Knowledge Type: Clinical Articles

 

Staphylococcus aureus is a gram-positive pathogen and is one of the major human pathogens with a tendency to develop resistant strains to antibiotics. A penicillin-binding protein, PBP-2a, is responsible for mediating the resistance and allows division and growth of the organism in the presence of methicillin, resulting in strains of methicillin-resistant Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus is one of the major causes of hospital-acquired and community-acquired infections including skin and soft tissue infections, bacteraemia, pneumonia, surgical site infections, and sepsis(1). Higher rates of mortality and morbidity have been associated with infections involving methicillin resistant strains of Staphylococcus aureus. According to a national Australian study, it was identified that MRSA accounted for about 24% of all S. aureus bacteraemia infections. The study also showed that the all-cause 30-day mortality for methicillin-susceptible strains was only 17.7% whereas for MRSA, it was 30% (2).

Initiation of an appropriate antimicrobial therapy is significant for the treatment of methicillin-resistant Staphylococcus aureus bacteraemia. Intravenous vancomycin is the drug of choice for MRSA. However, increasing resistance against vancomycin monotherapy and owing to some limitations of vancomycin (poor tissue penetration, slower bactericidal effect, and high rates of mortality of MRSA bacteraemia), research is being conducted to determine other effective antimicrobial regimens. A number of other antimicrobial agents have been identified including linezolid, daptomycin, and ceftaroline. Although these agents have shown effectiveness against MRSA infections, the effects were not superior to vancomycin and most of these agents are associated with higher cost of therapy and/or serious adverse effects (2).

In recent years, several studies have been conducted to evaluate the effectiveness of combination therapy of vancomycin with β-lactam antibiotics. An inverse relationship (seesaw effect) was identified between vancomycin and β-lactam sensitivity in some MRSA strains that drew attention towards combination therapy of vancomycin with β-lactam antibiotics. Vancomycin showed synergistic effect when combined with different β-lactam antibiotics in several experimental models. Truong et al conducted a study in which a significant reduction in clinical failure was observed when combination therapy of vancomycin and various β-lactams were used (MIC < 2mg/l) (3).

In 2011, a pilot, open label, multicentre, parallel group clinical trial (CAMERA1) was performed in which patients with MRSA bacteraemia were randomly treated with either monotherapy with vancomycin intravenously at the standard dose, or combination therapy of vancomycin with flucloxacillin 2 gram every 6-hours for the first week. A total of 60 patients were enrolled in the study in which standard therapy group (29 participants) were given vancomycin alone and combination group (31 participants) were given vancomycin plus flucloxacillin. The results showed that the combination therapy resulted in shorter duration of bacteraemia 1.94 (SD 1.79) days as compared to 3.00 (SD 3.35) days in the group receiving standard therapy. It was indicated that the mean time for bacteraemia to resolve was 65% in the combination group as compared to that of the standard therapy group (RR 0.65, 95%CI, 0.41–1.02 p=0.06). 90% of patients in the combination group showed clearance of bacteraemia in four days, in contrast to nine days in the standard therapy group. However, in terms of the 28-day mortality (RR1.33, 95%CI 0.52–3.41, p=0.52), 90-day mortality (RR1.1, 95%CI 0.50-2.42, p=0.81) and complications (liver toxicity, nephrotoxicity, sepsis, need for ICU or other complications), no noteworthy difference was identified between the two groups (2).

Another study, CAMERA-2 was designed to further study the effect of combination therapy of β-lactam antibiotics with vancomycin in patients. Similar results were identified in this study regarding shortening of bacteraemia duration. However, incidence of higher rates of acute kidney injury (AKI) identified in the combination therapy resulted in the early termination of the study (3).

Combination therapy of β-lactam antibiotics with vancomycin in MRSA bacteraemia may shorten the duration of bacteraemia, however, no clinically significant effect on the rate of mortality and morbidity has been identified which necessitates further studies to explore the efficacy and safety of other combination therapies for MRSA bacteraemia.

Pharmacists being the expert of medicines, are an important part of multidisciplinary healthcare teams to manage the use of medicines in patients. Pharmacists, with other healthcare stakeholders, work together towards medication safety and for the Quality Use of Medicines including antimicrobial stewardship. Implementation of antimicrobial stewardship for MRSA bacteraemia is essential due to its high mortality and morbidity rates. A patient-directed approach is highly essential to effectively manage MRSA bacteraemia in hospital and community settings. Following are some of the areas where pharmacists can contribute their role:

• Contribution in developing local procedure and guideline by effectively utilising national standard guidelines such as Therapeutic Guidelines and by reviewing recent research evidence.
• Providing input on appropriate selection of antibiotic, dose, and duration of therapy.
• Involve in therapeutic drug monitoring of vancomycin to achieve the target trough levels for vancomycin.
• Monitoring the outcome of treatment.
• Monitoring the safety profile of vancomycin (Nephrotoxicity).
• Monitoring of drug-drug interactions.

Vulvovaginal candidiasis is a type of fungal infection characterized by inflammation of vagina and vulva caused by candida species. It is the second most common cause of vaginitis after bacterial vaginosis. Clinical presentation includes intense vaginal itching, irritation, feeling of burning and soreness and dyspareunia, curdy “cheese”-like discharge, and oedema with normal vaginal pH. Most common causative pathogen is Candida albicans that accounts for 80 to 90% of infection and Candida glabrata is the second highest causative specie. Authors have classified vulvovaginal candidiasis into two major categories: uncomplicated and complicated vulvovaginal candidiasis (VVC). Infections with mild to moderate symptoms and less than four episodes in a year caused by Candida albicans are mainly classified as uncomplicated vulvovaginal candidiasis. While infections caused by other pathogens or with more severe symptoms are classified as complicated vulvovaginal candidiasis. Infections in women where more than 4 episodes occur in a year and have risk factors are classified as complicated recurrent vulvovaginal candidiasis (RVVC). It is estimated that nearly three quarters of all women (70-75%) will develop this infection at least once in their life and half of these women will have another episode (50%), whereas about 5-10% may develop recurrent vulvovaginal candidiasis in their lives (1).

Self-diagnosis or miss-diagnosis makes it difficult to determine prevalence of Vulvovaginal candidiasis. Symptoms of vaginal infections including dysuria, redness, itchiness, vaginal discharge, and pain etc are highly non-specific and often result in over-diagnosis or under-diagnosis by women based on these symptoms (2). Consideration to differential diagnosis is highly important to consider other diagnosis such as bacterial vaginosis, dermatoses, atrophic vaginitis, trichomonas vaginalis. Also, the availability of most antifungal drugs without a prescription and their increase usage makes it difficult to correctly perform epidemiology studies (3).

There are multiple risk factors which account for recurrent vulvovaginal candidiasis in women and are broadly classified as host related factors and behavioural factors.

Occurrence of recurrent vulvovaginal candidiasis in diabetic women is more common than non-diabetic women. High levels of glucose results in the impairment of defensive mechanism and promote adhesion of Candida specie to the vaginal wall. It has been estimated that in diabetic women, the prevalence of vulvovaginal candidiasis is between 32 to 76.5% whereas as only 11 to 23% in women without diabetes (4). Also, women with a history of gestational diabetes mellitus during pregnancy are at higher risk of developing type 2 diabetes particularly in women greater than 35 years of age. A prospective cohort study was conducted in which the risk of developing type 2 diabetes was assessed using the reproductive histories of women. Results showed increased risk of type 2 diabetes mellitus in women with history of gestational diabetes and multiple pregnancies with a hazard ratio of 3.87 (95% CI 2.60-5.75). The American Diabetes Association recommends the screening of women with a history of gestational diabetes at 4-12 weeks postpartum and then at least every 3 years (5).

Some authors have also identified the use of oral contraceptives as one of the risk factors for vulvovaginal candidiasis. Some studies have reported that the incidence of vulvovaginal candidiasis is higher (39-58% versus 20-38%) when women are using oral contraceptive pills as contraception than in women not taking oral contraceptive pills. Also, the prevalence of recurrent vulvovaginal candidiasis is found to be more in women using oral contraceptives pills for longer time. Oral contraceptives are made of higher hormonal dose of synthetic estrogen and progesterone that promote Candida growth by increasing glycogen in vagina and increase the available carbohydrate as nutrients for candida specie. It also stimulate Candida hormone receptors that increases the adhesion of candida to the vaginal walls (1).

The first step in the management of recurrent vulvovaginal candidiasis is to confirm the diagnosis by microbial investigation and identification of the specie. Also, attempts should be made to identify the triggering or precipitating factor such as screening for diabetes or discontinuation of the combined oral contraceptive(6).

After excluding the possibility of other vaginal infections and taking the vaginal swab for cultures and sensitivities, if cultures confirm the presence of Candida albicans then the Therapeutic Guidelines recommends treatment course with fluconazole with a dosage of 150mg on Day 1, 4 and 7 and followed by once-a-week dosing of 150mg fluconazole for a further 6 months. In case of pregnancy or if the patient is planning to conceive, oral fluconazole is not recommended as it is TGA category D drug. Alternative choice in case of pregnancy or planning for pregnancy would be clotrimazole 1% cream administered as 1 applicatorful intravaginally at night for 14 consecutive nights then once a week administration of clotrimazole 500mg pessary inserted vaginally at bedtime for the next 6 months. If cultures indicate the presence of Candida glabrata and azole-resistant species, then therapeutic guidelines recommend the treatment course with nystatin 100000 units/5g vaginal cream to be applied intravaginally with applicator once daily at night-time for 2 weeks (14 nights) in a month for a total of 6 months (3).

Treatment regimen consisting of induction and maintenance regimen has shown to reduce the symptoms and recurrences of recurrent vulvovaginal candidiasis. The intention of maintenance therapy is to supress the symptoms and does not target the elimination of infection therefore chances of recurrence is 50% after the maintenance therapy is stopped which is considered as challenge in the management of recurrent vulvovaginal candidiasis. Also, the emergence of azole-resistant strains due to repeated use of fluconazole imposes another challenge. In case of azole-resistance, other agents that can be used are boric acid vaginal suppositories or capsules, nystatin vaginal suppositories, amphotericin B vaginal suppositories or cream, or flucytosine cream (2).

Also, patient counselling on general management is also important that includes avoiding the use of harsh soaps and perfumes to avoid vulvar irritation. Also, keeping the vaginal area clean and dry and avoiding long exposure to hot tub use. Cool bath may sooth the irritation and provide some relief (7).

The response to the treatment can be monitored by looking at the positive outcomes of the treatments that includes resolution of the symptoms and reduction in the number of reoccurrences. If the desired response is not achieved to the treatment regimen for recurrent vulvovaginal candidiasis, then microbiological cultures can be repeated to assess the development of resistance to the treatment. Also, reassessment of the alternative causes of the symptoms can be done if no adequate clinical response is achieved.

A new boxed warning is being added to the product information and consumer medicine information documents of systemic fluoroquinolone products. This warning advises that “fluoroquinolones… have been associated with disabling and potentially irreversible serious adverse reactions involving different body systems that have occurred together in the same patient.”

Fluoroquinolones are broad-spectrum antibiotics. Medications in this class that are currently available for systemic use include:

• Ciprofloxacin (oral, parenteral);
• Moxifloxacin (oral, parenteral); and
• Norfloxacin (oral).

In the majority of cases, fluoroquinolones are not first-line antibiotics. They are typically reserved for infections where alternative agents are ineffective or contraindicated. This is due to the rising level of resistance to this antibiotic class around the world. Judicious use is recommended to extend their clinical life. Another reason to be cautious about the use of these medicines is the potential for serious and long-lasting adverse reactions.

The European Medicines Agency (EMA) conducted a review of this issue in 2018. This review found that fluoroquinolones are associated with prolonged, serious, and disabling reactions. These reactions may affect several systems, organ classes and senses and may, in some cases, be irreversible.

These reactions include:

• Tendonitis;
• Tendon rupture;
• Arthralgia;
• Pain in the extremities;
• Gait disturbance;
• Neuropathies associated with paraesthesia;
• Depression;
• Fatigue;
• Memory impairment;
• Sleep disorders; and
• Impaired hearing, vision, taste, and smell.

These reactions have been associated with the use of fluoroquinolones via the oral, parenteral, and inhalation routes.

Effects on tendons

Tendonitis and tendon rupture are known adverse events associated with fluoroquinolones. Any tendon can be affected, but the Achilles tendon is most commonly implicated. The estimated incidence is between 0.14% and 2%. Onset can occur within days of initiating a fluoroquinolone, and almost all reported cases have occurred with one month. However, a longer latency of up to six months has been reported.

Risk factors for tendon effects may include older age, obesity, and physical exertion. As long-term use of glucocorticoids is independently implicated in tendinopathies, the concomitant use of a glucocorticoid may potentiate the risk with fluoroquinolones.

Adverse events affecting tendons can lead to prolonged disability or the need for surgical repair. If a patient develops tendon pain or inflammation, it is recommended that the fluoroquinolone be discontinued, and the affected limb rested.

Nervous system effects

Mononeuropathies and polyneuropathy have been reported in association with fluoroquinolone use. The resultant sensory disturbances can have a significant impact on functional ability and quality of life.

A large nested case-control study evaluated the risk of peripheral neuropathy with fluoroquinolones compared to amoxicillin + clavulanic acid. This study found that current fluoroquinolone use was associated with a significantly higher risk of peripheral neuropathy (adjusted incidence rate ratio [aIRR]: 1.47; 95% CI: 1.13-1.92). The risk was found to increase with increasing duration of fluoroquinolone use. There was no significant association with amoxicillin + clavulanic acid (aIRR: 1.10; 95% CI: 0.86-1.40).

Peripheral neuropathy is likely a rare adverse event. Risk factors may include high body mass index, alcohol abuse, amyloidosis, Sjögren syndrome, and shingles. For patients who develop symptoms of neuropathy during fluoroquinolone therapy, discontinuation of the fluoroquinolone is recommended to avoid the development of an irreversible condition. Symptoms that could indicate neuropathy include burning, tingling, numbness, and weakness.

Psychiatric adverse effects

Fluoroquinolones are associated with psychiatric adverse effects. These may be mild and include confusion, restlessness, and insomnia. Severe events such as catatonia, psychosis, and suicidal depression have also been reported. The usual reported incidence is 1% to 4.4%. However, one study reported an incidence of 13.6% in patients over 80 years with a history of neurologic or psychiatric disorders.

The potential for fluoroquinolones to cause these effects is thought to be related to their structural similarity to gamma-aminobutyric acid (GABA) and their high permeability across the blood-brain barrier. This allows access to the central nervous system (CNS) where these drugs may inhibit GABAergic neurotransmission.

A recent retrospective analysis of US data found that the class is associated with a range of psychiatric effects, although there are some key differences for the individual drugs. Ciprofloxacin was more frequently associated with adverse events of anxiety, depression, and suicidal ideation compared to other fluoroquinolones. Moxifloxacin may have a lower risk of depression and suicidal ideation but was more strongly associated with delirium. The study authors suggest that moxifloxacin may be preferred over ciprofloxacin for patients with pre-existing depression.

Risk factors for psychiatric adverse events appear to include high fluoroquinolone dose and a history of neurological or psychiatric disorders. However, it should be noted that psychiatric adverse events have been reported in patients with no relevant psychiatric history. Patient age may also be a significant variable with patients under 65 years experiencing more adverse events related to affective disorders, and older adults more likely to experience psychosis and delirium.

Recommendations:

The potential for fluoroquinolones to cause severe and long-lasting adverse events, combined with increasing levels of resistance, means that the use of this class should be restricted. These antibiotics are reserved for infections where alternative therapies are ineffective or contraindicated. In general, fluoroquinolones should not be used to treat infections that are non-severe or self-limiting. Their use should also be avoided in patients who have previously experienced severe adverse effects with a fluoroquinolone, unless there are no other appropriate alternatives.

Prior to initiating a fluoroquinolone, individual risk factors should be considered. As fluoroquinolones are cleared via the kidneys, renal impairment may increase the risk of adverse effects. Dose alteration is required for ciprofloxacin and norfloxacin when used in renal impairment.

Treatment with a fluoroquinolone be discontinued at the first signs of musculoskeletal, neurological, or psychiatric adverse effects.

An updated consensus statement on the management of Buruli ulcer has recently been published. Buruli ulcer is a skin infection caused by the bacteria Mycobacterium ulcerans. This condition is named after the Buruli district in Uganda where many of the earliest documented cases occurred. The condition is sometimes also referred to as Bairnsdale or Daintree ulcer.

The M. ulcerans bacterium produces the mycolactone toxin which can cause significant tissue damage. Infection typically begins with a dermal papule or subcutaneous nodule. Over the following weeks or months, these painless lesions can develop into necrotic ulcers. Less common presentations are plaques without ulceration or atypical cellulitis involving all or part of a limb.

While Buruli ulcer is considered a tropical or subtropical condition around the world, it does occur in cooler regions of Australia. In Australia, outbreaks have previously been limited to coastal regions of Victoria and north Queensland. However, infections have now been reported in many suburbs of Melbourne, coastal regions of New South Wales, and the Northern Territory. The spread into new areas of Australia has been accompanied with an increased incidence of infection.

Treatment includes effective wound care in combination with antibiotics. Surgery may be required in some cases.

Antibiotic therapy

The complex cell wall structure of the Mycobacterium species makes them intrinsically resistant to many antibiotics. Many antibiotics commonly used for skin and soft tissue infections, such as flucloxacillin and cefalexin, are not effective in the treatment of Buruli ulcer.

Dual antibiotic therapy is recommended for the treatment of Buruli ulcer. This increases the effectiveness of therapy and minimises the risk of resistance emerging. Observational data supports the use of rifampicin with either clarithromycin or a quinolone in Australian cases. A Victorian study demonstrated that this therapy was associated with excellent cosmetic outcomes and a cure rate of 99.2%. In this study, cure was defined as healing within 12 months.

The current consensus guidelines recommend the following oral therapies:

• Rifampicin 10 mg/kg per day (up to 600 mg daily)

PLUS one of:

• Clarithromycin 7.5 mg/kg twice daily (up to 500 mg every 12 hours) OR
• Moxifloxacin 400 mg once daily OR
• Ciprofloxacin 500 mg every 12 hours.

Clarithromycin and ciprofloxacin doses should be adjusted according to renal function. If rifampicin is contraindicated or not tolerated, clarithromycin may be prescribed in combination with a quinolone.

Rifampicin

Rifampicin belongs to the rifamycin class of antibiotics. It is broad-spectrum with activity against Mycobacteria, most Gram-positive bacteria, and some Gram-negative bacteria.

Doses are typically given once a day and should be taken on an empty stomach, either half an hour before meals or two hours after a meal. To avoid unnecessary concern, patients should be advised that rifampicin can cause a red-orange discolouration of urine, faeces, sweat, and tears. This can cause permanent staining of soft contact lenses.

Rifampicin is implicated in many clinically important drug interactions. It is a potent inducer of various drug metabolising enzymes and transporters, including cytochrome P450 enzymes and P-glycoprotein. Rifampicin can accelerate the metabolism of some co-administered medicines which may result in reduced efficacy. For example, rifampicin has been shown to decrease lurasidone exposure by 81% and this combination is contraindicated. Conversely, in the case of pro-drugs, it may increase their efficacy and risk of adverse events by accelerating their metabolic activation. For example, rifampicin increases the conversion of clopidogrel to its active metabolite. This combination should be avoided as it may increase the risk of bleeding.

Rifampicin can cause liver dysfunction. Caution is required in patients with liver disease and patients receiving other hepatotoxic agents.

Clarithromycin

Clarithromycin is a macrolide antibiotic. The consensus statement advises that clarithromycin plus rifampicin is preferred for patients who are pregnant.

Clarithromycin has many clinically relevant drug interactions. It is a strong inhibitor of CYP3A4 and inhibits P-glycoprotein and organic anion transporting polypeptide (OATP) 1B1. The manufacturer contraindicates use with many drugs including colchicine, domperidone, oral midazolam, ticagrelor, and simvastatin. As simvastatin is extensively metabolised by CYP3A4, concomitant use of clarithromycin can lead to increased simvastatin levels and a higher risk of myopathy. Caution is also required with other statins. Fluvastatin and pravastatin are safer options as their metabolism is not dependent on CYP3A4.

Azithromycin is another antibiotic in this class that may have activity against M. ulcerans. However, there is less experience with azithromycin in this setting.

Quinolones

Moxifloxacin and ciprofloxacin belong to the quinolone class of antibiotics. It is preferable for ciprofloxacin to be taken on an empty stomach. However, both of these agents may be taken without regards to meals. Co-administration with food does delay absorption but there is not a substantial impact on the extent of absorption.

Important points:

• Photosensitivity – ciprofloxacin may cause photosensitivity reactions. Patients should be advised to avoid direct exposure to sunlight and to wear protective clothing and a broad-spectrum sunscreen when outdoors. Moxifloxacin has not been associated with phototoxicity.
• Driving ability – quinolones can cause dizziness, light-headedness, and visual disturbances. Patients should be advised that these medications may affect their ability to drive or operate machinery.
• Tendinopathies – quinolones can cause tendinopathies. Factors that may increase the risk include older age, strenuous physical activity, renal impairment, and coadministration with corticosteroids. Patients should be advised to consult their doctor if they develop any signs of tendonitis.
• Neuropathy – quinolones are rarely associated with peripheral neuropathy. The antibiotic should be discontinued at the first symptoms of neuropathy to prevent the development of a potentially irreversible reaction.

General information

It is recommended that full blood examination, and hepatic and renal function be checked at baseline and repeated periodically where required. Alcohol should be avoided during therapy to minimise the risk of liver injury.

Prolongation of the QT interval can occur with clarithromycin and the quinolone antibiotics. An electrocardiogram is recommended at baseline and again two weeks later for patients at increased risk, i.e. patients with pre-existing cardiac disease and those taking another medication associated with QT prolongation. Many medications are associated with prolongation of the QT interval, including hydroxychloroquine, domperidone, and methadone. A complete list is maintained at www.qtdrugs.org.

Drug interactions are very common with these antibiotics. Patients should be advised to check with their healthcare professional before starting any new medication, including alternative and over-the-counter medicines.

Buruli ulcer lesions are notoriously slow to heal and may even enlarge upon initiation of antibiotic therapy. Evidence supports a treatment duration of eight weeks in most cases. There is some evidence to support a six-week duration in patients with small lesions at low risk of relapse, and a four-week course for patients who have undergone surgical excision. As the median time to heal is around four to five months, patients should be warned that ulcers may not have healed completely by the time the antibiotic course is finished.

Paradoxical reactions can occur during or after antibiotic therapy. These reactions, also known as immune reconstitution inflammatory reactions, are associated with increased tissue necrosis and delayed healing. These reactions are common, affecting around one in five patients treated with antibiotics. Older adults and those with oedematous lesions may be at greater risk. Early identification of paradoxical reactions is important to prevent significant tissue loss.

Prevention

The exact mode of transmission of M. ulcerans is not currently understood, which makes it difficult to implement effective preventative strategies. However, there is increasing evidence that mosquitos, possums, and environmental factors play a role in transmission in Australia.

Based on this information, the consensus statement makes the following recommendations to reduce the risk of Buruli ulcer:

• Avoid mosquito bites (i.e. mosquito repellents, protective clothing, fly screens, etc.);
• Minimise potential mosquito breeding sites (i.e. remove sources of still water around the home);
• Wear gloves and protective clothing when gardening or working outdoors;
• Keep any cuts and abrasions clean and use effective wound management practices; and
• Minimise contact with possums and their excreta.

An adverse event can be defined as an unintended occurrence associated with the use of a therapeutic good. This may be related to the use of a medicine, vaccine, or medical device. Adverse events are a leading cause of unplanned hospital admissions and deaths. Some studies suggest that medication-related adverse events contribute to between 10% and 30% of all hospital admissions in older patients.

Improving the understanding of adverse events is an important part of ongoing monitoring activities. The Therapeutic Goods Administration (TGA) regulates therapeutic goods in Australia and collects adverse event reports. Reporting suspected adverse events to the TGA is important as it allows safety issues to be identified early. Reports can be submitted by consumers, healthcare professionals, pharmaceutical companies, and medical device suppliers.

What is the purpose of reporting?

When a therapeutic good is first registered on the Australian Register of Therapeutic Goods, information on its safety and efficacy may be limited to clinical trials. Clinical trials do provide important information on adverse events. However, they cannot detect all possible adverse events for a number of reasons, including:

• The duration of a clinical trial may not be sufficient to detect events that take time to develop
• The trial population may not be large enough to detect very rare events
• The population may not be diverse enough to detect events that are more likely in specific patient groups (e.g. those with certain comorbidities, specific age groups, etc.).

This is why ongoing safety monitoring activities are so important. The TGA collects adverse event reports in the Database of Adverse Event Notifications (DAEN). There is a separate database for medicines and medical devices. Reports can be made for all medicines. This includes prescription and non-prescription medicines and complementary medicines such as herbal preparations and nutritional supplements.

The TGA is particularly interested in reports related to:

• New therapeutic goods (the Black Triangle Scheme helps to identify prescription medicines that are new or being used in a different way. For these medicines, the black triangle symbol appears on the product information (PI) and consumer medicine information (CMI) with a reminder to report adverse events);
• Medicine and/or vaccine interactions;
• Unexpected adverse events (i.e. those that do not appear in the product information or product labelling); and
• Serious adverse events (including those suspected of causing death, hospitalization, absence from productive activity, increased investigational or treatment costs, and birth defects).

The TGA encourages reporting of all suspected adverse events. It is not necessary to be certain that a particular therapeutic good caused the adverse event. Even where causality is uncertain, an individual report is still valuable as it contributes to the overall safety data for that therapeutic good. Each report helps the TGA assess the possible role the therapeutic good played in causing the adverse event and helps expand the known safety profile of the therapeutic good.

How to report:

Adverse event reports for medicines and vaccines can be submitted online. Reports can be quickly submitted without registering. However, registering yourself as a user provides additional features such as pre-populating your contact details and the ability to save drafts and view or amend previously submitted reports.

Alternatively, reports related to a vaccine can be submitted via email, fax, or mail using the National Adverse Events Following Immunisation (AEFI) reporting form. Reporting adverse events for vaccines provided under the National Immunisation Program (NIP) can be done via the local health authority who will then share the information with the TGA.

When submitting an adverse event report to the TGA, it is helpful to provide as much detail as possible. The following information is considered the minimum required:

• Your contact details (so that further information can be sought if required);
• Patient identifier (e.g. initials, date of birth, or age. The patient’s name should not be used);
• Details of the product involved; and
• Details of the suspected adverse event.

Outcomes:

The TGA uses information from adverse event reports to identify potential safety signals. When a safety signal is recognised, a detailed evaluation is conducted to establish the therapeutic good’s possible role in the event.

In Australia, it is mandatory for sponsors to report serious adverse events suspected of being related to their therapeutic good. However, reporting by healthcare professionals and consumers is voluntary. It is thought that less than 5% of adverse reactions are actually reported. Under-reporting has the potential to allow rare adverse events to go undetected for longer.

The following actions may be taken by the TGA in response to a safety signal:

• Publishing a Medicines Safety Update or Safety Alert on the TGA website
  • For example, a safety alert was recently published to highlight the potential for liver injury with Garcinia gummi-gutta (Garcinia cambogia) or hydroxycitric acid (HCA).
• Communicating the new safety information to healthcare professionals. This may include details of how to prevent an adverse event or assess risk factors in patients.
• Updates to the product labelling or PI and CMI documents
  • For example, an updated warning regarding the rare risk of cardiovascular death was added to the PI for azithromycin. In this case, there was insufficient evidence to establish or exclude causality. However, the warning provides further information to prescribers and may prompt clinicians to consider screening high-risk patients.
• Limiting the population the product can be used in
  • For example, oral promethazine products should not be used in children under six years of age due to the increased risk of adverse events in this population
• Suspending or cancelling the registration of the product
  • For example, the TGA cancelled the registration of pholcodine cough medicines in 2023 for safety reasons. An investigation found a link between pholcodine use and anaphylactic reactions to neuromuscular blockers during general anaesthesia. The decision to cancel pholcodine products took into account the severity of the potential reaction, the limited efficacy of the product, and the ready availability of therapeutic alternatives.
• Recalling a product
• Requiring the sponsor to conduct postmarket studies if additional information is required

Conclusion:

Reporting adverse events is essential for the ongoing safety monitoring of therapeutic goods. It helps to identify less common adverse events and populations that may be more susceptible. Healthcare professionals are encouraged to submit adverse event reports to support the ongoing monitoring of therapeutic goods in Australia.

If you would like to learn more about reporting adverse events, the Australian Commission on Safety and Quality in Health Care provides an online learning module.

Pharmacogenomics is an emerging field that looks at how genetic variations influence drug effects in individuals. Genetic variations can lead to differences in drug absorption, distribution, metabolism, and excretion (sometimes referred to as ‘ADME’). Variations in ADME processes can cause significant differences in drug exposure between individuals, translating into differences in efficacy and adverse effects.

In some cases, pharmacogenetic testing may be used to inform prescribing practices and individualise medicine use. The potential benefits include enhanced efficacy of prescribed therapies, reduced adverse drug reactions, and reduced drug wastage. A report commissioned by the Australian Centre for Health Research estimated that pharmacogenetic testing could save the Australian healthcare system over $1 billion annually.

Genes associated with altered drug responses include those that code for drug-metabolising enzymes, drug transporters, and human leukocyte antigen (HLA).

Drug-metabolising enzymes

The cytochrome P450 family of enzymes plays a major role in drug metabolism. Cytochrome P450 3A4 is involved in the metabolism of around 55% of prescription drugs, while CYP2D6 or CYP2C19 are involved in the metabolism of around 25% of prescription medicines. However, these enzymes are highly polymorphic, which can cause significant inter-individual differences in drug effects.

In terms of drug response, genetic variations can result in the following phenotypes:

• Poor metabolisers (i.e. have absent or markedly reduced enzyme);
• Intermediate metabolisers (i.e. have reduced enzyme);
• Extensive metabolisers (also referred to as “normal” metabolisers); and
• Ultra-rapid metabolisers (i.e. have high enzyme activity).

Codeine and CYP2D6

Codeine is an interesting example of how polymorphisms can have serious implications for a patient. For codeine to exert its opioid activity, it must be converted to its active metabolite, morphine. This reaction is catalysed by CYP2D6. Patients who are poor metabolisers will have a poor response to codeine. Conversely, patients who are extensive metabolisers or ultra-rapid metabolisers are at a greater risk of experiencing side effects. This is due to a greater conversion of codeine to morphine, which has a 200-fold greater affinity for the mu-opioid receptor. In these patients, serum morphine levels may be much higher than expected, and opioid toxicity is more likely to occur, even at commonly used doses.

Pharmacokinetic studies have found that the use of codeine in people defined as poor metabolisers leads to a 96% lower morphine exposure compared to normal metabolisers. These individuals also showed no difference in analgesia for codeine compared to placebo. Ultra-rapid metabolisers had a 45% higher exposure to morphine compared to normal metabolisers. These patients may be more likely to experience toxicity, even at low codeine doses.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that codeine be avoided in patients who are CYP2D6 ultrarapid metabolisers to avoid severe toxicity. They also recommend avoiding codeine in patients who are poor metabolisers due to the risk of poor effect. Where an alternative opioid is required, tramadol should be avoided as this agent also requires CYP2D6 for conversion to its more active metabolite.

The prevalence of different CYP2D6 phenotypes varies considerably according to ancestral background. On average, it is estimated that around 1-2% of people are ultra-rapid metabolisers, and around 5-10% of people are poor metabolisers. People of North African, Ethiopian and Arab backgrounds are more likely to be ultra-rapid metabolisers, with a reported prevalence of up to 28%.

Cytochrome P450 and depression

The management of depression can be challenging, with 50% of patients not responding to their initial antidepressant and less than 50% of patients achieving remission within 12 months of starting drug therapy. Part of this issue may be related to cytochrome P450 polymorphisms.

Two main enzymes are involved in the metabolism of antidepressants, CYP2D6 and CYP2C19. One retrospective study investigated the impact of cytochrome P450 polymorphisms on health resource utilisation in patients with anxiety and depression. The authors found that patients prescribed a medication not aligned with their pharmacogenetic test results had 69% more healthcare visits than patients whose therapy was aligned with their pharmacogenetics. These patients also had three times more medical absence days and four times more disability claims.

The potential impact of these findings is significant. One Australian study found that a quarter of people taking antidepressants were taking one that did not align with their CYP2D6 and CYP2C19 genotypes. These patients were also found to be more likely to switch between antidepressants, which is suggestive of poor therapeutic effects or adverse effects.

Thiopurine methyltransferase

Thiopurine methyltransferase (TPMT) is an enzyme that is crucial for the metabolism of thiopurines. Individuals with an inherited deficiency of this enzyme are at higher risk of adverse effects when treated with a thiopurine.

Profound deficiency of TPMT is found in around 0.3% of the population. These patients may develop severe myelosuppression when treated with usual doses of thiopurines. Around 11% of the population are carriers for this deficiency and may also have some degree of reduced tolerance to thiopurines. The Australian product information recommends testing patients for TPMT activity before starting mercaptopurine, azathioprine, and tioguanine.

Drug transporters

Organic anion-transporting polypeptides (OATP) are a family of transporters that move a wide range of endogenous and exogenous organic compounds. These transporters have a wide tissue distribution and play a role in drug uptake into various tissues, including hepatic uptake prior to drug elimination.

OATP1B1 and simvastatin

The SLCO1B1 gene provides instructions for making the protein, OATP1B1. The OATP1B1 protein is mainly found in the liver and plays an important role in the hepatic elimination of many compounds, including some drugs.

Inherited polymorphisms in the SLCO1B1 gene that lead to reduced function of OATPB1 have been associated with statin-induced myopathy. This is due to reduced hepatic uptake of the statin, which leads to higher plasma levels. Simvastatin is particularly affected by this polymorphism. The CPIC recommend that patients with decreased or poor metaboliser phenotypes should receive a lower dose of simvastatin or be prescribed an alternative statin.

Human leukocyte antigen

Variations in HLA genotype can be used to predict the likelihood of immune-mediated reactions, some of which can be severe and life-threatening.

For example, it is recommended to test for HLA-B*5701 status prior to initiating abacavir therapy. Patients who test positive have a significantly higher risk of hypersensitivity reactions. These reactions can present with symptoms similar to pneumonia, bronchitis or pharyngitis, influenza-like illness, or gastroenteritis.

Some examples of drugs that may be affected by gene variants are shown in Table 1.

Table 1. Drugs affected by gene variants

Gene	Examples of drugs affected	Result
CYP2D6	Codeine	Poor metabolisers – drug is ineffective Ultra-metabolisers – higher risk of toxicity
	Selective serotonin reuptake inhibitors (SSRIs)	Ultra-metabolisers – poor response Poor metabolisers – may need lower dose
CYP2C19	Clopidogrel	Poor metabolisers – reduced effect. Consider alternative therapy.
DPYD	Capecitabine Fluorouracil	Deficiency of dihydropyrimidine dehydrogenase increases risk of severe toxicity.
SLCO1B1	Simvastatin	Gene variants can significantly increase or decrease risk of myopathy.
HLA	Allopurinol	Variants associated with higher risk of allopurinol-related hypersensitivity syndrome and SJS/TEN
	Carbamazepine	Some variants may predispose to SJS, TEN, DRESS, and AGEP.

Abbreviations: AGEP, Acute Generalized Exanthematous Pustulosis; DRESS, Drug Rash with Eosinophilia and Systemic Symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Phenoconversion

Additional factors may need to be considered when interpreting pharmacogenetic results due to phenoconversion.

Phenoconversion refers to the mismatch between an individual’s genotype and phenotype, i.e. their actual drug metabolising capacity differs from what genetic testing predicts. This could be related to a range of factors, such as drug interactions.

Many medications have significant effects on metabolising enzymes. For example, a patient with a genotype for normal codeine metabolism may be converted to a poor metaboliser if codeine is co-administered with a strong inhibitor of CYP2D6 (e.g. terbinafine).

Some examples of agents known to inhibit and induce major drug metabolising enzymes are shown in Table 2.

Table 2. Medications associated with phenoconversion

Enzyme	Inhibitors	Inducers
CYP2C9	Amiodarone Fluconazole Fluoxetine Fluvoxamine Voriconazole	Carbamazepine Rifampicin St John’s wort
CYP2C19	Fluoxetine Fluvoxamine Omeprazole Paroxetine Topiramate	Apalutamide Rifampicin Ritonavir St John’s wort
CYP2D6	Amiodarone Bupropion Cinacalcet Duloxetine Fluoxetine Methadone Paroxetine Terbinafine
CYP3A4	Aprepitant Ceritinib Clarithromycin Cobicistat Idelalisib Posaconazole Ritonavir Voriconazole	Apalutamide Carbamazepine Encorafenib Lumacaftor Phenytoin Rifampicin St John’s wort
UGT1A1	Erlotinib Nilotinib Sorafenib Pazopanib	Carbamazepine Phenytoin Rifampicin
TPMT	Aspirin Furosemide Olsalazine Sulfasalazine NSAIDs Thiazide diuretics

 

The extent to which these agents impact drug metabolism will depend upon the dose administered and the duration of therapy. For enzyme-inhibiting drugs with a long half-life and high affinity for drug-metabolising enzymes, their effects can persist for many days after their last dose. For example, phenoconversion following chronic fluoxetine therapy is reported to persist for six weeks after discontinuation.

Other factors have also been implicated in phenoconversion. These include advanced age, frailty, obesity, cancer, inflammation, smoking, alcohol, and vitamin D exposure. However, further study of the impact of these factors is required.

Summary

Genetic variations have been implicated in an increased susceptibility to adverse reactions and reduced therapeutic efficacy. Pharmacogenetic testing may offer a means of individualising drug therapy to optimise both drug efficacy and tolerability. Unfortunately, high-level evidence for pharmacogenetic testing currently exists only for a relatively small number of genes.

The Royal College of Pathologists of Australia maintains a summary of drugs and their evidence for pharmacogenetic testing.

The Australian Commission on Safety and Quality in Healthcare recently released the Chronic Obstructive Pulmonary Disease Clinical Care Standard. This is the first national standard on chronic obstructive pulmonary disease (COPD), a common condition thought to affect around one in 13 Australians over the age of 40.

The new standard aims to reduce potentially preventable hospitalisations and improve overall outcomes for people with COPD. One of the main causes of preventable hospitalisations in this population is COPD exacerbations. An exacerbation is characterised by acute worsening of symptoms beyond what would be considered normal day-to-day variations. This may include increasing dyspnoea, worsening of chronic cough, and changes in sputum. Reducing exacerbations is a primary goal of COPD management.

Tobacco smoking is the most common risk factor for COPD. According to the Australian Burden of Disease Study 2024, tobacco contributed to 65% of the total burden from COPD. There has been a reduction in the rate of burden attributed to tobacco in Australia over the past few decades. This is likely due to the significant decrease in smoking prevalence. However, as there is a long lag time between smoking and developing disease, its contribution to disease burden is still high.

The evidence clearly demonstrates that smoking cessation is the most important intervention to prevent or minimise lung damage and reduce mortality in patients with COPD who smoke. Patients who currently smoke should be encouraged to quit smoking and offered evidence-based smoking cessation interventions.

Other interventions with evidence to support a reduction in exacerbations include:

• Optimisation of pharmacological therapies;
• Keeping up-to-date with recommended vaccinations; and
• Pulmonary rehabilitation.

Optimisation of pharmacological therapies.

Pharmacological therapies are an important part of COPD management as they can reduce symptoms and prevent exacerbations. The COPD-X Handbook provides information on a stepwise approach to therapy.

Therapy starts with a short-acting reliever that is used on an as-needed basis. This reliever may be a short-acting beta₂-agonist (SABA) or a short-acting muscarinic antagonist (SAMA). A long-acting bronchodilator, either a long-acting muscarinic antagonist (LAMA) or long-acting beta₂-agonist (LABA), may then be added. Depending on the response, a combination of LAMA + LABA may be considered. An inhaled corticosteroid may also be required for patients with moderate to severe COPD.

There are many different inhaler products and devices available. Some devices require the patient to load a capsule into the inhaler before each dose, while others are pre-loaded. Some devices, such as the metered dose inhaler, require a high level of coordination and manual dexterity. However, regardless of the type of device, optimal use of inhalers presents more challenges than most other dose forms. Therefore, patients must be trained on how to use each specific device correctly. The Lung Foundation Australia provides instructional videos for various inhaler devices.

Where possible, it is recommended to minimise the number of different inhaler devices used by a patient. Having multiple devices with different methods of use may increase the chances that the patient will not use their devices correctly. Incorrect inhaler technique is common, with reports that up to 90% of patients do not use their devices correctly. Poor inhaler technique can reduce drug delivery to the lungs, resulting in reduced efficacy and an increased risk of exacerbations. One study demonstrated a two-fold increase in the rate of severe exacerbations in the previous three months for patients with at least one critical device error compared to patients with no critical errors.

Inhaler technique should be regularly checked. In particular, it should be checked before considering an escalation of therapy, after a change in treatment, and after an exacerbation. The clinical care standard advises that all clinicians involved in a patient’s care can play a role in checking and correcting inhaler technique.

Reducing the complexity of therapy may also play a role in improving compliance with therapy. Many combination inhalers are now available, which have the potential to reduce the number of devices and doses that a patient needs to use.

Vaccinations

People with COPD are at higher risk of experiencing complications from many infections. Bacterial and viral infections are also known triggers for COPD exacerbations. Therefore, it is recommended that people with COPD are up-to-date with vaccinations for influenza, COVID-19, and pneumococcal disease.

Additional vaccines, such as a herpes zoster vaccine, may also be recommended. One meta-analysis found that people with COPD have a 41% higher risk of herpes zoster compared to healthy controls. The risk of complications may also be higher, with one study finding that COPD was associated with a 53% increased risk of post-herpetic neuralgia.

Shingrix® (varicella-zoster vaccine) is currently funded under the National Immunisation Program (NIP) for all adults 65 years of age and older, Aboriginal and Torres Strait Islander people from 50 years of age, and people 18 years of age or older with moderate to severe immunocompromise.

Pulmonary rehabilitation

Pulmonary rehabilitation has been shown to improve symptoms and reduce the risk of COPD exacerbations. These programs usually run over six to eight weeks and combine exercise, education, and self-management techniques. Patients who have completed a pulmonary rehabilitation program should be encouraged to continue with their exercise program to ensure the benefits are maintained.

The clinical care standard recommends that pulmonary rehabilitation be offered to all patients with COPD. For patients admitted to the hospital with a COPD exacerbation, the standard advises to begin within four weeks. This reduces the short-term risk of re-admission while also improving symptoms and quality of life following the exacerbation.

People with diabetes are at a greater risk of many infections. This includes infections of the urinary tract, respiratory tract, skin and soft tissues. Infections are a significant cause of morbidity and mortality in this population. While the reasons for this elevated risk are complex, impaired innate and adaptive immune responses within the hyperglycaemic environment are thought to be important factors.

Poor glycaemic control is associated with a higher risk of infection. One large cohort study found that, for most infection types, the rate of infections rose steadily with increasing HbA_1c. This was particularly true for patients with a HbA_1c ≥ 11%. Chronic complications of diabetes, such as neuropathy, can also predispose to infections.

The urinary tract is one of the most common sites of bacterial infections in people with diabetes. While the frequency of urinary tract infections (UTIs) is increased, this population is also likely to experience a worse prognosis. They are more likely to require hospitalisation for their UTI, and serious complications are more common.

Emphysematous pyelonephritis

Emphysematous pyelonephritis (EPN) is one of the most serious types of UTI. Although this is an uncommon condition, it is highly associated with diabetes, with around 95% of cases occurring in patients with uncontrolled diabetes mellitus.

Emphysematous pyelonephritis is an acute necrotising infection of the renal parenchyma and surrounding tissues. It is caused by bacteria that are able to ferment glucose to produce carbon dioxide. Potential causative pathogens include Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. In almost 70% of cases, E. coli is isolated on urine or pus cultures.

If not diagnosed early, this condition can be life-threatening, with mortality mostly related to septic complications. Patients may initially present with non-specific symptoms, although the clinical triad of fever, flank pain and nausea is typically seen. In severe cases, altered consciousness and shock may be apparent. Predictors of poor prognosis include thrombocytopenia, azotaemia, and high urinary red blood cell counts. Diagnosis is supported by imaging of the abdomen and pelvis, which will show the presence of intra-renal gas.

Initial treatment includes broad-spectrum antibiotics, fluid and electrolyte resuscitation, acid-base balance, percutaneous catheter drainage, and rapid glycaemic control. Empiric antibiotic therapy should target gram-negative bacteria while also considering local resistance patterns and individual patient factors. Third or fourth-generation cephalosporins or carbapenems may be considered. Factors that may favour the use of a carbapenem include hospitalisation with antibiotic use within the previous 12 months, the need for emergency haemodialysis, or the presence of disseminated intravascular coagulation. One study demonstrated that these factors had a significant correlation with cephalosporin resistance.

While emphysematous pyelonephritis is rare, it should be considered in patients with diabetes who present with pyelonephritis. Early recognition and initiation of appropriate therapy are essential to minimise mortality and potentially reduce the need for nephrectomy.

Sodium-glucose cotransporter-2 inhibitors

While diabetes itself is a risk factor for UTIs, one class of medications used to treat diabetes has been suggested to increase this risk even further. Concerns were raised about sodium-glucose cotransporter-2 (SGLT2) inhibitors and their potential to increase the risk of urinary tract and genital infections. This is related to the way in which they reduce blood glucose levels. As they work to inhibit glucose reabsorption in the proximal tubules, glucose levels in the urine are elevated. The resulting glycosuria is hypothesised to enhance bacterial growth within the urogenital environment.

Dapagliflozin and empagliflozin are SGLT2 inhibitors. They are available as single-ingredient preparations and fixed-dose combinations with metformin or linagliptin.

While urogenital infections have been reported in association with these medicines, data from large randomised clinical trials and real-world population-based studies suggest that they may not increase the risk of UTIs. One meta-analysis demonstrated that while SGLT2 inhibitors may increase the risk of genital infections, the class is not generally associated with an increased risk of UTI. However, dapagliflozin was associated with an increased risk of UTI compared to placebo when given at a dose of 10mg daily (RR 1.33, 95% CI 1.10–1.61), but not at 5mg daily. This elevated risk was not seen with empagliflozin at any dose nor with dapagliflozin when compared to active comparators.

This lack of observed UTI risk despite the favourable conditions these medicines provide for bacterial growth could be related to their diuretic effect. Therefore, the UTI risk profile may be different for patients with abnormal urinary flow.

Pathogens

Urinary tract infections occurring in people with diabetes are more likely to be caused by resistant pathogens. This includes extended-spectrum β-lactamase-positive Enterobacteriaceae, fluoroquinolone-resistant uropathogens, carbapenem-resistant Enterobacteriaceae, and vancomycin-resistant Enterococci.

The increased incidence of resistant infections in this group could be related to a general increased consumption of antibiotics for UTIs and other infections. This highlights the importance of antimicrobial stewardship initiatives to ensure that antimicrobial use is optimal in this group. For example, asymptomatic bacteriuria is more common in people with diabetes. However, this should not be treated with antibiotics unless the patient is pregnant or undergoing certain elective urological procedures. In other cases, the evidence suggests that treatment of asymptomatic bacteriuria does not reduce the incidence of symptomatic UTI or long-term complications and may increase the risk of resistant infections.

Type 2 diabetes is also a risk factor for fungal UTIs, typically with Candida spp. Fluconazole is often the agent of choice for the treatment of fungal UTIs. It has high oral bioavailability, a long half-life, and achieves adequate levels in the urine. Fluconazole is active against C. albicans and the most common non-albicans Candida species. Higher doses are typically required for infections caused by C. glabrata (recently renamed Nakaseomyces glabrata). The most recent AURA report (Antimicrobial Use and Resistance in Australia Surveillance System) finds that azole resistance among this species is 8.6% and may be increasing. Amphotericin B is a potential alternative where resistant yeasts are involved. However, liposomal formulations of amphotericin B do not achieve high urinary concentrations. Therefore, they are not suitable for lower UTIs.

Prevention

Optimal control of diabetes is essential to minimise the risk of infections as well as other diabetes complications. The Royal Australian College of General Practitioners (RACGP) make the following recommendations for the optimal management of type 2 diabetes:

• Eat according to the Australian dietary guidelines; individual dietary review is recommended if cardiovascular disease is present;
• Weight loss, if appropriate;
• At least 30 minutes of moderate physical exercise on most days (total ≥150 minutes/week);
• Cease smoking, where relevant;
• Limit alcohol intake to ≤2 standard drinks per day;
• Aim for 6–8 mmol/L fasting and 8–10 mmol/L postprandial blood glucose levels
• HbA_1c goals should be individualised, but a general goal would be ≤7% (6.5–7.5%) or ≤53 mmol/mol (48–58 mmol/mol);
• Address cardiovascular risk factors, as appropriate (i.e. blood pressure, blood lipids, etc.); and
• Consider vaccination, e.g. against seasonal influenza and pneumococcal disease.

Other preventative measures that may be considered to reduce the risk of UTIs include adequate hydration, avoidance of constipation, and attention to hygiene.

Antiemetics can be used to treat or prevent nausea and vomiting due to a range of causes. Their use can significantly improve quality of life and prevent complications such as dehydration and electrolyte disturbances.

Several neural pathways are involved in the development of nausea and vomiting. These include dopaminergic, serotonergic, histaminergic, cholinergic, neurokinin and cannabinoid receptor-mediated pathways. No antiemetic is universally effective, as no agent acts on all of these receptors.

The choice of antiemetic is influenced by the cause of nausea and vomiting, severity of symptoms, preferred route of administration, and the patient’s previous response to therapy. If a poor response occurs to one agent, a medication from a different class may be considered. Combination therapy using antiemetics with different mechanisms of action may also be considered.

Dopamine antagonists

Dopamine acts on D2 receptors in the chemoreceptor trigger zone (CTZ) to induce nausea and vomiting. Dopamine antagonists treat and prevent nausea and vomiting by blocking these receptors. Domperidone and metoclopramide also have prokinetic effects, which may be useful if symptoms are due to gastroparesis.

While dopamine is involved in the development of nausea and vomiting, it has a number of other functions in the brain. These include motor control, cognitive function, pleasure/reward, and hormonal control. Therefore, dopamine antagonists are associated with adverse effects, such as extrapyramidal side effects (EPSE) and elevation of prolactin levels.

The risk of EPSE is greatest with high doses and rapid intravenous administration of dopamine antagonists. Caution should be used in patients who are elderly as they may be more sensitive to the adverse effects of this class. These agents should generally be avoided in patients with Parkinson’s disease as they can cause significant exacerbation of parkinsonian symptoms. Of the dopamine antagonists, domperidone is least likely to cause this issue as it does not readily cross the blood-brain barrier.

Domperidone

Domperidone is indicated for the short-term treatment of intractable nausea and vomiting from any cause. Domperidone has been associated with an increased risk of serious ventricular arrhythmias and sudden cardiac death. This risk may be higher in patients taking doses greater than 30mg a day and in those over 60 years of age. Domperidone is contraindicated in patients with pre-existing prolongation of cardiac conduction intervals, significant electrolyte disturbances, or underlying cardiac conditions such as congestive heart failure.

Domperidone is primarily metabolised via CYP3A4. To minimise adverse effects, domperidone is contraindicated with potent inhibitors of CYP3A4 (e.g. azole antifungals, macrolide antibiotics, diltiazem, verapamil, amiodarone, aprepitant, fosamprenavir, ritonavir, saquinavir).

Metoclopramide

Metoclopramide is used to control nausea and vomiting associated with medications, uraemia, radiation sickness, malignancy, labour, infectious disease, and postoperative vomiting.

Metoclopramide is available as an oral tablet and an injection for intramuscular or intravenous use. The onset of effect is 1-3 minutes following an IV dose, 10-15 minutes for an IM dose, and 30-60 minutes following an oral dose; effects persist for 1-2 hours.

To minimise the risk of EPSE, metoclopramide is recommended for short-term use only (up to five days). Children are also at greater risk of EPSE with metoclopramide and it should be avoided in patients younger than 20 years.

Prochlorperazine

Prochlorperazine is used for the treatment of nausea and vomiting due to various causes and is available as a tablet and an injection. In addition to its action on dopamine receptors, prochlorperazine also has antagonist effects at α-adrenoceptors, histamine receptors, and cholinergic receptors, and potentiates noradrenaline. This may result in adverse effects such as orthostatic hypotension, reflex tachycardia, sedation, dry mouth, and constipation.

Droperidol

Droperidol can be used to prevent or treat postoperative nausea and vomiting. It is available as an injectable for IV or IM use. The usefulness of droperidol is limited by its sedating tendency and risk of EPSE.

5HT₃ antagonists

5-HT₃ antagonists block serotonin peripherally (in the gastrointestinal system) and centrally in the CTZ. It is thought that chemotherapeutics and radiotherapy can cause the release of 5-HT in the small intestine to trigger a vomiting reflex. These agents are effective in managing nausea and vomiting associated with cancer therapy and surgery.

The 5-HT₃ antagonists available in Australia are:

• Granisetron;
• Ondansetron;
• Palonosetron; and
• Tropisetron.

All of these agents appear to be similarly effective overall. However, palonosetron is more effective for preventing postoperative vomiting than ondansetron. When used for chemotherapy-induced nausea and vomiting, 5-HT₃ antagonists are more effective for acute rather than delayed symptoms.

5-HT₃ antagonists have a favourable side effect profile; common adverse effects include constipation, headache, and dizziness.

These agents are available in a range of presentations, including tablets/capsules, orally disintegrating tablets, oral liquid, and injections.

Substance P antagonists

Substance P antagonists prevent the binding of substance P to the neurokinin type 1 receptor (NK-1R) in the CTZ. This class includes:

• Aprepitant;
• Fosaprepitant;
• Fosnetupitant (only available in combination with the 5-HT₃ antagonist, palonosetron)
• Netupitant (only available in combination with palonosetron).

Fosnetupitant and fosaprepitant are phosphorylated pro-drugs of netupitant and aprepitant, respectively. This improves their water solubility. Following IV administration, they are rapidly converted to their active form.

Substance P antagonists are indicated for the prevention of acute and delayed nausea and vomiting associated with chemotherapy. For this purpose, they are typically administered in combination with a 5-HT₃ antagonist and a corticosteroid (e.g. dexamethasone). Aprepitant is also indicated for the prevention of postoperative nausea and vomiting.

Common side effects for this class include diarrhoea, fatigue, headache, and dizziness. There are many potential drug interactions with this class due to their effects on cytochrome P450. Aprepitant inhibits, induces and is metabolised by CYP3A4, and is also a moderate inducer of CYP2C9. Caution is required when administering with other medicines metabolised by these enzymes as therapeutic effect may be altered and adverse effects may be increased. Combination with pimozide, terfenadine, astemizole, or cisapride is contraindicated.

Netupitant is metabolised by, and moderately inhibits, CYP3A4. Combined use with a strong CYP3A4 inducer should be avoided as netupitant levels may reduce significantly. Caution should be used when combining netupitant with medicines that rely on CYP3A4 for metabolism as their levels may rise, increasing the risk of adverse effects. It is worth noting that netupitant has a long half-life (~88 hours), so this inhibitory effect may last for four days or more.

Antihistamines

Antihistamines reduce nausea and vomiting by blocking the effects of histamine in the CTZ. Cyclizine and promethazine are the antihistamines typically used for the management of nausea and vomiting in the hospital setting. Agents such as levomepromazine are not marketed in Australia but may be accessed via the Special Access Scheme. Other antihistamines are available over the counter for the management of motion sickness (e.g. dimenhydrinate in a fixed-dose combination with hyoscine).

Antihistamines can cause sedation. Due to their anticholinergic properties, they may also cause side effects such as dry mouth and constipation. Promethazine also has some anti-serotonin effects.

Promethazine is available as tablets and as an injection. It is a known vesicant, and the manufacturer recommends deep intramuscular injection into a large muscle as the preferred method of parenteral administration. Intravenous or inadvertent intra-arterial or subcutaneous administration can result in complications that may be severe (e.g. thrombophlebitis, venous thrombosis, phlebitis, nerve damage, abscess, tissue necrosis, and gangrene). However, care is required wherever injectable promethazine is used, as all administration routes can result in tissue damage. The Institute for Safe Medication Practices (ISMP) strongly advises against the use of injectable promethazine in favour of safer alternatives, such as 5-HT₃ antagonists.

Summary

A summary of commonly used antiemetics is shown in Table 1. If a poor response occurs to one agent, a drug from a different class may be considered. Alternatively, combination therapy using antiemetics with different mechanisms of action may also be considered.

Table 1. Overview of antiemetic agents

Drug	Form	Usual dosing	Notes
Dopamine antagonists
Domperidone	Tablets	3 times daily	Can cause EPSE Avoid in Parkinson’s disease
Droperidol	Injection	Single dose
Metoclopramide	Tablets, injection	3 times daily
Prochlorperazine	Tablets, injection	3 times daily
5-HT3 antagonists
Granisetron	Tablets, injection	Daily
Ondansetron	Tablets, wafer, oral liquid, injection	2-3 times daily
Palonosetron	Injection	Single dose	Long half-life (~40 hours)
Tropisetron	Injection	Daily
Substance P antagonists
Aprepitant	Capsule	Single dose	Many clinically significant drug interactions
Fosaprepitant	Injection	Single dose
Fosnetupitant + palonosetron	Injection	Single dose
Netupitant + palonosetron	Capsule	Single dose
Antihistamines
Cyclizine	Tablets, injection	Up to 3 times daily	May cause sedation
Promethazine	Tablets, oral liquid, injection	Up to 4 hourly

 

 

The scheduling of paracetamol will change on 1 February 2025, affecting pack sizes and how paracetamol-containing products can be accessed. These changes are intended to minimise harm related to intentional paracetamol overdose while also maintaining appropriate access for therapeutic use.

The upcoming changes are summarised in Table 1. These restrictions apply to all paracetamol-containing products, including combination products with additional active ingredients (e.g. paracetamol-containing cold and flu tablets).

Table 1. Summary of changes to paracetamol scheduling

	Current rules	Rules from 1st February 2025
Immediate-release tablets and capsules
Unscheduled (i.e. non-pharmacy retailers)	Maximum pack size of 20	Maximum pack size of 16
Schedule 2 (Pharmacy Only)	Maximum pack size of 100	Maximum pack size of 50*
Schedule 3 (Pharmacist Only)	N/A	Pack sizes up to 100
Schedule 4 (Prescription Only)	No change
Packaging for general sale	Blister or bottle	Blister packaging only
Other forms
Modified-release tablets	No change
Paracetamol liquid	No change

* Poisons regulations governing the storage and display of Schedule 2 medicines differ slightly in Queensland and Western Australia. In these states, the maximum pack size available for self-selection in a pharmacy will be 16 tablets or capsules; packs of 16 to 100 will be stored behind the counter.

Implementation of changes

Non-pharmacy retailers must comply with these new pack limits from 1 February 2025. They are also encouraged to restrict sales to a single pack at a time.

Pharmacies will also need to implement these changes for the storage and supply of paracetamol products from 1 February 2025. Manufacturers have already begun to supply wholesalers with products that are compliant with the new restrictions in terms of pack size and updated labelling. However, pharmacies have been granted a 12-month labelling exemption. During this period, pharmacies may continue to supply paracetamol-containing products with the existing labelling as long as they comply with the new storage and supply conditions.

Why are these changes being made?

While paracetamol has an excellent safety profile when used therapeutically, it is hepatotoxic and potentially fatal in overdose. Given the ready availability of paracetamol, it is perhaps not surprising to know that it is commonly involved in overdoses. Recent Australian evidence shows that paracetamol is:

• The most common cause of severe acute liver injury;
• The most common reason for calls to Poisons Information Centres;
• One of the most common medications involved in deliberate self-poisoning;
• Involved in a large percentage of accidental paediatric exposures; and
• Involved in a significant number of overdoses with therapeutic intent.

The Therapeutic Goods Administration (TGA) estimate that around 225 people are hospitalised with liver injury, and 50 people die from paracetamol overdose each year in Australia.

The final decision to make these changes was the result of a lengthy consultation period. This included an independent expert report examining the incidence of serious injury and death from intentional paracetamol overdose; advice from the Advisory Committee on Medicines Scheduling (ACMS); and submissions from individuals, and organisations representing consumers, healthcare practitioners, and industry.

The Independent expert report on the risks of intentional self-poisoning with paracetamol was commissioned by the TGA to examine the reasons for the increasing rate of intentional paracetamol overdoses. In particular, the report focussed on the rising prevalence in young people involving paracetamol sourced from non-pharmacy settings (i.e. supermarkets and convenience stores).

This report found that the majority of paracetamol self-poisonings are impulsive but with suicidal intent. This was true across all age groups. The paracetamol taken was present in the home in more than half of all cases, with only around 10% of individuals reporting a recent paracetamol purchase. Where purchases were made, one or two packs were typically bought. The pack sizes most commonly involved were 20/24s and 96/100s; unscheduled products were involved in between 25% and 30% of events.

The largest pack size available is often consumed in an intentional self-poisoning. Therefore, the idea of reducing pack sizes is often suggested as a harm minimisation strategy. Evidence shows that the introduction of reduced pack sizes is associated with reduced harm from self-poisoning. For example, the United Kingdom made changes to the scheduling of paracetamol in 1998. This has been associated with a 43% reduction in paracetamol-related deaths, a 61% reduction in registration for liver transplants due to paracetamol-induced hepatotoxicity, and a reduction in the median number of tablets taken in an intentional overdose (from 50 to 20 tablets for males and from 20 to 16 tablets for females). However, while there has been a significant reduction in the severity of paracetamol poisonings, the frequency of reported cases has not decreased.

Treatment of paracetamol overdose

While paracetamol overdose is common, severe liver injury and death are not common outcomes. This is due to the efficacy of therapies, although this is dependent upon the time to initiation of therapy.

The management of a paracetamol overdose will depend upon the context. For example:

• Overdose involving immediate-release compared to modified-release products;
• Unintentional overdoses in children younger than six years; and
• Unintentional overdose with therapeutic intent (also referred to as repeated supratherapeutic ingestion [RSTI]).

For example, activated charcoal may be used for gastrointestinal decontamination in patients presenting early (i.e. within two hours of ingesting immediate-release preparations and four hours for modified-release). However, this would not be useful in RSTI, where the paracetamol ingestion occurs over a long period.

Acetylcysteine:

Acetylcysteine is a paracetamol antidote used for patients at risk of hepatotoxicity. It is highly effective when given early, particularly within eight hours of ingestion. The therapeutic effect of acetylcysteine occurs via several mechanisms.

When administered in therapeutic quantities, paracetamol is primarily metabolised via glucuronidation and sulfation. Less than 5% is oxidised by cytochrome P450 to generate the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Glutathione present in the liver can normally detoxify the small amounts of NAPQI produced, thereby preventing cellular injury. This occurs via irreversible conjugation of NAPQI to the sulfhydryl groups of glutathione.

However, when excessive amounts of paracetamol are taken, the glucuronidation and sulfation pathways become saturated. Metabolism via the CYP450 pathway then increases with a greater quantity of NAPQI produced. This leads to the depletion of glutathione reserves and the accumulation of toxic metabolites, which are the causes of hepatic injury.

Acetylcysteine is a sulfhydryl donor which can directly conjugate with NAPQI to prevent hepatic injury. Other possible mechanisms include providing cysteine (an essential precursor of glutathione) and increasing blood flow and oxygen delivery to the liver.

The Updated Guidelines for the Management of Paracetamol Poisoning in Australia and New Zealand provide details of the protocols recommended for various clinical situations. Expert advice is recommended in the following cases as the risk of hepatotoxicity and complications is greater:

• Overdoses involving more than 50g or 1g/kg (whichever is less);
• High paracetamol levels (>3 times the nomogram line);
• Overdoses involving IV paracetamol;
• Hepatotoxicity (i.e. ALT > 100 IU/L); and
• Neonatal poisonings.

Advice can be sought from a clinical toxicologist or from a Poisons Information Centre (13 11 26).

Summary

These changes to paracetamol scheduling are intended to minimise the harm related to intentional overdoses. There have been no changes to treatment guidelines or dosing recommendations. Patients can be assured that paracetamol remains a safe medication when used appropriately.

Additional steps that can be taken to minimise paracetamol-related harm include:

• Encouraging patients to avoid stockpiling medication;
• Encouraging patients to store all medicines out of the reach of children;
• Educating patients to be aware of the active ingredients in the medications they use. This can avoid inadvertent overdosing from taking more than one paracetamol-containing product at the same time; and
• Educating patients on the correct dose and dosing interval for paracetamol.