Knowledge Type: Clinical Articles

Interstitial cystitis (IC) or bladder pain syndrome (BPS) is a chronic bladder health issue. In the healthy bladder, a natural barrier protects the bladder lining from irritating and toxic substances found in the urine. That barrier is called the glycosaminoglycan (GAG) layer. If this barrier is damaged, urine comes in direct contact with the tissues of the bladder lining and, over time, can cause damage to this tissue as well as allowing bacteria to adhere. Chronic inflammation also affects the integrity of the GAG layer. Replenishing the defective GAG layer with naturally occurring mucopolysaccharides such as hyaluronic acid and chondroitin sulphate can repair this damaged layer.

iAluRil is available as a 50ml prefilled syringe containing hyaluronic acid (1.6% – 800mg/50ml, sodium chondroitin sulphate(2% – 1g/50ml), and calcium chloride (0.87% – 440mg/50ml). It is not listed on the Pharmaceutical Benefits Scheme (PBS).

Indications:

• Interstitial cystitis/painful bladder syndrome;
• Chemical cystitis – damage to the bladder lining caused by chemotherapy;
• Radiotherapy-induced cystitis – damage to the bladder lining caused by radiation to the pelvis; and
• Recurrent urinary tract infections.

Dosage and Administration:

For bladder pain syndrome, the recommended protocol is one prefilled syringe intravesically once a week for the first month, then once every two weeks for a month, followed by once a month until remission.

One prefilled syringe is administered intravesically into the empty bladder (using a catheter). Once iAluRil is instilled into the bladder, it is held for at least half an hour to give time to bond or as long as it is practical or possible. Once it can be held no more, normal urinating can empty the bladder.

No side effects are reported other than irritation that is due to the procedure, not the product itself.

Pertuzumab is a recombinant humanised monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER-2) preventing its binding with other members of the HER family. This inhibits intracellular signalling, arresting cell growth and inducing apoptosis. Additionally, pertuzumab mediates an immune response that lyses tumour cells. Pertuzumab differs to trastuzumab, as it binds to a different extracellular region of the HER-2 antigen.

Pertuzumab has proven to show additional benefit to metastatic HER-2 positive breast cancer patients who progressed on trastuzumab. These favourable results prompted pertuzumab to be researched in the HER-2 positive neoadjuvant setting; NeoSphere clinical trial. The NeoSphere trial demonstrated that early or locally advanced HER-2 positive breast cancer patients who received pertuzumab in addition to trastuzumab plus chemotherapy (docetaxel), in the neoadjuvant setting achieved a higher proportion of pathological complete response (pCR). Given this trial data, it is important to note that pCR still requires verification as to if it can be used as a reliable primary endpoint and early indicator of benefit in neoadjuvant studies for HER-2 targeted agents.

The NeoSphere trial consisted of four treatment groups; A (trastuzumab plus docetaxel), B (pertuzumab, trastuzumab plus docetaxel), C (pertuzumab and trastuzumab) and D (pertuzumab plus docetaxel). Group B had a significantly improved pCR rate of 45.8% compared with group A (29%), D (24%) and C (16.8%). At five year follow up, Group B had the highest progression and disease-free survival, and patients who achieved total pCR in the study had longer progression-free survival than those who did not. In terms of safety and tolerability, the number of serious adverse events was similar across groups A, B and D and lowest in C.

The TRYPHAENA trial aimed to evaluate the cardiac safety of the combination of pertuzumab, trastuzumab and chemotherapy in the neoadjuvant setting for patients with early HER-2 positive breast cancer. The study concluded that the combination of pertuzumab, trastuzumab and chemotherapy resulted in low rates of left ventricular systolic dysfunction.

Published clinical trial data on the efficacy and safety of pertuzumab in the neoadjuvant setting for HER-2 positive locally advanced or early breast cancer patients has lead to worldwide prescribing of pertuzumab to extend to this scope of practice. In Australia, currently the PBAC has not approved PBS funding for pertuzumab for neoadjuvant treatment in patients with HER-2 positive locally advanced or early breast cancer. However, ROCHE has established the HerStart co-pay program, which assists patients with funding neoadjuvant pertuzumab therapy.

On the 21^st of April 2020, landmark policy changes occurred to medication review programs, allowing for Hospital-initiated medication reviews to be federally funded. These changes were in response to the ‘Interim Report: Neglect’ released by the Royal Commission into Aged Care Quality and Safety. Since this date, the government has expanded the funding of medication review programs (HMR and RMMR’s) to allow certain hospital-based doctors to refer patients directly to a community based accredited pharmacist for a comprehensive medication review.  These doctors now include; specialist physicians, palliative care physicians, specialist pain physicians, specialist psychiatrists and general practitioners.  This pathway of funding for a comprehensive medication management review is known as a “Hospital-initiated medication review” or HIMR.

Many studies have proven that discontinuity of care can occur when a patient transitions from the hospital to the community. Discontinuity of care can be due to poor communication between patients and primary healthcare professionals, particularly in relation to medication changes, contributing to medication misadventure in the post-discharge period. The Final Report: Implementing and evaluating a parallel post-discharge HMR Model, investigated the application of a HIMR system in Australia.  The Report concluded that the average time taken to conduct a HIMR (6.54±4.73 days) was less than a HMR (11.11±7.44), meaning direct referral to an accredited pharmacist is more time-efficient than through a general practitioner (previous program model). The introduction of federally funded HIMR aims to expand access to medicine management services, improve patient care and reduce medication misadventure in the immediate post-discharge period.

At the time the Federal government introduced changes to the HMR and RMMR program rules, no clear guidelines on how hospital sites should implement these changes existed. In response, SHPA created a framework (Hospital-initiated medication reviews: Hospital Pharmacy Practice Update) which provides general guidance on how ‘at risk’ patients could be identified and referred from hospital settings for a medicines review. The framework outlines the process for; screening and referral of patients, home visits, HMR reports, medication management plans and follow up.

If you wish to review the framework written by SHPA Transitions of Care and Primary Care Leadership Committee please go to: shpa.org.au.

The Therapeutic Goods Administration (TGA) is adding boxed warnings to the product information and consumer medicine information of all products containing pregabalin or gabapentin. These warnings advise that pregabalin and gabapentin pose a risk of abuse and dependence, and pregabalin may be associated with misuse.

Pregabalin and gabapentin are known as gabapentinoids. These agents were originally developed for the treatment of epilepsy but have increasingly been used in the treatment of neuropathic pain. In the 2019-2020 financial year, over 3.2 million pregabalin prescriptions were supplied on the Pharmaceutical Benefits Scheme (PBS). This is a significant increase from the almost 1.4 million prescriptions dispensed in the 12 months after pregabalin was first listed on the PBS in March 2013.

Misuse and abuse of gabapentinoids appear to be increasing in line with their increased overall use. Misuse and abuse include the self-administration of higher than prescribed doses, combining with other central nervous system (CNS) depressants, and diversion. Euphoria is listed as a common side effect of pregabalin, which may explain why this agent is liable to misuse. This effect appears to be dose-dependent, with higher doses also associated with relaxation, uninhibited behaviour, improved sociability, dissociation, and hallucinations. Euphoria was not reported during pre-marketing trials for gabapentin. However, evidence now suggests that gabapentin can produce euphoria similar to pregabalin. These effects tend to be less potent with gabapentin and have a more delayed onset. Tolerance is reported to quickly develop to the euphoric effects of gabapentinoids. This can lead to recreational users increasing the dosage, often far beyond the recommended daily maximum dose.

The Therapeutic Guidelines advise that pregabalin and gabapentin cause minimal toxicity on their own, with sedation the most common effect in single-drug poisonings. However, morbidity and mortality are significantly higher when combined with other medications. Serious breathing difficulties can occur in people taking gabapentin or pregabalin who have any of the following respiratory risk factors:

• Use of other CNS depressants, such as opioids and benzodiazepines;
• Conditions that reduce lung function, such as chronic obstructive pulmonary disease (COPD); and
• Advanced age.

Gabapentinoids have also been associated with withdrawal symptoms when abruptly discontinued. Symptoms may include insomnia, headache, nausea, anxiety, hyperhidrosis, and diarrhoea. Withdrawal symptoms have been reported following discontinuation of both long-term and short-term treatment, and may be severe in people taking high doses. It is recommended that these agents be discontinued gradually over at least one week.

The TGA advice for healthcare professionals includes:

• Check for a history of substance use disorder before prescribing a gabapentinoid;
• Regularly monitor patients during treatment, particularly those with current or past use of opioids or benzodiazepines;
• If a gabapentinoid must be prescribed with another CNS depressant, the patient should be carefully monitored for signs of CNS depression; and
• When combined with another CNS depressant, the dosage and duration of therapy should be limited to the minimum required for therapeutic effect.

Gabapentinoids have become integral to the management of neuropathic pain. The appropriate use of these agents has the potential to improve pain and reduce the need for other analgesics such as opioids. However, if a gabapentinoid is not appropriate for a patient, alternatives such as a tricyclic antidepressant or a serotonin and noradrenaline reuptake inhibitor may be considered.

On January 25 2020, the Therapeutic Goods Administration (TGA) approved Australia’s first COVID-19 vaccine. Comirnaty® is now provisionally approved for active immunisation to prevent COVID-19, caused by SARS-CoV-2, in individuals aged 16 years and older. Several other COVID-19 vaccines have been granted a provisional determination which means they are eligible to apply for provisional registration.

Table 1. COVID-19 vaccines in the provisional approval pathway

Sponsor	Name	Vaccine type	Current status
Pfizer	BNT162b2 [mRNA] (Comirnaty®)	Messenger RNA	Provisional approval
Biocelect (on behalf of Novavax)	NVX-CoV2373	Protein sub-unit	Provisional determination
Janssen-Cilag	Ad26.COV2.S	Viral vector	Provisional determination
AstraZeneca	ChAdOx1-S [recombinant]	Viral vector	Provisional determination

Comirnaty® is a messenger RNA vaccine. This vaccine provides instructions for cells to produce the SARS-CoV-2 spike antigen. The spike antigen is a protein embedded in the SARS-CoV-2 virus that facilitates its entry into human cells. Following administration of this vaccine, the body temporarily makes its own version of the spike protein. This protein will be recognised as foreign and trigger the production of neutralising antibodies and cellular immune responses. Messenger RNA is not very stable and is readily degraded in the body. Therefore, the RNA in Comirnaty® is formulated in lipid nanoparticles to protect it from degradation and facilitate its entry into host cells. However, once the RNA has been used, it is quickly destroyed by the cell.

The TGA conducted a thorough and independent review before granting provisional approval to this vaccine. This review concluded that the vaccine meets the high safety, efficacy, and quality standards required for use in Australia. However, as the decision relied on short-term data, ongoing clinical trials and post-marketing assessment must provide evidence of long-term efficacy and safety to ensure continued approval.

A multinational, placebo-controlled clinical trial involving over 43,000 participants demonstrated the short-term safety and efficacy of Comirnaty®. Subjects were randomly assigned in a 1:1 ratio to receive two doses of either the vaccine or a saline placebo given 21 days apart. This trial determined the overall vaccine efficacy to be 95%. This corresponds to eight cases of COVID-19 occurring in the vaccine population, compared to 162 in the placebo group. There were no clinically meaningful differences in efficacy for participants at risk of severe COVID-19, including those with asthma, a body mass index ≥ 30, chronic pulmonary disease, diabetes mellitus, or hypertension. Ongoing clinical trials are required to determine the duration of protection afforded by this vaccine.

Safety over the median two month follow-up period was similar to other viral vaccines. The more common adverse events include pain at the injection site, fatigue, and headache. These were typically transient and of mild or moderate severity. The incidence of serious adverse events was low and occurred in the vaccine and placebo groups at comparable rates.

Messenger RNA vaccines are more fragile than traditional vaccines and require different storage conditions. The Comirnaty® vaccine should be stored in the original package at -90°C to -60°C. Once removed from the freezer, the unopened vaccine can be stored for up to five days at 2°C to 8°C, and up to two hours at temperatures up to 30°C. Once thawed, the vials should not be re-frozen. Comirnaty® is presented as multi-dose vials which must be diluted before use, as described in the product information. Patients are to receive two intramuscular doses at least 21 days apart.

While the approval of this vaccine relies on limited data, it is worth noting that Comirnaty® has been authorised for use in many other countries and millions of doses have already been administered worldwide. The TGA will continue to monitor the safety of this vaccine in Australia and overseas. Batch assessment is also required for each batch before it can be supplied in Australia.

Initial supplies of COVID-19 vaccines will be limited. The Australian COVID-19 Vaccination Policy provides details of the Australian approach to vaccination, including the responsibilities of the Australian, State, and Territory governments. Some of the key points are described below:

• COVID-19 vaccines will be available for free to all Australian citizens, permanent residents, and most visa-holders;
• The Australian government will be responsible for ensuring appropriate logistics and storage chains are in place for each vaccine type;
• Initial vaccine supplies will be directed towards priority groups, which may vary depending upon the vaccine candidate;
• Preliminary priority groups are those with an increased risk of exposure (e.g. health and aged care workers), those with an increased risk of developing severe disease or outcomes from COVID-19 (e.g. people with chronic lung disease), and people working in services that are critical to societal functioning (e.g. emergency services personnel); and
• As vaccine supplies improve, as many Australians as possible will be encouraged to receive a vaccination.

International labels will be used on COVID-19 vaccines during the initial global rollout to expedite their distribution. This means that some Australian-specific information may be absent from the vaccine labels of early lots. Healthcare professionals should review the Australian product information for further information on each COVID-19 vaccine as they become approved.

A new Poisons Standard is due to come into effect on 1 February 2021. The Poisons Standard (also referred to as the Standard for Uniform Scheduling of Medicines and Poisons) is a legislative means of classifying medicines and poisons, with the following schedules relevant to clinical practice:

• Schedule 2 (Pharmacy Medicine) – substances that can be purchased from a pharmacy or licensed person without a prescription;
• Schedule 3 (Pharmacist Only Medicine) – substances that are available from a pharmacist without a prescription;
• Schedule 4 (Prescription Only Medicine or Prescription Animal Remedy) – substances that should only be used or supplied on the order of a permitted prescriber; and
• Schedule 8 (Controlled Drug) – substances that require additional restrictions to reduce abuse, misuse, or dependence.

Some of the major changes to the Poisons Standard February 2021 are summarised below.

Scheduling of triptans:

Eletriptan, rizatriptan, sumatriptan, and zolmitriptan each have a new entry in Schedule 3. This means that these agents can be provided to patients without a prescription if they have a stable, well-established pattern of symptoms. The Schedule 3 entry applies to oral preparations containing 40mg or less per dosage unit of eletriptan, 5mg or less of rizatriptan, 50mg or less of sumatriptan, or 2.5mg or less of zolmitriptan. Packs must not contain more than two dosage units. All other presentations of these medicines will remain prescription only.

Scheduling of higher strength ibuprofen preparations:

The Schedule 3 entry for ibuprofen has been amended to allow the over-the-counter supply of immediate-release preparations containing 400mg or less per dosage unit. The pack must contain no more than 12 dosage units and be labelled not for the treatment of children under 12 years of age.

Scheduling of low-dose cannabidiol:

Certain low dose cannabidiol (CBD) preparations will be down-scheduled from Schedule 4 to Schedule 3. To meet the criteria for inclusion in Schedule 3, the product must be included on the Australian Register of Therapeutic Goods (ARTG), be for use in adults, and have a maximum dose of 150mg per day. There are currently no CBD products approved in Australia that meet this criteria.

This down-scheduling follows a TGA safety review of low dose CBD. The review focused on safety rather than efficacy and did not make recommendations regarding possible indications. The review found that CBD offers a favourable safety and tolerability profile at low doses. Unlike tetrahydrocannabinol (THC), the other major cannabinoid found in cannabis, CBD does not cause psychomotor or cognitive impairment or strong psychoactive effects.

The dose cut off for inclusion in Schedule 3 is intended to prevent the use of over-the-counter CBD in conditions where medical supervision is required (e.g. epilepsy or schizophrenia), whilst also taking into account the safety of the CBD itself.

Updates to additional recommendations:

The Appendix D listing for acitretin has been updated to advise that female patients should avoid becoming pregnant in the 36 months after completing treatment.

This change from the previously recommended 24 months reflects the advice in the current acitretin product information. The update was made in response to published information indicating that the half-life of acitretin may be significantly longer than initially thought. Studies demonstrate that acitretin can be converted to etretinate in the presence of alcohol. Both acitretin and etretinate are teratogenic. However, etretinate remains in the body for longer and has a mean elimination half-life of 120 days.

Addition of new substances:

A number of new substances will be included in the Poisons Standard for the first time. This includes Schedule 4 entries for cariprazine (an antipsychotic), bilastine (an antihistamine), filgotinib (a janus kinase inhibitor), and trifarotene (a topical retinoid). A separate Schedule 4 entry has also been added for SARS-CoV-2 (COVID-19) vaccines. While any proposed vaccine for COVID-19 would be covered by the existing entry of ‘Vaccines for human therapeutic use’, a separate item has been created to maintain consistency with other vaccines specified in the Poisons Standard.

Summary:

The above scheduling changes come into effect on 1 February 2021. The current Poisons Standard can be found on the Federal Register of Legislation website.

The National Health Act 1953 has been amended to require the inclusion of active ingredient names on prescriptions supplied under the Pharmaceutical Benefits Scheme (PBS) and Repatriation PBS (RPBS).

This amendment, which comes into effect on 1 February 2021, requires the following:

• The active ingredient must be included on all PBS prescriptions (exceptions exist for handwritten prescriptions, paper-based medication charts in the residential aged care setting, medicinal products with four or more active ingredients, and specific items excluded for practicality and safety reasons);
• The brand name may also be included on the prescription if the prescriber considers it clinically necessary (e.g. to ensure continued therapy of the same brand, or when not specifying the brand could pose a potential patient safety risk);
• If the brand name is included on the prescription, the active ingredient(s) must appear first; and
• Prescribing software must not automatically include brand names on prescriptions by default.

This legislation forms part of a broader government initiative to standardise medication information and support the safe use of medicines. A range of supporting material has been developed to ensure that healthcare professionals and patients are adequately informed of these changes. These include:

• Amended packaging and labelling requirements by the Therapeutic Goods Administration (TGA);
• Development of the National Guidelines for On-Screen Display of Medicines Information which states that the active ingredient should be displayed before the brand name; and
• Shared health summaries on the My Health Record system display active ingredient before brand name.

It is anticipated that active ingredient prescribing will increase patient understanding of their medications and increase the uptake of generic and biosimilar medicines. It is important that patients are aware of the active ingredients of their medicines as the brand name is not always a unique identifier. Many medications are available in multiple different brand names which can be confusing. For patients who are not aware of the active ingredient, there is a risk of accidentally doubling up on a medicine or even failing to take a medicine if the name on the package does not match the name on the prescription. Active ingredient prescribing may also promote the use of generic medicines. Increased uptake of generic medicines will provide patients with immediate cost savings, while also helping to ensure the long-term sustainability of the PBS.

The Australian Commission on Safety and Quality in Healthcare (the Commission) has published the Active Ingredient Prescribing User Guide to assist prescribers in prescribing by active ingredient. It also contains the following lists to provide guidance on when a brand name should be included on a prescription: the ‘List of Medicines for Brand Consideration’ and the ‘List of Excluded Medicinal Items’. These two lists will be reviewed by the Commission at least twice a year.

The List of Medicines for Brand Consideration contains medicines that prescribers may consider prescribing by brand as well as active ingredient. Clinical software systems will alert prescribers when a medicine is on this list and provide a hyperlink to the List of Medicines for Brand Consideration. Medications on the list are annotated with detailed reasoning for their inclusion. For example, insulin is included as it is a high-risk medication that is available in many different presentations with the same or very similar active ingredient name. This list is not intended to be prescriptive or exhaustive. The choice to specify a brand remains that of the prescriber and should be documented in the patient’s record.

In contrast, the List of Excluded Medicinal Items contains medicines that should be prescribed by brand only for practical and safety purposes. Selected products from the following categories are included in this list:

• Products containing four or more active ingredients (e.g. Restore O.R.S);
• Vaccines and allergenic extracts (e.g. ADT™ Booster);
• Ocular lubricants and ophthalmologicals (e.g. Refresh Tears Plus®);
• Dermatological preparations – topical emollients and washes (e.g. EgoPsoryl-TA™);
• Treatments for haemorrhoids and constipation (e.g. Micolette®);
• Diagnostic tools (e.g. Keto-Diastix®);
• Iron preparations (e.g. Ferro-tab®);
• Vitamins, minerals and trace elements (e.g. Paediatric Seravit®);
• Various general nutrients, other nutrients (e.g. Chlorvescent®);
• Triple therapy to treat Helicobacter pylori (e.g. Nexium® Hp7®); and
• Some non-medicinal items (e.g. Iodosorb® Powder).

Active ingredient prescribing does not affect a patient’s ability to choose the brand they prefer or a prescriber’s clinical decision making. Patients will still be able to request their brand of choice, and prescribers will retain the option to specify that brand substitution is not permitted. While active ingredient prescribing is only mandated for PBS and RPBS prescriptions, the same principles extend to private prescriptions.

The Australian Commission on Safety and Quality in Health Care (the Commission) has just released Australia’s first National Safety and Quality Digital Mental Health (NSQDMH) Standards. Implementation of these standards will ensure a nationally consistent level of care for people who use digital mental health services.

Digital mental health refers to services that target mental health problems using online or mobile technologies. Services may be delivered via telephone, videoconferencing, web-based programs, SMS, or mobile health applications (apps). One of the advantages of this type of delivery method is the ability to reach people quickly. This may be of particular benefit in historically underserved populations, such as rural and low socioeconomic areas. Other potential advantages include improved patient autonomy and improved collaboration by digitally linking multiple professionals to the same patient. For many patients, digital interventions can be as effective as face-to-face therapy. In addition, the improved overall efficiency of these services may also free up resources so that healthcare professionals can dedicate more time to more severe cases.

The Commission states that the primary goal of the NSQDMH Standards is to “improve the quality of digital mental health service provision and to protect service users, and where relevant, their support people, from harm.” Further information and guidance is available on the Commission’s website to support the implementation of these standards in clinical practice.

The three NSQDMH Standards are:

1. Clinical and Technical Governance Standard
   Service providers are encouraged to implement a clinical and technical governance framework to ensure that the services provided are person-centred, safe and effective. Good clinical and technical governance ensures that all members of the healthcare team are accountable and deliver high-quality digital mental health services.

2. Partnering with Consumers Standard
   Effective partnerships with consumers are important as the evidence suggests this is associated with improvements in clinical outcomes, adherence to therapy, functional status, and the delivery of preventive care services. Service providers are encouraged to communicate with users in a way that is appropriate for their level of health and digital literacy. This partnership ensures that services are relevant, usable and accessible.

3. Model of Care Standard
   Establishing a model of care for each digital mental health service is crucial to ensure the delivery of safe, high-quality care while also minimising the risk of harm. There are a number of inherent risks with a remote model of care. For example, body language changes and other subtle cues that may indicate potential risk are often not available to the service provider. To overcome this issue, the model of care should incorporate risk screening and also take a systematic approach to recognise and respond to the early signs of deterioration.

There has been a significant increase in the use of digital mental health services over the past decade. This year, the demand for remote services has continued to grow due to COVID-19. While there is a large range of digital mental health resources available in Australia, it can be challenging to navigate the system. e-Mental Health in Practice (eMHprac) is a government-funded project that aims to raise awareness and knowledge of these programs. A directory of publicly funded, evidence-based digital health programs is available on their website. They also offer online and face-to-face training opportunities for service providers.

For a prescription medication to be registered on the Australian Register of Therapeutic Goods (ARTG), the sponsor must lodge a complete dossier with the Therapeutic Goods Administration (TGA). This submission must contain, or provide reference to, data to demonstrate the quality, safety, and efficacy of the medicine.

This registration process takes, on average, 11 months. However, medications for serious and life-threatening conditions may be eligible for fast track approval using the priority review or provisional approval pathway.

Priority review pathway

Priority review allows approval of prescription medicines up to three months quicker than the usual process. Sponsors are required to submit the same amount of evidence as needed for the standard approval pathway, but the TGA commits to reviewing the data and making a decision earlier.

For a medicine to be eligible for a priority review, it must be a new treatment for a serious or life-threatening condition, and there must be substantial evidence to demonstrate that the medicine provides a significant benefit over existing therapies.

Provisional approval pathway

It may sometimes be considered appropriate to approve a medication when there is less evidence available. In such cases, the TGA allows medicines to be provisionally approved while further research is conducted. It is anticipated that the provisional approval pathway could allow Australians to receive major therapeutic advances up to two years faster than the usual process.

For a medicine to be eligible for provisional approval, it must meet the following criteria:

• Be a new prescription medicine or an already registered prescription medicine that has a new indication;
• Be indicated for the treatment, prevention, or diagnosis of a life-threatening or seriously debilitating condition;
• Either no therapeutic goods are fully registered for the same indication, or preliminary clinical data demonstrates that the medicine is likely to provide a significant improvement over existing therapeutic goods;
• Preliminary clinical data demonstrates that the medicine is likely to be a major therapeutic advance; and
• Evidence must be provided of a plan to submit more comprehensive clinical data before the end of the provisional registration period.

An example of a recent provisionally approved medicine is remdesivir. Remdesivir is an antiviral that has shown promise as a treatment for severe coronavirus infection. The TGA provided provisional approval for this agent within two weeks of receiving the submission due to the potential for substantial benefit to Australian patients.

When provisional approval is granted, it is valid for an initial period of two years. However, up to two extensions may be granted, taking the maximum approval period to six years under this pathway. Medicines that have received a provisional approval are identified as such in the product information and consumer medicines information documents. These medicines are also automatically included in the Black Triangle Scheme, and healthcare professionals are encouraged to report any suspected side effects to the TGA to build the medicine’s safety profile further.

Antimicrobial resistance is considered by many to be one of the biggest threats to global health and food security. The direct consequences of antimicrobial resistance can include longer illness, prolonged hospital stay, increased mortality, and an overall increase in healthcare costs. This Antimicrobial Awareness Week, the World Health Organization (WHO) is raising awareness and encouraging best practices to limit the emergence and spread of antimicrobial resistance globally.

In Australia, antimicrobial resistance is already a major healthcare problem. The Australian Commission on Safety and Quality in Health Care and the Council of Presidents of Medical Colleges recently released a joint statement on the issue. This statement calls for improved compliance with prescribing guidelines to stem the rise in antimicrobial resistance. The results of the National Antimicrobial Prescribing Surveys (NAPS), available from the National Centre for Antimicrobial Stewardship, are referred to as evidence of the need for change.

The following is a brief summary of results from the 2018 hospital NAPS:

• 21.4% of prescriptions for antimicrobials were assessed as being inappropriate (compared to 22.4% in 2017);
• Documentation of review or stop date was 45.2% (up from 40.7% in 2017);
• Rate of documentation of indication was 80.3% (up from 77.7% in 2017); and
• Surgical prophylaxis that extends beyond 24 hours was 28.0% (down from 30.0% in 2017).

The NAPS program forms part of the Antimicrobial Use and Resistance in Australia (AURA) surveillance system. The 2019 AURA report reveals some interesting trends in microbial resistance around the country. While the national rate of antibiotic resistance has remained relatively constant for a number of priority organisms, the following changes may be important to consider in the clinical setting:

• Escherichia coli – resistance to common therapies continues to increase which may translate to higher rates of treatment failure and increased use of last-line agents, such as carbapenems;
• Enterococcus faecium – the absolute number of isolates with vancomycin resistance is increasing (although the overall rate of vancomycin resistance is declining). The prevalence of vancomycin resistance in this bacteria is higher in Australia than any European country;
• Neisseria gonorrhoeae – the total number of notifiable cases is increasing along with increasing rates of resistance to azithromycin;
• Neisseria meningitidis – the number of notifiable cases is increasing as well as high rates of reduced benzylpenicillin susceptibility and increased rates of benzylpenicillin resistance;
• Salmonella Typhi and Salmonella Paratyphi – high rates of ciprofloxacin resistance;
• Staphylococcus aureus – community-associated methicillin resistance has increased in remote and very remote regions.

New antimicrobials are needed to increase the treatment options for drug-resistant infections. However, new drugs alone will not solve the problem. The Global Action Plan on Antimicrobial Resistance, endorsed by the WHO, details the following five objectives to minimise antimicrobial resistance:

1. Communication, education, and training to improve awareness and understanding of antimicrobial resistance;
2. Surveillance and research to strengthen the evidence base;
3. Improved sanitation, hygiene, and infection prevention measures to reduce the incidence of infection;
4. Optimise antimicrobial use in both human and animal health; and
5. Increased investment in new medicines, diagnostic tools, vaccines, and other inventions.

While the issue of antimicrobial resistance is a global challenge, individuals can play an important role. Healthcare professionals can limit the emergence and spread of resistance by referring to current guidelines and clinical information when diagnosing infections and prescribing and dispensing antimicrobials. Prevention of infection is also an important part of minimising antimicrobial resistance. All healthcare workers play an important role here by adhering to and promoting infection prevention and control principles.

The Antimicrobial Stewardship Clinical Care Standard is an excellent reference to support clinical decision making and to facilitate quality improvement processes within a healthcare service. This should be used in conjunction with the current version of the Therapeutic Guidelines: Antibiotic, or local antimicrobial formulary.