of sleep)
  • Non-pharmacological strategies
Genito-urinary anticholinergics (oxybutynin, propantheline, tolterodine and solifenacin) Oxybutynin
  • With other anticholinergics
  • Frailty
  • Polypharmacy
  • Risk of falls
  • Neurodegenerative diseases
  • Constipation
  • Cognitive impairment
N/A
Non-selective NSAIDs, (indomethacin, diclofenac, ketorolac, piroxicam, meloxicam, ibuprofen, naproxen, ketoprofen and mefenamic acid) Diclofenac

Indomethacin

Ibuprofen

Ketoprofen

Piroxicam

Meloxicam

Ketorolac

  • History of gastrointestinal bleeding
  • ↑ bleeding risks
  • Frailty
  • Poor renal function
  • Peptic ulcer disease
  • Multimorbidity
  • Chronic kidney disease
  • Heart failure
  • Cardiovascular diseases
Paracetamol
Selective NSAIDs (celecoxib and etoricoxib) N/A
  • History of gastrointestinal bleeding
  • ↑ bleeding risks
  • Frailty
  • Poor renal function
  • Heart failure
  • Cardiovascular disease
  • Chronic kidney disease
  • Long-term use
  • Taking ACE inhibitors or diuretics
  • Paracetamol
  • Celecoxib
Opioids (morphine, pethidine, fentanyl, dextropropoxyphene, hydromorphone, buprenorphine, oxycodone and codeine) Pethidine

Fentanyl

Codeine

Hydromorphone

Dextropropoxyphene

  • Polypharmacy
  • Risk of falls
  • Frailty
  • Poor renal function
  • Neurodegenerative diseases
  • Constipation
  • Opioid dependency
  • Long-term use
  • Impaired cognition
  • Chronic pain
  • Physiotherapy
  • Paracetamol
  • Oxycodone
  • Buprenorphine
Oral anticoagulants – direct thrombin inhibitors (dabigatran) Dabigatran
  • ↑ bleeding risk
  • Multimorbidity
  • Peptic ulcer disease
  • Frailty
  • Risk of falls
  • Poor blood pressure control
  • Chronic kidney disease
  • Poor renal function
N/A
Oral anticoagulants – Factor Xa inhibitors (apixaban and rivaroxaban) Rivaroxaban
  • Peptic ulcer disease
  • ↑ bleeding risk
  • Risk of falls
  • Multimorbidity
  • Polypharmacy
  • Poor renal function
  • Chronic kidney disease
N/A
Sedating antihistamines Promethazine
  • Taking other sedating medications
  • Cognitive impairment
  • Taking anticholinergics
  • Frailty
  • Neurodegenerative diseases
  • Risk of falls
  • Polypharmacy
Non-sedating antihistamines (e.g. fexofenadine)
Sulfonylureas Glibenclamide

Glimepiride

  • With other glucose-lowering medications
  • High risk of falls
  • Frailty
  • Chronic kidney diseases
  • Polypharmacy
  • Multimorbidity
  • Renal impairment
  • Irregular diet
  • Dehydration
  • Metformin
  • Gliclazide
  • DPP-4 inhibitors (sitagliptin, saxagliptin)
  • SGLT2 inhibitor (dapagliflozin)
Tramadol N/A
  • Multimorbidity
  • Frailty
  • Neurodegenerative diseases
  • Risk of falls
  • Polypharmacy
  • Poor renal function
  • Cognitive impairment
  • Long-term use
  • Taking antidepressant medications
  • Epilepsy
  • Risk of seizures
  • Paracetamol
  • NSAIDs
Tricyclic antidepressants Doxepin

Dosulepin (dothiepin)

  • With other anticholinergics
  • Frailty
  • Polypharmacy
  • Risk of falls
  • Neurodegenerative diseases (e.g. delirium)
  • Constipation
  • Cognitive impairment
  • With other sedating medications
  • Risk of postural hypotension
  • Benign prostatic hyperplasia
  • SSRIs (e.g. citalopram, paroxetine)
  • SNRIs (e.g. duloxetine)
  • Mirtazapine
Zolpidem and zopiclone N/A
  • Dependency
  • Taking other sedating medications
  • Frailty
  • Neurodegenerative diseases
  • Risk of falls
  • Polypharmacy
  • Cognitive impairment
  • Long-term use
  • Melatonin
  • Nonpharmacological strategies (e.g. sleep hygiene)

Abbreviations: ACE, angiotensin converting enzyme; DPP4 inhibitor, dipeptidyl peptidase-4; SSRI, selective serotonin reuptake inhibitor; SNRIs, serotonin and noradrenaline reuptake inhibitors; NSAID, non-steroidal anti-inflammatory drug; SGLT2, sodium-glucose transport protein 2

This list of PIMs was obtained by consensus agreement of 33 experts with specialties across 15 areas. One limitation of the study is that participants were not asked to provide sources of evidence to support their recommendations. Therefore, it is possible that the recommendations reflect clinical practice rather than current scientific evidence. Other factors not considered include medication dosage, frequency, and route of administration. It is also worth highlighting that the medications suggested as potentially safer alternatives may not have the same level of evidence to support their efficacy for all indications. For example, paracetamol is suggested as an alternative to opioids and NSAIDs, although paracetamol may not be an effective alternative in all clinical scenarios.

The harm related to PIMs contributes to loss of independence and poorer quality of life for older adults. It is also responsible for a significant amount of healthcare resource utilisation. Lists of PIMs may be useful as decision-support tools when assessing the appropriateness of a medication for an older person. However, they do not replace clinical judgment in individual cases. In some cases, a PIM may be the most appropriate option for an older individual after accounting for allergies, drug interactions, and other medical conditions. Wherever a PIM is used in an older patient, regular medication review is vital to ensure the benefit continues to outweigh the potential risks.

Intranasal Corticosteroids in Allergic Rhinitis

Rhinitis is an inflammation of the lining of the nose, causing congestion, rhinorrhoea, sneezing and itching. It is classified as allergic (hay fever) or non-allergic (including drug-induced, irritant, occupational) rhinitis.

Allergic rhinitis is a major respiratory disease due to its increasing prevalence and major impacts on quality of life. It is a major risk factor for asthma. Uncontrolled moderate to severe allergic rhinitis can affect asthma control. Asthma occurs in 30% of patients with allergic rhinitis, and allergic rhinitis occurs in more than 80% of patients with asthma.

Effective treatment of allergic rhinitis can improve asthma symptoms. Sleep disorders and sleep apnoea may also develop from chronic nasal congestion due to allergic rhinitis. Sleep apnoea may result in increased cardiovascular risk, diabetes, depression, and accidents.

Allergic rhinitis is associated with an immunoglobulin E (IgE)-mediated immune response to environmental allergens. These allergens can be seasonal (e.g. pollens) or perennial (e.g. dust mites, pet dander). Chemical irritants, such as cigarette smoke, can further exacerbate symptoms. Allergens should be identified and avoided where possible. Environmental controls, such as general measures to reduce house dust mites, may help improve symptoms.

Intranasal corticosteroids are administered directly to the nasal mucosa in the form of a nasal spray to manage allergic rhinitis, rhinosinusitis (infectious rhinitis) and nasal polyps. INCS reduce the influx of inflammatory cells into the nasal mucosa in response to allergic stimuli. This reduces the release of inflammatory mediators and the development of nasal hyperresponsiveness.

Intranasal corticosteroids are the treatment of choice in patients with moderate to severe allergic rhinitis symptoms and in patients with mild, persistent symptoms. Optimal improvement in symptoms is reached after several days of regular use, although some symptoms may start to improve within a few days. They are still effective if used on an as-needed basis for episodic symptoms.

Sodium chloride 0.9% nasal irrigation may help clear nasal passages by washing out allergens and sticky mucus and reduce congestion and irritation.

Common adverse effects of INCS are:

  • Nasal stinging
  • Itching
  • Nosebleed
  • Sneezing
  • Sore throat
  • Dry mouth and cough

Intranasal corticosteroids rarely cause systemic adverse effects when used at recommended doses. They should be used with caution in patients with glaucoma or cataracts. They are generally considered safe to use in pregnancy. Budesonide, mometasone and fluticasone are preferred in the first trimester as there is greater experience with these agents.

The recommended minimum age for the available INCS are:

  • Beclomethasone 50mcg/spray – from age 12 and older
  • Budesonide 32mcg/spray or 64mcg/spray – from age 6 and older
  • Ciclesonide 50mcg/spray – from age 6 and older
  • Fluticasone furoate 27.5mcg/spray – from age 2 and older
  • Fluticasone propionate 50mcg/spray – from age 12 and older
  • Mometasone 50mcg/spray – from age 3 and over.

General patient counselling points:

  • Shake the bottle well before each use.
  • Prime the spray before initial use or if it has not been used recently.
  • Gently blow nose to clear the nasal passages (or use a saline rinse to clear nasal obstruction and then waiting for 10 minutes before using the nasal spray).
  • Tilt head slightly forward.
  • Gently insert the nozzle into the left nostril, aiming towards the left ear, away from the septum. Use your right hand for the left nostril and left hand for the right nostril. This reduces the amount of drug deposited onto the septum.
  • Press to spray (do not sniff hard, as this can force the dose into the throat).
  • Repeat for the other nostril.
  • Wipe the tip of the spray device with a dry tissue and put the cap back on.
  • Optimal effects may be seen after 7 days of continual use.
  • For intermittent symptoms, consider using 2-4 weeks before exposure to know allergens (e.g. pollen) to prevent symptoms.
  • If two different nasal sprays are used, there should be an interval of at least 10 minutes between sprays.

Combination products containing an INCS and intranasal antihistamine (INAH) are also available. These formulations are used in patients with allergic rhinitis with moderate to severe symptoms, those with mild, persistent symptoms, and those with mild symptoms not responding to antihistamines. Combination treatments offer the advantages of both medications and are more efficacious and faster acting than monotherapy.

The minimum recommended age for use of INCS/INAH formulations is:

  • Azelastine 125mcg/fluticasone propionate 50mcg (Pharmacy Only medicine) – age 12 and older. Offers nasal symptom relief from 5 minutes and ocular symptom relief from 10 minutes.
  • Olopatadine 600mcg/spray/mometasone furoate 25mcg (Prescription Only medicine) – age 6 and older. Offers nasal symptom relief from 10 minutes.

Counselling points:

The information that should be provided to patients is much the same as per INCS products.

If the patient is already taking an oral antihistamine, it should be stopped before starting the combination nasal spray. Combining an oral and intranasal antihistamine does not provide additional benefit.

Although the efficacy of each INCS is thought to be similar, choice may be affected by many factors including dosing, cost and tolerability.

Updated COVID-19 Vaccine Recommendations

While COVID-19 may no longer be considered a public health emergency, it continues to have a significant impact on health services and the community. Residential aged care homes (RACH) continue to experience outbreaks. As of 11 April 2024, there were 209 active outbreaks in RACHs across the country. Outbreaks are highest in New South Wales and Victoria, with these states recording 29 and 27 new outbreaks in the previous seven days, respectively. In Australia, over 100,000 infections have already been reported this year. However, given the reduced volume of testing, this figure likely underestimates the actual number of cases.

Over 70.7 million COVID-19 vaccine doses have been administered in Australia since the vaccination program began in early 2021. Vaccination remains the most important measure to protect people at risk of severe disease. However, only 22.9% of people aged 65-74 and 38.1% of those over 75 have received a booster in the last six months.

The Australian Technical Advisory Group on Immunisation (ATAGI) has recently updated its advice on the use of COVID-19 vaccines. This advice contains important information regarding:

  • Recommendations for additional doses of COVID-19 vaccine;
  • Timing of vaccination; and
  • The preferred COVID-19 vaccines for various age groups.

Table 1 provides an overview of the COVID-19 vaccines used in Australia.

Table 1. COVID-19 vaccines registered in Australia (adapted from ATAGI 2024)

Vaccines Omicron XBB.1.5 Bivalent Original
Comirnaty® Omicron XBB.1.5 (raxtozinameran) Spikevax® XBB.1.5 (Andusomeran) Comirnaty® Original/Omicron BA.4-5 (tozinameran/ famtozinameran) Comirnaty® (tozinameran)
Formulations 6 month – <5 year* 5 – <12 years ≥ 12 years ≥ 12 years ≥ 12 years 6 month – <5 year 5 – <12 years
Presentation Maroon or yellow cap Blue cap Grey cap Pre-filled syringe Grey cap Maroon cap Orange cap
Dose 3 mcg 10 mcg 30 mcg 50 mcg 15/15 mcg 3 mcg 10 mcg

*Not yet available

The Omicron XBB.1.5 vaccines are currently preferred as they provide a better immune response against Omicron variants. Early data suggests that these newer vaccines are as well tolerated as the original and bivalent formulations of Spikevax® and Comirnaty®. In the three days after receiving an XBB.1.5 COVID-19 vaccine, no adverse effects were reported for 73% of Comirnaty® recipients and 54% of Spikevax® recipients. For each XBB.1.5 vaccine, local reactions were the most common adverse effects, followed by fatigue, muscle or joint pain, and headache. The rate of reported medical attendance following vaccination with Comirnaty® XBB.1.5 and Spikevax® XBB.1.5 was low at 0.3% and 0.4%, respectively. The AusVax Safety website provides additional safety data for each vaccine.

An Omicron XBB.1.5 vaccine is not yet available for infants and children under five years of age. However, Comirnaty® Omicron XBB.1.5 (6 months – 5 years formulation) has been approved by the Therapeutic Goods Administration (TGA). Once this product is available, it will be the preferred vaccine for this age group. Until then, the age-appropriate original Comirnaty® vaccine should be used in this population, where indicated.

Vaccine timing:

A primary vaccination course is recommended for all adults 18 years of age or older, and from six months of age for children with risk factors for severe disease or death from COVID-19. A primary course is now considered one dose for most people. However, for people with severe immunocompromise, a primary course is two or three doses.

The current ATAGI recommendations for the administration of additional COVID-19 vaccine doses include:

  • Every six months for adults ≥ 75 years;
  • Every 12 months (with consideration of six-monthly dosing) for adults aged 65-74 years;
  • Every 12 months (with consideration of six-monthly dosing) for adults aged 18-64 years with severe immunocompromise;
  • Consideration of an annual dose for all other adults; and
  • Consideration of an annual dose for children aged 5 to <18 years with severe immunocompromise.

Examples of severe immunocompromise for which additional doses of COVID-19 vaccine may be required can be found in the Australian Immunisation Handbook. These include:

  • Haematological malignancies (treated and untreated);
  • Malignancy, solid organ transplantation, autoimmune and inflammatory conditions currently treated with therapies such as conventional chemotherapy, significant doses of conventional immunosuppressants, and some monoclonal antibodies;
  • HIV with a CD4+ cell count below 200;
  • Primary immunodeficiency (e.g. complement defects); and
  • Chronic kidney disease requiring dialysis.

The recommended timing of additional vaccine doses is summarised in Table 2. Where it is stated that additional doses may be considered, this should include an individual risk-benefit assessment.

Table 2. Recommended timing of COVID-19 vaccine doses following primary course (adapted from ATAGI 2024)

Age Severe immunocompromise Without severe immunocompromise
≥ 75 years

Every 6 months

65 – 75 years

Annual (may consider 6-monthly dosing)

18 – 64 years Annual (may consider 6-monthly dosing) Consider annual dosing
5 – 17 years Consider annual dosing Not recommended
< 5 years

Not recommended

ATAGI advises that COVID-19 vaccines may be administered at the same time as any other vaccine for people five years of age or older.

Treatment:

Most cases of COVID-19 are mild and can be managed symptomatically at home. Specific antiviral treatments are available for higher-risk groups.

Two oral treatments for COVID-19 are available: Lagevrio® (molnupiravir) and Paxlovid® (nirmatrelvir and ritonavir). From 1 March 2024, the Pharmaceutical Benefits Scheme (PBS) eligibility criteria were modified for these therapies. People who test positive for COVID-19 may now be eligible for PBS-subsidised therapies if they meet the following criteria:

  • Are 70 years of age or older (regardless of risk factors and presence of symptoms);
  • Are 50 years of age or older and have two additional risk factors for developing severe disease;
  • Are a First Nations person aged 30 years or older with one additional risk factor for developing severe disease; or
  • Are 18 years of age or older and moderately to severely immunocompromised or have previously been hospitalised for COVID-19.

For the purpose of PBS eligibility, risk factors include:

  • Residing in an aged care facility;
  • Living with disability with multiple conditions and/or frailty;
  • Neurological conditions (e.g. stroke, dementia) and demyelinating conditions (e.g. multiple sclerosis);
  • Chronic respiratory conditions (e.g. COPD, moderate or severe asthma);
  • Obesity or diabetes (type I or II requiring medication);
  • Heart failure, coronary artery disease, cardiomyopathies;
  • Kidney failure or cirrhosis; and
  • Living remotely with reduced access to higher level healthcare.

Paxlovid® remains the preferred oral antiviral for COVID-19. Current evidence suggests that it is superior to Lagevrio® in terms of hospitalisation and mortality rates. However, Paxlovid® is contraindicated in severe renal or hepatic impairment and with some medications that are highly dependent on CYP3A for clearance. Lagevrio® is only PBS-subsidised when Paxlovid® is contraindicated.

Summary

The recommendations for COVID-19 vaccination have recently been updated. Some of the more significant points include the preference for the Omicron XBB.1.5 vaccines and changes to the definition of a primary dose. Vaccination continues to be an important measure to reduce the risk of severe disease and death from COVID-19.

Medication-Overuse Headache

Medication-overuse headache is a neurologic disorder that can cause significant disability and suffering. This condition typically only occurs in patients with migraine or tension headaches and is associated with overuse of medications for the treatment of the primary headache. Responsiveness to prophylactic therapies may also be reduced, leading to a cycle of increased medication use and increasing headache frequency and intensity. Alternative names for this condition include analgesic rebound headache, drug-induced headaches, and medication misuse headaches.

The International Classification of Headache Disorders (ICHD) defines medication-overuse headache as: “Headache occurring on 15 or more days/month in a patient with a pre-existing primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 or more or 15 or more days/month, depending on the medication) for more than 3 months. It usually, but not invariably, resolves after the overuse is stopped.”

The prevalence of medication-overuse headache is estimated to be around 1% in the general population but may be up to 50% in specialised headache clinics.

While the pathophysiology of medication-overuse headache is not fully understood, it is thought to be related to central sensitisation. Some evidence suggests that there may also be a behavioural component, with some studies finding a higher prevalence of substance use disorders in people with medication overuse headache. Some neurobiological pathways may be common to both substance-related disorders and medication-overuse headache.

Animal models demonstrate that chronic analgesia exposure causes increased excitability in parts of the nervous system related to headache pathogenesis. This includes upregulation of calcitonin gene-related peptide (CGRP), substance P, and nitric oxide synthase in trigeminal ganglia; reduced nociceptive threshold of central trigeminal neurons; and increased susceptibility to develop cortical spreading depression.

Medications that are considered potent inducers of medication overuse headache include opioids, triptans, and ergot alkaloids. Patients may be at risk if they are taking these medications more than ten days per month. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) can also induce this disorder if taken for more than 15 days per month. Medication overuse headache can also develop in headache-prone individuals when acute headache medications are taken for other indications.

Other potential risk factors for medication-overuse headache include:

  • High headache frequency at baseline;
  • Age <50 years;
  • Female sex;
  • Anxiety or depression;
  • Physical inactivity;
  • Chronic musculoskeletal complaints;
  • Smoking; and
  • Metabolic syndrome.

Management:

The management of medication-overuse headache typically involves withdrawal of the overused medication. Patients may experience unpleasant withdrawal symptoms during this period. Symptoms will vary depending on the medicine but may include increased headache, vomiting, restlessness, sleep disturbances, and anxiety. The duration of withdrawal symptoms is typically up to four days for triptans, seven days for ergotamine, and up to ten days for analgesics. Simple analgesics, triptans, and ergot alkaloids can be discontinued abruptly without dose tapering. However, gradual dose reduction may be required for patients taking opioids or benzodiazepines.

Medications that have been overused should be avoided during the withdrawal period. However, bridging therapy may be considered, particularly for patients with severe symptoms. The Therapeutic Guidelines recommend a long-acting NSAID or a short course of prednisolone for bridging therapy, as follows:

  • Naproxen modified-release tablets 750mg once daily for five days in the first week, then three to four days per week in the next two weeks, then stop; or
  • Prednisolone or prednisone 50mg once daily for three days, then reduce gradually over seven to ten days to zero.

Following this, the guidelines advise that the usual acute medication may be restarted with restrictions on dose frequency (i.e. opioids and triptans to be used less than ten days a month, non-opioid analgesics for less than 15 days per month). However, it is important that these patients receive education and appropriate follow-up to reduce the risk of recurrence.

Studies support the addition of prophylactic medications for patients with primary migraine or tension headaches to return to an episodic pattern. Preventative medications with significant evidence to support them in this setting include:

  • Topiramate;
  • Onabotulinumtoxin A; and
  • Monoclonal antibodies against CGRP (e.g. erenumab, fremanezumab).

Other prophylactic medications, such as beta-blockers, may also be considered as appropriate.

Summary

Medication overuse headache can have a significant impact on a patient’s quality of life. The accurate diagnosis of this condition is important as patients often improve following discontinuation of the overused medication. Follow-up care is important for these patients as relapse and recurrence are common.

Data and Decisions for the Three Different CDK4/6 Inhibitors

Hormone receptor-positive and HER2 receptor-negative (HR+/HER2-) breast cancer can be treated with CDK4/6 inhibitors. When cyclin-dependent kinase (CDK) cellular biology becomes dysregulated, cell proliferation occurs, and this has led to the discovery of three current CDK4/6 inhibitor drugs to treat HR-positive HER2-negative breast cancer: palbociclib, ribociclib and abemaciclib (1).

All CDK4/6 inhibitors (CDK4/6i) used for HR+/HER2- breast cancer should be used in combination with an endocrine inhibitor such as an aromatase inhibitor or Fulvestrant. (2) If using palbociclib in endocrine pre-treated patients, then fulvestrant would be the recommended endocrine inhibitor of choice (2).

Seven pivotal trials have determined the efficacy of all three current CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer. Although one should be prudent when directly translating across three different trials, the progression-free survival (PFS) hazard ratios are similar between the three molecules (3).

It should also be noted that in pre-treated patients, the combination of ribociclib or abemaciclib with fulvestrant produced greater overall survival (OS) than with fulvestrant alone. Although statistical significance wasn’t seen with palbociclib in combination with fulvestrant for OS in pre-treated patients, the population studied received significantly more pre-therapy than trials with ribociclib or abemaciclib (3).

Overall survival was a secondary endpoint in the first-line metastatic trials. Abemaciclib did not reach statistical significance for OS after 70.2 months of follow-up. A recent presentation of 8 years of follow-up in the abemaciclib MONARCH-3 study showed an increase in overall survival of 13 months (66.8 months vs 53.7 months). Although this effect unfortunately did not quite reach statistical significance, it is worth noting (4). Ribociclib reached statistical significance for OS in several trials compared to endocrine therapy alone for first-line metastatic HR+/HER2- breast cancer. Palbociclib did not reach statistical significance. However, there is controversy in regard to the veracity of this finding for palbociclib. Survival data was missing, and post-progression therapy in the control arm was higher in the palbociclib trial (3). After 7.5 years, 10% of patients are still on palbociclib, and real-world data outside of a trial setting showed an OS benefit (3).

The disparate results in OS and the very similar results in PFS between the three molecules have caused some debate as to the reasons behind this. Overall survival was a secondary endpoint in each of the studies, and this highlights the importance of primary and secondary endpoints when analysing the results of trials. In fact, it has been suggested both the MONALEESA trial and PALOMA-2 trial were only powered to <70% for OS and the differences could very well be attributed to chance. As discussed previously, the post-progression treatment rates were different and, as palbociclib underwent regulatory approval, those on ribociclib in the MONALEESA trials who progressed received palbociclib, a different drug to the treatment arm. In the palbociclib (PALOMA-2 trial) trial, those who progressed received the same drug palbociclib post-progression. There were also differences in disease-free intervals in the exclusion criteria for the trial designs that may possibly imply differences in endocrine sensitivities. Other differences existed in patient recruitment across trials and there is debate if they were a potential cause of difference. This is always a factor to consider with no head-to-head trials to draw from (3).

The Monarch-E trial combined abemaciclib with endocrine therapy for HR-positive, HER2-negative early breast cancer that was node-positive and at high risk of recurrence (5). This phase III open-label trial assigned patients to receive either abemaciclib for two years combined with anti-estrogen therapy for five years or anti-estrogen therapy alone for five years. At the initial follow-up of 27 months, the results were statistically significant in favour of the treatment arm (2). At an additional follow-up of 42 months, this statistically significant result was maintained, and data presented at the ASCO conference showed a statistically significant five-year invasive disease-free survival (IDFS) benefit (6).

The NATALEE trial is investigating ribociclib 400mg daily using the 21-day treatment and seven-day rest protocol for three years for early breast cancer. Patients were included who had stage IIA, IIB, or III hormone receptor–positive, HER2-negative breast cancer and were at risk of recurrence. The final analysis has been done, and the results are positive for ribociclib for this new indication and even for patients with node-negative disease. (7) Upon publication, there is anticipated much discussion about the pros and cons of abemaciclib vs ribociclib for the treatment of high-risk HR+/HER2- early breast cancer.

One of the most important aspects for pharmacists managing CDK4/6 inhibitors is interpreting the adverse effect profile of the three current agents in use for individual patients. This will be even more important with TGA approval and PBS approval for early breast cancer. It is easier to be less cautious in the metastatic setting than in those with quite likely curable early breast cancer.

The differing adverse effect profiles are due to the difference in affinity for each of the two receptors amongst the three molecules. Neutropenia and other haematological adverse effects are more common with ribociclib and palbociclib. The neutropenia seen with CDK4/6 inhibitors is distinct from that seen with other cytotoxic agents in that it is easily reversible, reflecting a cytostatic effect on the bone marrow and rarely associated with febrile neutropenia. Ribociclib is associated with QT prolongation, and baseline ECG should be done and monitored during treatment. Diarrhoea is mostly associated with abemaciclib and it is important to discuss this with patients at the start of treatment to come up with a plan as to how to treat with loperamide and electrolytes and when to seek medical or emergency help. (7) Liver toxicities are associated with the CDK4/6 inhibitors abemaciclib and ribociclib, and liver enzymes should be monitored (3).

Patient counselling on the rare but serious side effect of interstitial lung disease should occur, and patients should be cognizant of cough or shortness of breath. Blood clots are also rare but serious potential side effects, and although rare, one has to consider this in particular in the early breast cancer setting as to whether the risk outweighs the potential reward for those at particular risk of VTE and potential prophylactic anticoagulation. (7) There is also an increase in hypertension and other cardiovascular events amongst patients treated with CDK4/6 inhibitors (8).

There are potential drug interactions associated with all three molecules, both metabolic in terms of CYP3A4 inhibition or induction. P-gp drug interactions and pharmacodynamic drug interactions, particularly with QT prolongation for ribociclib are also possible.

The CDK4/6 inhibition and the resulting choice of drugs are an exciting development in the treatment of both metastatic and now early breast cancer. Pharmacists must strive to play a pivotal role in the management of these medications to ensure to get the most out of these exciting new treatment protocols.

Changes Affecting Submissions for Unapproved Therapeutic Goods

The Therapeutic Goods Administration (TGA) has announced plans to transition Special Access Scheme (SAS) and Authorised Prescriber (AP) submissions to a fully digital model. Once this is implemented, paper-based submissions (including faxed and emailed submissions) will no longer be accepted.

The online system has been designed to allow real-time access to notifications and submission data across multiple platforms, e.g. computer, smart phone, tablet, etc. Transition to this system is intended to improve the security of interactions between the TGA and healthcare practitioners and simplify these processes.

The transition process will be occurring in two stages, with the TGA providing the following proposed timeline:

  • 1 April 2024 (Phase 1)
    • Submissions for SAS Category B pathway and AP scheme will only be accepted via the SAS/AP Online System.
  • 1 July 2024 (Phase 2)
    • Submissions for SAS Category A and C pathways will only be accepted via the SAS/AP Online System.

In 2023, 84% of SAS and AP submissions were received via the online system. Of the submissions that utilised a paper-based method, the majority were for SAS Category A and C pathways and generally originated from tertiary hospitals. The longer transition time for moving these pathways to the online system is hoped to provide hospitals with adequate time to change their processes.

Pathways for accessing unapproved therapeutic goods

The TGA encourages the use of TGA-approved medications, i.e. medications entered on the Australian Register of Therapeutic Goods (ARTG). This ensures that the therapeutic good has been evaluated by the TGA for quality, safety, and effectiveness. However, there may be times when a therapeutic good is required that is not on the ARTG. In these cases, the SAS or AP pathways may be considered.

The SAS can be used to access unapproved medications for individual patients. The SAS is divided into three categories:

  • Category A
    • The patient must be seriously ill with a condition from which death is reasonably likely to occur within months or premature death is reasonably likely in the absence of early treatment
    • Unapproved products can be accessed immediately
    • The TGA must be notified within 28 days of use
    • The prescriber must be a medical practitioner
  • Category B
    • The TGA must be provided with a brief clinical justification to support the use of the good for the medical condition in question
    • TGA approval is required before the therapeutic good can be supplied
    • This category may be used by medical practitioners and other health practitioners
    • Goods that may be accessed depend upon the health professional’s scope of practice, qualifications, condition being treated, and state/territory requirements
  • Category C
    • Includes a range of unapproved therapeutic goods that the TGA deems to have an established history of use
    • Unapproved products can be accessed immediately
    • The TGA must be notified within 28 days of use
    • All listed criteria must be met in order to prescribe a product listed in Category C.

Medical practitioners can use the AP pathway to access unapproved medications for multiple patients with the same condition. Authorised prescribers do not need to seek approval for each individual patient but must provide the TGA with a report every six months of how many patients have been treated with each unapproved product.

The prescriber is responsible for deciding which pathway should be used in each case. An interactive tool is available on the TGA website to guide decision making. Suspected adverse events or defects must be reported to the TGA within 15 days of learning of the issue.

Background to transition

In 2015, the Medicines and Medical Devices Regulation (MMDR) review recommended the TGA create an online system to improve access to unapproved goods. The TGA launched their online system in 2018 with the intention of fully transitioning to digital submissions by July 2019. However, user feedback suggested that further improvements were required before the online system could be used exclusively.

Since then, the TGA has made a significant investment in improving the system, including:

  • Improvements to the user registration process;
  • Streamlined navigation of the application process;
  • Redistribution of the TGA workforce to improve internal efficiencies in processing submissions;
  • A streamlined process for therapeutic vape submissions;
  • Improved functionality of AP reporting to reduce administrative burden; and
  • The ability for pharmacists to validate the application and notification status in real-time.

Additional upgrades are planned for this year to improve security and efficiency. For example, health practitioner registration status will be automatically validated against the Australian Health Practitioner Regulation Agency (AHPRA) registry to prevent the creation of fraudulent accounts. Ways to optimise how information is managed and shared within organisations are also being investigated. The TGA will continue to review and seek feedback on the system to optimise efficiency.

Further information

  • The TGA provides guidance for the SAS and AP Online System
  • The TGA can also provide direct assistance in transitioning to the online system by emailing [email protected]

Pneumoccoccal Vaccines

There are currently four pneumococcal vaccines available in Australia. These vaccines protect against disease caused by Streptococcus pneumoniae. While asymptomatic nasopharyngeal carriage can occur, S. pneumoniae is thought to be responsible for at least one million deaths around the world each year. S. pneumoniae can cause severe invasive disease, including meningitis, pneumonia and bacteraemia, as well as non-invasive disease, such as otitis media.

The polysaccharide capsule of S. pneumoniae is a major virulence factor which allows the bacteria to evade host immune responses. While there are over 100 known serotypes, only a small number of these are responsible for the majority of pneumococcal disease. Serotypes 1 and 19A are the predominant causes of invasive disease, although serotypes 4, 5, 7F, 8, 12F, 14, and 18C are also commonly implicated. Non-bacteraemic pneumonia in adults is most commonly associated with serotype 14.

The introduction of vaccines against the most clinically relevant serotypes has led to a significant reduction in pneumococcal disease globally. However, this has led to a relative increase in the prevalence of non-vaccine serotypes.

The Australian Immunisation Handbook recommends pneumococcal vaccination for the following groups:

  • Infants and children;
  • Non-indigenous adults ≥ 70 years of age
  • Aboriginal and Torres Strait Islander adults ≥ 50 years of age; and
  • Children, adolescents and adults with risk factors for pneumococcal disease.

Risk conditions for pneumococcal disease include a previous episode of invasive pneumococcal disease, immunocompromising conditions, cerebrospinal fluid (CSF) leak, chronic respiratory disease, chronic kidney disease, chronic liver disease, cardiac disease, extremely premature birth, trisomy 21, diabetes, smoking, and harmful use of alcohol. Not all individuals with a risk condition for pneumococcal disease are eligible to receive a dose funded by the National Immunisation Program (NIP).

Pneumococcal vaccines can be divided into two types: pneumococcal conjugate vaccines (PCV) and pneumococcal polysaccharide vaccines (PPV). Both vaccine types contain antigenic polysaccharides from pneumococcal serotypes that commonly cause disease.

Pneumococcal conjugate vaccines

The polysaccharides in PCVs are attached to a carrier protein in order to increase their immunogenicity. The carrier protein used is a non-toxic variant of diphtheria toxin known as CRM197 protein. A single mutation of the diphtheria toxin eliminates its toxicity while retaining its immunostimulant properties.

The immune response to the bacterial polysaccharide is a T-cell-independent process. However, conjugation to the CRM197 protein modifies this response to be T-cell-dependent. This results in a stronger immune response and the generation of memory B-cells. Pneumococcal conjugate vaccines also reduce asymptomatic carriage of the vaccine serotypes, which may provide indirect protection for unvaccinated people.

The PCVs available are:

  • Prevenar® 13
    • 13-valent (13vPCV)
    • 2.2µg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F
    • 4.4µg of pneumococcal purified capsular polysaccharides for serotype 6B
    • Indicated for use in people from 6 weeks of age and older
  • Prevenar® 20
    • 20-valent (20vPCV)
    • 2.2µg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F
    • 4.4µg of pneumococcal purified capsular polysaccharides for serotype 6B
    • Approved indication has recently been extended to include infants and children from 6 weeks of age
  • Vaxneuvance®
    • 15-valent (15vPCV)
    • 2.0µg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F
    • 4.0µg of pneumococcal purified capsular polysaccharides for serotype 6B
    • Indicated for use in people from 6 weeks of age and older

Prevenar® 20 and Vaxneuvance® are considered extended valency vaccines as they cover more serotypes than Prevenar® 13. However, these newer vaccines are not currently covered on the NIP.

Pneumococcal polysaccharide vaccine

Pneumovax® 23 contains the purified capsular polysaccharides from 23 of the most prevalent or invasive S. pneumoniae types, including the six serotypes most commonly responsible for antibiotic-resistant pneumococcal infections. According to surveillance data from the United States, this vaccine covers at least 90% of pneumococcal blood isolates and around 85% of all pneumococcal isolates found at sites generally considered sterile.

The immune response to this vaccine is primarily an IgM response with some contribution from IgG. Protective antibodies are generated without the involvement of T-cells, resulting in a less robust response and a shorter duration of immunity compared to conjugated vaccines. Immunocompromised adults and children younger than two years of age are also likely to respond poorly to this vaccine. However, when a PCV is used as the priming vaccine, the immunologic response to subsequent doses of a PPV is significantly greater.

Pneumovax® 23:

  • 23-valent (23vPPV)
  • Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F
  • May be used in people ≥ 2 years of age (poor immune response in younger individuals)
  • May be given by intramuscular or subcutaneous injection. The intramuscular route is preferred to minimise injection site reactions.

The recommendations for 23vPPV administration have changed and it is no longer recommended for healthy non-Indigenous adults aged 70 years or older. This vaccine is still recommended for Aboriginal and Torres Strait Islander adults aged 50 years or older and adults with risk conditions. This advice follows trial data showing that conjugate vaccines are effective in older adults for the prevention of vaccine-type pneumococcal pneumonia and invasive pneumococcal disease. According to Australian data, most disease caused by the additional serotypes contained in 23vPPV occurs in Indigenous adults and individuals with risk conditions. Therefore, the 23vPPV is now only offered to those groups.

The serotypes contained in each of these vaccines are shown in Table 1.

Table 1. Serotypes covered by each pneumococcal vaccine

Vaccine Shared serotypes Additional serotypes
Prevenar® 13 1, 3, 4, 5, 6B, 7F, 9V,

14, 18C, 19A, 19F, 23F

6A
Vaxneuvance® 6A, 22F, 33F
Prevenar® 20 6A, 8, 10A, 11A, 12F, 15B, 22F, 33F
Pneumovax® 23 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20,

22F, 33F

Vaccine recommendations:

While the optimal vaccine schedule is presently under review in Australia, the current recommendations from the Australian Immunisation Handbook are:

  • Universal childhood schedule
    • All non-Indigenous children, and Aboriginal and Torres Strait Islander children living in ACT, NSW, Tasmania and Victoria
    • Three doses of pneumococcal conjugate vaccine
    • Doses at age 2 months, 4 months and 12 months.
  • At-risk children 12 months or under
    • All children with risk conditions, and Aboriginal and Torres Strait Islander children living in NT, Qld, SA and WA
    • Four doses of pneumococcal conjugate vaccine and two doses of 23vPPV
    • Conjugate vaccine at 2 months, 4 months, 6 months and 12 months.
    • 23vPPV at 4 years with a second dose at least 5 years later.
  • Children over 12 months, adolescents and adults of any age diagnosed with a risk condition
    • Single dose of conjugate vaccine at diagnosis
    • Then two doses of 23vPPV (first dose 12 months after 13vPCV or at age 4 years, whichever is later, then second dose at least 5 years later).
  • Aboriginal and Torres Strait Islander adults aged ≥ 50 years
    • Single dose of conjugate vaccine and 2 doses of 23vPPV (first dose 12 months after conjugate vaccine, and second dose at least 5 years later).
  • Non-Indigenous adults aged ≥ 70 years
    • Single dose of conjugate vaccine

Additional resources:

Potential Anaesthesia Risk with GLP-1 Agonists

The tirzepatide (Mounjaro®) product information has been updated to include a warning of pulmonary aspiration in patients undergoing general anaesthesia or deep sedation.

Tirzepatide is indicated for the treatment of type 2 diabetes. It is a long-acting agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Its action on the GLP-1 receptor stimulates insulin secretion in hyperglycaemic states, suppresses glucagon secretion, delays gastric emptying, and decreases appetite. Activation of GIP receptors enhances some of the effects of GLP-1 stimulation, particularly in regard to appetite. This dual mechanism significantly improves glycaemic control, insulin sensitivity, and lipid metabolism while reducing body weight.

Delayed gastric emptying

The effect of tirzepatide and other GLP-1 agonists on gastric emptying may increase the risk of aspiration during anaesthesia. Aspiration of regurgitated gastric contents into the lungs is a serious event that can lead to pneumonitis, aspiration pneumonia, or other lung injury. Patients taking a GLP-1 agonist may have high gastric volumes despite appropriate fasting before the procedure. During anaesthesia, the presence of food or fluid contents in the stomach is a major risk factor for aspiration.

Other GLP-1 agonists available in Australia are shown in Table 1. Dulaglutide and semaglutide are considered long-acting agents, and liraglutide is short-acting. While GLP-1 agonists were originally used in the management of type 2 diabetes, the expansion of indications and off-label use for weight loss has led to a significant increase in their use.

Table 1. GLP-1 agonists registered in Australia

Drug Registered indication Half-life (approx.)
Dulaglutide Type 2 diabetes 4.7 days
Liraglutide Weight loss

Type 2 diabetes

13 hours
Semaglutide Type 2 diabetes 7 days
Tirzepatide Type 2 diabetes 5 days

A recently published study investigated the potential for semaglutide to increase residual gastric content (RGC) despite adequate preoperative fasting. Patients undergoing upper gastrointestinal endoscopy who had taken semaglutide within 30 days had their RGC compared to patients who had not taken semaglutide. The findings suggest that semaglutide increased the risk of elevated RGC almost five-fold.

The effect of GLP-1 agonists on gastric emptying is thought to be most pronounced at the beginning of therapy. Tachyphylaxis occurs with ongoing use, particularly in the case of long-acting agents. Evidence suggests that the dosing regimen may affect this, with intermittent dosing (as may occur when used for weight loss) showing a similar effect on gastric emptying to acute dosing.

It should be noted that delayed gastric emptying is often associated with diabetes, regardless of GLP-1 agonist use. In addition, many commonly prescribed medications can also slow gastric emptying. This includes opioids, proton pump inhibitors, anticholinergics, calcium channel blockers, and levodopa. Concomitant use of a GLP-1 agonist with another drug that slows gastric emptying may further increase the risk of aspiration during anaesthesia.

Managing therapy during the perioperative period

Holding medications that delay gastric emptying can help to reduce the risk of pulmonary aspiration. However, three to five half-lives are normally required to clear a drug from the body. This may not be practical for surgery scheduling, particularly when considering the long half-lives of many GLP-1 agonists. For example, semaglutide has a half-life of around one week. In addition, it may not be desirable to hold the medication for so long, given their clinical benefits on glucose control and cardiovascular health.

Further evidence is required to guide recommendations in this area. In patients with type 2 diabetes, the glycaemic benefits of continuing GLP-1 agonist therapy throughout the perioperative period may outweigh the potential issues related to delayed gastric emptying. They offer effective glycaemic control with a low risk of fasting hypoglycaemia. Therefore, continuing their use before surgery could potentially deliver cardiovascular benefits, improve wound healing, and avoid wound infections. However, the risk-benefit profile may not be the same when these agents are used for weight loss. Higher doses are used in the management of obesity, which may have a more pronounced effect on gastric emptying. In addition, patients may be more likely to use these agents intermittently, which could mitigate the development of tachyphylaxis.

The American Society of Anesthesiologists recommends that prescribers consider withholding the GLP-1 agonist for one dose before an elective procedure (i.e., hold on the day of surgery for daily dosing, hold for one week before surgery for weekly dosing). This advice remains the same regardless of the indication for the GLP-1 agonist. If holding the dose is not possible, they advise that ‘full stomach’ precautions should be implemented. The Australian and New Zealand College of Anaesthetists (ANZCA) highlights GLP-1 agonists as a risk factor and advises that gastric ultrasound can be used to mitigate risk and guide perioperative management. Other possible strategies to reduce the risk of aspiration include using a longer fasting duration and consideration of a prokinetic (e.g. metoclopramide or erythromycin).

Summary

Tirzepatide and GLP-1 agonists slow gastric emptying. A potential adverse event related to this effect is aspiration during anaesthesia or deep sedation, even in patients who have fasted according to standard recommendations.

The risk of aspiration is potentially higher in patients who have recently started a GLP-1 agonist, use intermittent dosing, or take another medication that delays gastric emptying. It is currently unclear when gastric emptying returns to normal after cessation of a GLP-1 agonist, and more evidence is needed to understand the potential role of withholding these agents during the perioperative period. ANZCA has recommended the use of gastric ultrasound as a means of assessing the aspiration risk of individual patients.

Mycobacterium bovis BCG for Bladder Cancer

Bacillus Calmette and Guerin (BCG) is an attenuated strain of Mycobacterium bovis, the pathogen responsible for bovine tuberculosis. Calmette and Guérin cultivated this stable, non-virulent substrain during the development of their tuberculosis vaccine, which was first administered to humans in 1921. As there was no method of preserving viable mycobacterium at that time, BCG required continuous culture. By 1961, the original BCG strain had been serially passaged 1,173 times, resulting in the development of several daughter strains. These strains were then named after the manufacturer and place of origin.

As a result, BCG is not a well-defined pharmacological agent. Rather, it is a term applied to a pool of BCG strains that have acquired phenotypic and genotypic variations due to in vitro culturing in different laboratories under different conditions. These strains can be grouped as shown in Table 1.

Table 1. Groups of BCG substrains

Group Description Names
1 Early strains – closest genetically to original strain BCG Russia

BCG Moreau

BCG Japan

2 Deletion of IS6110 gene upstream of phoP BCG Sweden

BCG Birkhaug

3 Established after 1931 BCG Glaxo

BCG Prague

BCG Danish

4 Late strains BCG TICE

BCG Frappier

BCG Phipps

BCG Connaught

BCG Pasteur 1173

Comparison of substrains

The various substrains have noted differences in immunogenicity, antibiotic susceptibility, and adverse effects. Some studies suggest that these distinctions translate into only small differences in the efficacy of BCG vaccines against tuberculosis. However, head-to-head studies looking at different substrains in bladder cancer are limited. This makes it difficult to compare the clinical efficacy of different strains in this setting.

One study compared the in vitro anti-tumour effects of eight different strains. This study demonstrates that BCG Russia and BCG Connaught are the most effective in inhibiting cell proliferation and inducing cytokine production, while BCG Glaxo was the least effective.

Boehm et al. (2017) conducted a systematic review and meta-analysis to examine whether different BCG strains are associated with different clinical responses in bladder cancer. Their analysis demonstrated that BCG significantly reduced disease recurrence compared to chemotherapy and surgery. However, no BCG strain was found to be significantly superior in preventing disease recurrence.

Supply issues

In recent years, manufacturing issues have led to global shortages of BCG products. Australia currently has a shortage of OncoTICE® (BCG Tice), the Australian-registered BCG product for bladder irrigation. This long-term supply interruption is expected to continue until at least the end of December 2024.

The Therapeutic Goods Administration (TGA) has authorised the supply of an internationally registered alternative under Section 19A of the Therapeutic Goods Act 1989. The alternative product, VesiCulture BCG, is registered in Denmark. The package insert and product labelling is in English.

It is important to appreciate that the strengths of these two products are expressed differently. An OncoTICE vial contains 2-8 × 108 colony-forming units (CFU), which may also be expressed as 500 million CFU. In contrast, the strength of VesiCulture is typically stated as 30mg per vial but may also be referred to as 2.5 x 108 CFU.

In clinical trials, a standard dose is often defined as 120mg for the Danish strain and 5 × 108 CFU for the TICE strain. This equates to four vials of VesiCulture or one vial of OncoTICE.

Some of the other key differences between VesiCulture and OncoTICE® are summarised in Table 2.

Table 2. Comparison of OncoTICE and VesiCulture (adapted from Link Communication 2023)

  OncoTICE® VesiCulture
Strain Tice BCG BCG Danish strain 1331
Contents of one vial 500 million CFU

(2-8 × 108 CFU)

30mg per vial

(Approx. 2.5 x 108 CFU)

Pack size One or three glass vials Four glass vials
Dosage Each instillation comprises 2-8 × 108 CFU (the contents of one reconstituted and diluted vial

of OncoTICE suspended in 0.9% sodium chloride up to a total volume of 50 mL)

Normal dose (120 mg) = 4 reconstituted vials. The required dose is resuspended in 50 ml sterile preservative-free 0.9% sodium chloride.
Standard dose 1 vial 4 vials
Storage of reconstituted product 2 hours at 2-8 °C. Protect from light Up to 4 hours at 2-8 °C. Protect from light

BCG Efficacy

The anti-tumour activity of BCG is thought to be related to local modulation of immune responses, leading to inflammation and the subsequent elimination of malignant cells. Interaction of BCG with urothelial cells may result in immunological effects, such as the induction of chemokines (e.g. interleukin-8), pro-inflammatory cytokines (e.g. granulocyte-macrophage colony-stimulating factor, tumour necrosis factor α, interleukin-6), and the upregulation of adhesion-molecule expression.

There are a number of conditions that should be met to improve the likelihood of treatment success with BCG. These include:

  • The patient must be immunocompetent to ensure a robust immune response;
  • The tumour burden should be small;
  • BCG must come into direct contact with the tumour; and
  • The dose must be adequate to stimulate an immune reaction.

The current evidence suggests that the use of an established BCG strain from another country does not disadvantage patients with bladder cancer. However, healthcare professionals are advised to take additional care when dispensing and administering any product that they are not familiar with.

Further information:

Patient Deterioration in the Healthcare Setting

Early recognition and prevention of patient deterioration is an important component of the healthcare system. The use of medical emergency teams (METs), also known as rapid response teams (RRTs), is recommended by the Australian Resuscitation Council to respond to instances of acute patient deterioration.

A small number of studies have demonstrated the benefits of pharmacist involvement in both MET and Code Blue teams. With up to a quarter of MET calls potentially caused by medicines, there is an obvious role for pharmacists as the majority of these could be potentially preventable.

Medicines affecting the cardiovascular system contributed to 60% of the total medication errors. Tachycardia due to omission of beta blockers, and hypotension due to cumulative toxicity or inappropriate use of antihypertensive during acute illness were the most common causes of potentially preventable medication-related MET calls.

A study conducted in the United States which reviewed surgical RRTs identified that 88% of calls were for impending respiratory failure due to excessive fluid administration in surgical patients.

Pharmacists can provide support by reviewing patients when they deteriorate and assist in identifying potential medicine causes. They can play an essential role by providing clinical advice on medication dosing, administration, and IV compatibility, and ensuring the MET team has the necessary medicines when they are required.

There are currently no standard recommendations for which medicines should be available for MET, and practice varies widely between hospitals. Principles to facilitate safe, timely and effective access to, selection of, and administration of medicines have been proposed. These include:

  • MET medicine management should be multidisciplinary, involving ward staff and MET nurses, doctors and pharmacists.
  • Medicines should be available to the MET to manage the common causes of MET activation, but not duplicate other resources.
  • Changes to medicine supplies should be based on the best available evidence, including feedback from ward and MET clinicians, data from local MET calls, interventions, and activation triggers, in addition to published literature and guidelines.

Frequent causes of patient deterioration and MET activation include pulmonary oedema, sepsis, arrhythmias and seizures.

Basic life support (BLS) steps include early detection and timely intervention of patient deterioration to stop progress to cardiac arrest. All hospital staff should be able to recognise cardiac arrest, call for help, start cardiopulmonary resuscitation and defibrillate using an automated defibrillator. The purpose of BLS is to maintain myocardial and cerebral oxygenation until advanced life support (ALS) personnel and equipment are available.