Off-label use of medicines

Case scenarios

Dimitri, a 45-year-old male, presents to the pharmacy with a prescription for quinine 300 mg, one at night. He asks to speak with you, the pharmacist, and explains that he read online that quinine is used for malaria. He is concerned that he might have been prescribed the wrong medicine. You ask Dimitri what his medicine was prescribed for, and he explains that he needed a medicine to help with his leg cramps at night. He has no other health conditions.

Introduction

Off-label use of medicines is an accepted part of pharmacy practice. Off-label prescribing is defined as the prescribing of a medicine for an indication, dose, route or patient group outside that approved by the Therapeutic Goods Administration (TGA) for a specific listed product on it’s register of therapeutic goods.¹ The term off-label use is often used interchangeably with off-label prescribing. Off-label use is not restricted to prescription medicines but may also extend to non-prescription medicines and medical devices. Off-label use of medicines is also a form of medicine repurposing.²

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The role of the TGA

The TGA is responsible for evaluating, assessing and monitoring the efficacy, safety and quality of therapeutic goods in Australia.³ The TGA maintains a public register of therapeutic goods, known as the Australian Register of Therapeutic Goods (ARTG). Goods listed in the ARTG have been evaluated and assessed by the TGA for their safety and quality and have met strict ingredient, manufacturing and labelling requirements. Therapeutic goods are listed on the ARTG for one or more specific indications, therefore these goods can only be marketed for the indications included in the register. These approved indications, however, do not prevent a prescriber from prescribing a therapeutic good ‘off-label’; that is, for an indication other than those that have been approved by the TGA.⁴

Regulatory oversight by the TGA of off-label use of medicines is undergoing change in Australia. In March 2024, the TGA established the Medicines Repurposing Program.⁵ This program uses an evidence-based approach to identify new therapeutic indications for existing medicines listed on the ARTG, in order to potentially enable these to be subsidised under the Pharmaceutical Benefits Scheme (PBS), making them more accessible to patients.^2,5 Currently, off-label use of medicines is not subsidised by the PBS. To be eligible for selection for repurposing, the medicines must meet two criteria⁵:

1. The medicine must be currently listed on the ARTG.
2. The medicine must be for a new, distinct indication.

Any approval by the TGA and subsidy under the PBS would be subject to the availability of good clinical evidence to support the new indication and a positive recommendation by the Pharmaceutical Benefits Advisory Committee.⁵ This shift in regulatory oversight by the TGA is significant, as it shows recognition of the value of re-evaluating the regulatory status of some off-label medicine use, if there is good evidence to support such use and where such evidence may have become available after the original marketing approval was given. This approach supports more up-to-date, evidence-based quality use of medicines.

At the same time, this does not mean that all off-label use of medicines will be subject to regulatory oversight by the TGA. Some medicines may lack sufficient high-
quality clinical evidence to support their use in the new indication, making them unsuitable for inclusion in the program. However, this will not preclude their use as an off-label medicine outside the program. Off-label supply and use outside the program will continue to be legal in Australia.⁶ The TGA states that off-label use ‘is a clinical decision, made at the discretion of the treating clinician’.⁶ This means health professionals, including pharmacists, have obligations and responsibilities to ensure all medicines supplied are safe and appropriate for the individual patient. Consequently, it is important for pharmacists to understand the risks involved in the supply of off-label medicines and know how to best fulfil their professional obligations and responsibilities to ensure appropriate and safe use.

Prevalence of off-label use of medicines

Research shows widespread off-label use of medicines in Australia, including many examples in pharmacy practice and circumstances in which off-label use may be appropriate.^2,7 Off-label use of medicines may be appropriate when treating complex conditions such as psychiatric illness where there may be an overlap in symptoms between different mental health disorders, or where certain patient groups were excluded from pre-registration clinical trials.⁸ 

A 2021 review of publicly available data, including two state-wide public hospital formularies, the Queensland List of Approved Medicines (Qld LAM) and the South Australian Medicines Formulary (SAMF), reported rituximab as being used off-label for indications such as myositis, immune thrombocytopenia and pemphigus vulgaris.² The use of rituximab for these off-label indications is evidence-based and included in some treatment guidelines; however, as the evidence emerged after the product registration, many of these indications have not been approved by the TGA.

Rates of off-label use of medicines in children have also been found to be high in a hospital setting.^2,9 A study of 300 inpatients in a paediatric hospital found 57% of patients received at least one off-label medicine.⁹ Another study examining Australian PBS claims for a sample of children aged 0–17 years from January 2013 to December 2017 found psychotropic medicines, especially attention-deficit/hyperactivity disorder (ADHD) medicines, antidepressants and antipsychotics were among the medicines commonly prescribed off-label in young children below the minimum recommended age.¹⁰

Off-label supply of Pharmacist Only medicines

Off-label supply is not limited to medicines on prescription. There may be instances where the off-label supply of a Pharmacist Only (or Schedule 3) medicine may be appropriate. Doxylamine is an example of a medicine pharmacists could appropriately supply to help manage nausea and vomiting during pregnancy because its use is supported by clinical guidelines and a large body of high-quality evidence.¹¹

However, off-label supply of some Pharmacist Only medicines may be restricted by the requirements for Pharmacist Only supply set out in the Poisons Standard for areas such as indication, age group and location of use (e.g. ophthalmic).¹² In these instances, when supply by a pharmacist is restricted, the patient should be referred to their medical practitioner for a prescription as appropriate. Table 1 lists examples of Pharmacist Only medicines with these types of restrictions.

Pharmacists should consider their liability and accountability regarding off-label use of medicines.

Please refer to the Poisons Standard for information on any relevant restrictions placed on the supply of Pharmacist Only medicines.

In cases where there are restrictions placed on supply of a medicine as a Pharmacist Only product and the patient does not meet the criteria, use of the medicine would require a prescription and the patient should be referred to a medical practitioner.

Examples of off-label use in special patient groups

It is important for pharmacists to be alert to the fact that, quite often, the need to consider off-label use may apply to special patient groups or conditions; for example, in paediatrics, immunocompromised or multiple drug resistant scenarios, or for complex conditions.

The use of salbutamol metered-dose inhalers in children at doses higher than approved is one example where off-label use may be appropriate. Clinical evidence exists to support administration of higher doses of salbutamol in children for acute exacerbation of asthma. However, this information is not reflected in the current approved product information (PI).^9,13

Similarly, clonidine is often used off-label in Australia. Clonidine is approved for the treatment of essential hypertension, renal hypertension, prophylaxis of migraine and vascular headache in adult patients, and alleviation of vasodilation in menopausal flushing.¹⁴ However, clonidine is often prescribed as part of an evidenced-based approach to the treatment of ADHD in children despite this not being an approved indication.¹⁵

Other examples of potentially appropriate off-label use of a medicine include the use of semaglutide for weight loss and doxylamine for nausea and vomiting in pregnancy.^16,17

Psychotropic medicines are also often prescribed and used off-label. Particularly in complex conditions such as schizoaffective disorders and bipolar disorders.^1,18 It has been estimated that 40–75% of antipsychotic use among adults, and 36–93% of use in children, is considered off-label.⁷

Some risks to consider

While the clinical decision-making around appropriate off-label use of medicines may be supported by evidence-based research,^1,19 there are risks associated with using medicines for unapproved indications, especially if there may be limited or low-quality evidence to support such use.²⁰ The prevalence of off-label use in vulnerable populations such as those with mental health disorders, older people, and children also raises concerns around appropriate informed consent.⁷

Consumer medicine information (CMI) leaflets or the PI do not include information on off-label use and possible adverse effects, making it difficult for patients to make an informed decision on whether to use the medicines as prescribed.^2,9

There is also an increased risk of adverse events with off-label use, as many of the vulnerable populations in which they are used, including pregnant women, are often under-represented in clinical trials.^{1,10, 21} Adverse events may be associated with misdiagnosis or overtreatment.¹⁰

Ethical issues may also arise. For example, off-label use of medicine in children often involves adult data being extrapolated to determine a dose for the child’s age and weight, which may expose the child to an unknown risk of side effects, undertreatment or no benefit at all.^20,21 At the same time, there may be circumstances where the use of medicines off-label may be appropriate when certain pre-specified criteria (see Table 2) and evidence requirements are met, enabling access to treatment which would otherwise not be available to a patient.²⁰

References: O’Day8, CATAG22

Supporting the quality use of medicines

Pharmacists have an important role in supporting the quality use of medicines. This means they have a professional responsibility towards the patient to ensure the appropriateness of the use of medicines for non-approved use. The Council of Australian Therapeutic Advisory Groups has published Guiding Principles for the Quality Use of Off-label Medicines, which provides a useful framework for off-label use in pharmacy practice in general, as well as supporting the quality use of off-label medicines in Australian public hospitals.²²

Knowledge to practice

Risk management strategies for pharmacists

The following strategies have been developed by Pharmaceutical Defence Limited (PDL) and provide suggestions to good practice:

• Discuss any concerns you may have regarding the off-label use of a medicine with the prescriber.
• The pharmacist should then discuss these with the patient and acknowledge the prescriber’s instructions.
• Disclose to the patient that the medicine is being used off-label and how this may impact them. This will require the pharmacist to explain to the patient that the medicine has been prescribed for an indication that is not currently approved in Australia.
• Discuss any risks associated with the use of the medicine as off-label with the patient and any benefits of use for a non-approved indication.
• Understand that the patient may still choose to use the medicine as off-label. It should be made clear to the patient that if they choose to do so, they accept greater responsibility for any consequences if they use the medicine in a manner that is outside the guidance in the approved PI.
• If a pharmacist chooses to supply the medicine, they should advise the patient that the discussion and the patient’s acknowledgement and acceptance of potential risks will be documented.
• Patients should be adequately counselled on the indication, directions, interactions and potential adverse effects with any off-label use – just as they would with any other medicine. Allow patients the opportunity to ask questions and be able to give informed consent. Informed consent requires the patient’s decision to use the medicine off-label to be given freely and voluntarily only after they have been provided accurate and relevant information regarding their treatment and have an adequate knowledge and understanding of the benefits and risks.²³

Conclusion

A key consideration for pharmacists supplying a medicine off-label is whether the proposed use meets the agreed criteria for appropriateness and aligns with the guiding principles for off-label supply. This will be determined by the pharmacist’s knowledge, level of experience, the resources available, and an analysis of any risks or benefits to the patient. Pharmacists are required to ensure that patients can take or use any supplied medicine, including those to be used off-label. Pharmacists must also ensure they are competent to advise patients on the risks and benefits of off-label use of medicine. This means having knowledge that is current and evidence-based. Access to current and authoritative evidence-based resources is critical to pharmacists’ oversight of off-label use of medicines. Pharmacists should document all communication with prescribers and any counselling or education provided to the patient, including discussion of off-label use and informed consent.

Key points

• Off-label use of medicines is an accepted part of pharmacy practice.
• Pharmacists have an obligation to ensure all medicines supplied, including non-approved doses or indications for off-label use, are safe and appropriate for each patient.
• As part of ensuring quality use of medicines, pharmacists must understand the risks involved in the supply of medicines in these circumstances (e.g. limited evidence, vulnerable population groups).
• Off-label use of a medicine should only be considered when all other options, including the use of medicines approved by the TGA, are unavailable, exhausted, not tolerated or unsuitable.
• Ensure communication is open and transparent between prescriber, pharmacist and patient, and that all decisions made are based on informed consent.

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References 

1. Kyrios M, Levido J, Talbot D et al. Off-label prescribing of psychotropics in a psychiatric population in Australia. Australasian Psychiatry 2024. Epub 2024 March.
2. Howe K, Bourke S and Sansom L. The extent to which off-patent registered prescription medicines are used for off-label indications in Australia: a scoping review. PLoS one 2021 16(12):e0261022. 
3. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. 2024. At: www.tga.gov.au 
4. Australian Government Department of Health, Therapeutic Goods Administration. Establishment of the Medicines Repurposing Program. 2024. At: Establishment of the Medicines Repurposing Program | Therapeutic Goods Administration (TGA)  
5. Australian Government Department of Health, Therapeutic Goods Administration, Medicines Repurposing Program – Eligibility Criteria and Prioritisation Criteria. 2024. At: Medicines Repurposing Program – Eligibility criteria and prioritisation considerations | Therapeutic Goods Administration (TGA) 
6. Australian Government Department of Health, Therapeutic Goods Administration. Off-label use of medical devices. 2023. At: Off-label use of medical devices | Therapeutic Goods Administration (TGA) 
7. Bell A and Richards GC. Off-label medicine use. Aust J Gen Pract 2021;50(5)329–31. 
8. O’Day Richard. Ongoing challenges of off-label prescribing. Aust Presc 2023;46:86–9. 
9. Ballard C, Peterson G M, Thompson AJ, et al. Off-label use of medicines in paediatric inpatients at an Australian teaching hospital. J Paediatr Child Health 2013;49:38–42.  
10. Schaffer AL, Bruno C, Buckley NA, et al. Prescribed medicine use and extent of off-label use according to age in a nationwide sample of Australian children. Paediatr Perinat Epidemiol 2022;36:726–37.  
11. Heiner, L. Navigating nausea and vomiting during pregnancy. Australian Pharmacist 2024;43(1):48–53.  
12. Therapeutic Goods (Poisons Standard – February 2024) Instrument 2024 [Updated 2024 Jun]. At: The Poisons Standard (the SUSMP) | Therapeutic Goods Administration (TGA)
    
13. Therapeutic guidelines. 2023. Maintenance management of asthma in children; [updated 2021 Mar]. At: https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&guidelinePage=Respiratory&topicfile=asthma-maintenance-management-children&guidelinename=Respiratory&sectionId=toc_d1e96#toc_d1e47 
14. Australian Government Department of Health and Ageing. Therapeutic Goods Administration. APO-CLONIDINE clonidine hydrochloride 100 micrograms tablet bottle (2657760. At: APO-CLONIDINE clonidine hydrochloride 100 micrograms tablet bottle (265776) | Therapeutic Goods Administration (TGA) 
15. Therapeutic guidelines. 2023. Clonidine for attention deficit hyperactivity disorder in children; [2021 Mar]. At: https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&guidelinePage=Psychotropic&topicfile=attention-deficit-hyperactivity-disorder&guidelinename=Psychotropic&sectionId=toc_d1e409#toc_d1e409 
16. Therapeutic guidelines. 2023. Drug therapy to manage excess body weight; [updated 2023 Jun]. At: https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&guidelinePage=Cardiovascular&topicfile=cardiovascular-disease-risk-stratification&guidelinename=auto&sectionId=c_CVG_Excess-body-weight-obesity-and-atherosclerotic-cardiovascular-disease-risktopic_11#c_CVG_Excess-body-weight-obesity-and-atherosclerotic-cardiovascular-disease-risktopic_11  
17. Therapeutic guidelines. 2023. Oral antiemetics for nausea and vomiting during pregnancy; [updated 2022 Aug]. At: https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&guidelinePage=Gastrointestinal&topicfile=c_GIG_Gastro-oesophageal-reflux-in-adultstopic_1&guidelinename=auto&sectionId=c_GIG_Nausea-and-vomiting-during-pregnancytopic_5#c_GIG_Nausea-and-vomiting-during-pregnancytopic_5  
18. Krishnan RPR, Christopher Harrison, Buckley N et al. On- and off-label utilisation of antipsychotics in Australia (2000–2021): retrospective analysis of two medication datasets. Aust N Z J Psychiatry 2024;58(4)320–33.  
19. Landwehr C, Richardson J, Blint L et al. Cross-sectional survey of off-label and unlicensed prescribing for inpatients at a paediatric teaching hospital in Western Australia. PLoS one 2019;14(1):e0210237. At: https://doi.org/10.1371/journal.pone.0210237  
20. Gazarian M, Kelly M, McPhee JR, et al. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust 20 2006:185(10):544–8. 
21. Van Norman GA. Off-label use vs off-label marketing of drugs. JACC Basic Transl Sci 2023;8(2):224–33. 
22. Council of Australian Therapeutic Advisory Groups, Rethinking medicines decision-making in Australian hospitals. 2013. At: Rethinking medicines decision-making in Australian Hospitals – Council of Australian Therapeutic Advisory Groups (CATAG) 
23. Australian Commission on Safety and Quality in Health Care, Informed consent in health care: Fact sheet for clinicians. September 2020. At: Informed Consent – Fact sheet for clinicians | Australian Commission on Safety and Quality in Health Care 
24. Australian Government, Department of Health and Ageing.Therapeutic Goods Administration. Medicines Safety Update Volume 2 No 4 August 2011. At: www.tga.gov.au/sites/default/files/msu-2011-04.pdf 

Our authors

Dr Simone Henriksen (she/her) PhD (Law), LLB (Hons I), BPharm, MPS is a Professional Officer with PDL and a community pharmacist with over 30 years’ experience. She has previously owned and operated several pharmacies in Brisbane
and regional Queensland.

Amy Minion (she/her) BPharm, MBA, MPS is a Professional Development Pharmacist at PDL and has been a member of the PDL SA/NT Local Advisory Committee since 2017.

Our reviewer

Madlen Gazarian (she/her) MBBS (Hons I), MSc (ClinEpi), FRACP