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Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018

Scheduling medicines and poisons

10 September 2018

Book pagination

1.1 Sildenafil

1. Advisory Committee on Medicines Scheduling (ACMS #24)

Delegate's interim decision

The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is not to amend the current Poisons Standard in relation to sildenafil.

Reasons for interim decision

The reasons for the interim decision are as follows:

  1. the risks and benefits of the use of a substance:
    • Sildenafil does not satisfactorily meet the following Schedule 3 SPF criteria:[1]
      • The medicine is substantially safe with pharmacist intervention to ensure the quality use of the medicine. There may be potential for harm if used inappropriately. The consumer can identify the ailments or symptoms that may be treated by the medicine but counselling and verification by a pharmacist is required before use.
      This is because:
      • Erectile Dysfunction (ED) is a symptom with an underlying cause which should be diagnosed before treatment.
      • The use of the sildenafil at established therapeutic dosage levels may mask the symptoms or delay diagnosis of cardiovascular disease (CVD). ED is an independent risk factor for CVD.[2]
      • CVD cannot be diagnosed by a pharmacist. The list of diagnosis tools (including ECG and other cardiac testing) recommended by the Princeton III Consensus Recommendations for the Management of ED and CVD are not possible in a pharmacy setting.[3]
      • As well the Andrology Australia Clinical Summary Guide on Erectile Dysfunction[4] outlines the history, examination requirements and investigations for diagnosing ED of which a number are only possible by or accessible through a medical practitioner.
    • Sildenafil meets the following Schedule 4 SPF criteria:[1]
      • The ailments or symptoms that the substance is used for require medical, veterinary or dental intervention. Diagnosis, management or monitoring of the medical condition is such that it requires medical, veterinary or dental intervention before the substance is used.
      This is because:
      • The list of diagnosis tools (including ECG and other cardiac testing) recommended by the Princeton III Consensus Recommendations for the Management of ED and CVD are not possible in a pharmacy setting and require medical intervention.[5]
      • As well the Andrology Australia Clinical Summary Guide on Erectile Dysfunction[6] outlines the history, examination requirements and investigations for diagnosing ED of which a number are only possible by or accessible through a medical practitioner.
      • One of the causes of ED is CVD, a medical condition that requires medical intervention through diagnosis, management and monitoring.
    • Without medical diagnosis of the cause of the ED and of any potentially underlying serious medical conditions (such as CVD and diabetes) the risks associated with self-treatment of ED outweigh the benefits of improved consumer access to sildenafil through availability from a pharmacist.
    • There is no evidence that patients will consult with their general practitioner (GP) on the advice of their pharmacist.[7]
    • There is no evidence that the benefits of improved access for consumers are greatly outweighed by the risk of improper diagnosis or treatment of ED or associated risk factors by a pharmacist.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • ED is a symptom the potential causes of which cannot be diagnosed by the patient or pharmacist. The risk of facilitating ED treatment without appropriate diagnosis or treatment of any underlying serious medical conditions is too great to recommend sildenafil be moved to Schedule 3.
    • Sildenafil is for the treatment of the symptom but does not treat the underlying cause.
  3. the toxicity of a substance:
    • Although sildenafil has well known side-effects and drug interactions, the risk of facilitating ED treatment without appropriate diagnosis or treatment of any underlying serious medical conditions is too great to recommend sildenafil be moved to Schedule 3.
    • Risk of hypotension.
    • Sildenafil has a significant adverse effect profile that requires medical monitoring.
    • Drug-drug interactions may potentiate sildenafil toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Limited pack size is considered to not appropriately address risk of harms to consumers brought about by a lack of medical oversight in diagnosing the cause of ED before supply of sildenafil.
  5. the potential for abuse of a substance:
    • Misuse by men without erectile dysfunction is already known to occur, including in combination with illicit drugs such as MDMA (3,4-methylenedioxymethamphetamine).
    • Issues with counterfeit sildenafil are recognised, however increasing consumer access to sildenafil through down scheduling is not considered an appropriate mechanism to address this problem.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Educational campaigns to raise awareness of the association between erectile dysfunction and serious medical conditions and to direct men to discuss problems relating to their sexual function with their GP can be undertaken, without requiring sildenafil to be down scheduled.
    • Overcoming stigma with ED and improving treatment rates would be better addressed through consumer education and information.
    • It is not believed that consumers are more likely to speak to their pharmacist about ED rather than their GP.
    • No new relevant evidence supporting the down scheduling to Schedule 3 was provided in the applicant's submission. There was no evidence provided by the applicant on the New Zealand (NZ) experience of having sildenafil available from pharmacists despite it having been available since 2014.
    • A recent publication on the NZ pharmacists experience[8], although only involving 35 pharmacists, concluded that "New Zealand's model of pharmacist supply of sildenafil appears workable with some areas for improvement identified". However it was noted that "Many men requesting supply fell outside of the parameters, resulting in medical referral." It noted that "Many pharmacists estimated that over half (range 10-80%) of new requests for sildenafil resulted in medical referral without supply, commonly because of smoking, age over 70 years, or elevated blood pressure, occasionally diabetes and multiple medications were mentioned."
    • There was no proposed Appendix M education or checklist material included in the application so until this is provided, it is difficult to assess whether an Appendix M listing would mitigate the risks of down scheduling. An appendix M listing would need to address:
      • Development of accredited competency-based training for pharmacists by an appropriate accredited training body.
      • Requirements for pharmacists to have written documentation of their consultation, outlining the clinical assessment they undertook and whether they supplied medication or referred.
      • Well-developed clinical referral pathways for pharmacists that must be adhered to.
    • Appendix M is not appropriate for ED and sildenafil treatment given that ED is a symptom of other conditions which require medical practitioner diagnosis, monitoring and treatment.

Delegate's considerations

The delegate considered the following in regards to this interim decision:

  • The application to amend the current Poisons Standard with respect to sildenafil;
  • The applicant's presentation to the Advisory Committee on Medicines Scheduling;
  • The advice received from the Advisory Committee on Medicines Scheduling (ACMS#24);
  • The public submissions received before the first closing date;
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for sildenafil

Delegate's referral to ACMS

An application was submitted to amend the Poisons Standard with respect to sildenafil. The application proposed to create new Schedule 3, Appendix H and Appendix M entries for sildenafil and to amend the Schedule 4 entry.

Applicant's scheduling proposal and reasons

The applicant's proposed amendments to the Poisons Standard were:

Note

New text is shown as green, larger font, with a horizontal line above it.

Schedule 3 - New Entry

SILDENAFIL in divided preparations for oral use containing 50 mg of sildenafil per dosage unit in packs of not more than 8 dosage units when compliant with the requirements of Appendix M.

Schedule 4 - Amend Entry

SILDENAFIL except when included in Schedule 3.

Appendix H - New Entry

SILDENAFIL.

Appendix M - New Entry

SILDENAFIL.

Supply of Schedule 3 sildenafil will be contingent on:

  • the sponsor making Continuing Professional Development (CPD) accredited training available to pharmacists; and
  • the sponsor providing a patient assessment tool to facilitate screening and counselling by the pharmacist.

The applicant's reasons for the proposal were:

  • The proposal has been submitted to make sildenafil 50 mg available over the counter (OTC) without a prescription accompanied with appropriate informative consumer and pharmacist educational programmes and Schedule 3 advertising. The proposal will help reach men with erectile dysfunction (ED) who do not seek help from their doctor about their condition. It will also direct men away from the unregulated supply of imported ED medicines.
  • The proposal will provide a safer alternative route for genuine, clinically effective and high quality treatment and advice for those men already using or contemplating using unregulated internet sources of sildenafil 50 mg. It will also help destigmatise ED, raise awareness of the causes of ED and its association with more chronic conditions such as cardiovascular disease (CVD) and diabetes. It will encourage treatment seeking behaviour and offer the potential for earlier and more frequent interaction with the primary healthcare system.
  • The majority of men with ED are not reporting it to their doctor. The proposal will encourage men suffering from ED and with no known CVD into the healthcare system. This will provide the opportunity for advice and potential diagnosis of underlying CVD, particularly given the 3 to 5 year disease progression from onset of symptoms. There are clear health benefits in being able to bring these men into the healthcare system sooner than currently experienced, given the importance of primary prevention measures such as smoking cessation, regular exercise and healthy diet.
  • The efficacy of sildenafil 50 mg has been evaluated in the home setting in a representative group of subjects with ED of broad spectrum aetiology. As well as direct benefits to the consumer, the sildenafil clinical programme demonstrated that partner satisfaction with sexual intercourse also improved. In addition to improving the subject's ED, effective non-prescription treatment with sildenafil can provide broader benefits to improve the subject's quality of life (QoL) and their relationship with their partner.
  • The safety profile of sildenafil is well-established based on an extensive controlled clinical trial database and many years of marketing experience with the prescription product. Adverse events (AEs) are generally well-tolerated with very low rates of discontinuation of therapy. The commonly reported AEs in the cumulative clinical trials dataset are consistent with the adverse drug reactions (ADRs) reported in the product information (PI) document, showing that the PI is accurate and comprehensive.
  • A detailed assessment of the potential risks associated with non-prescription availability and advertising of sildenafil 50 mg demonstrates that they can be can be adequately addressed and managed in a non-prescription setting. The [REDACTED] Study has demonstrated that pharmacists can correctly make an assessment with appropriate pharmacy support, based on the proposed non-prescription model. Therefore, usage based on the supply framework for Schedule 3 sildenafil is considered safe and appropriate. A non-prescription status will likely not delay underlying diagnosis but rather encourage treatment-seeking behaviour by allowing the pharmacist to refer men found not suitable for sildenafil 50 mg to a physician for investigation, for potentially earlier diagnosis of any underlying conditions (such as CVD and diabetes). Furthermore, a non-prescription status will not increase misuse/abuse, but instead provide a controlled supply route for those men who are not able or willing to visit their physician in the first instance. This will provide men with the opportunity for interaction with a healthcare professional (pharmacist) who can provide helpful advice on managing ED and related conditions.
  • The non-prescription PI, patient information, and consumer and pharmacist educational programmes have been specifically designed to address the key risks associated with sildenafil 50 mg in a pharmacy setting. These materials include appropriate instructions, contraindications and/or warnings and precautions for use to minimise the key risks identified, i.e. nitrate interactions, priapism and non-arteritic anterior ischemic optic neuropathy (NAION). The materials also allow for clear identification of subjects who are fit for sex and those not fit for sex, to mitigate the hypothetical concern that sildenafil use would indirectly contribute to an increase in the risk of a CV event as a result of enabling sexual intercourse and sexual activity.
  • Any incremental risks associated with non-prescription availability and advertising of sildenafil 50 mg can be effectively managed in the pharmacy setting through the following key measures:
    • Pharmacist intervention at the point of sale;
    • Well-developed pharmacist educational programmes;
    • Pharmacist Training Guide and Checklist;
    • PI for healthcare professionals;
    • Product label (primary pack and CMI/leaflet); and
    • Consumer education activities.
  • Based on the evidence outlined in the application, the non-prescription sildenafil 50 mg dose has a favourable benefit-risk profile in the pharmacy setting which meets the:
    • Requirements under Section 52E of the Therapeutic Goods Act 1989;
    • Scheduling factors for a Schedule 3 Pharmacist Only Medicine in the Scheduling Policy Framework; and
    • Matters set out in the National Coordinating Committee on Therapeutic Goods (NCCTG) guideline for advertising of substances included in Schedule 3.
  • The applicant summarises that the important risks for non-prescription sildenafil 50 mg are consistent with those that have been established for sildenafil in the prescription setting. These risks can be effectively managed in the pharmacy setting through routine risk minimisation measures that have been specifically tailored for non-prescription use. Benefits outweigh the risks, and all risks can be appropriately managed through Schedule 3 availability.

Current scheduling status

Sildenafil is in Schedule 4 of the Poisons Standard as follows:

Schedule 4

SILDENAFIL.

The chemically and pharmacologically similar vardenafil and tadalafil are also in Schedule 4 of the Poisons Standard.

Scheduling history

Sildenafil

In August 1998, the National Drugs and Poisons Schedule Committee (NDPSC) noted that sildenafil was widely publicised in the media following its release in the United States of America. The committee members agreed that a Schedule 4 classification should apply from the time sildenafil was marketed in Australia. The committee considered that the contraindications, precautions and drug interactions were such that medical advice was required.

In July 2017, the ACMS considered an application to down-schedule sildenafil to a Schedule 3 Pharmacist Only Medicine. Based on the potential for incorrect assessment of ED by pharmacists, CVD risk, AEs, drug interactions, possible misuse/abuse, risk of worsened outcomes and no upper age limit, the committee recommended, and the delegate agreed, that the current scheduling of sildenafil remains appropriate.

Vardenafil

In June 2003, the NDPSC considered a proposal to schedule vardenafil as a new medicine. The committee decided to list vardenafil in Schedule 4 on the grounds that the condition being treated necessitated appropriate medical diagnosis and the use of this medicine required patient management and monitoring by a medical professional.

In November 2016, the ACMS considered a proposal to down-schedule vardenafil in oral preparations containing up to 10 mg to Schedule 3. The committee advised that the current scheduling of vardenafil remains appropriate on the basis that erectile dysfunction can be a marker of an underlying cardiovascular disease, diabetes or endocrine disorder and men should be assessed by a medical practitioner prior to (or at the very least concurrent with) initiation of phosphodiesterase type 5 (PDE5) inhibitor treatment. Furthermore, although vardenafil shows good toxicological profile and is well-tolerated, the cause/aetiology of the medical condition is of greater concern and should first be assessed by a medical practitioner. The committee also noted that PDE5 inhibitors are commonly misused, often in combination with other drugs such as MDMA (ecstasy/methamphetamines). The delegate agreed with the committee's advice, stating that as there are currently no risk management plans for Schedule 3 medicines, it is premature to down schedule vardenafil when there are no mandated requirements to minimise the risk relating to underlying medical conditions. The delegate also noted that no other PDE5 inhibitors have been down-scheduled.

In July 2017, the ACMS again considered an application to down-schedule vardenafil to a Schedule 3 medicine. The committee recommended that the current scheduling of vardenafil remains appropriate based on the potential for incorrect assessment for ED by pharmacists, CVD risk, AEs, drug interactions, possible misuse/abuse, and lack of risk management plans for Schedule 3 medicines. The delegate agreed with the committee's advice and the scheduling of vardenafil remained unchanged.

Australian regulatory history

The Australian Register of Therapeutic Goods (ARTG) has 101 products that contain sildenafil citrate.

In the last 30 years there have been 1104 reported cases of adverse events related to sildenafil in the Database of Adverse Events Notification (DAEN) - Medicines: 974 cases with a single suspected medicine and 42 cases where death was the reported outcome.

According to the TGA Ingredient Database, sildenafil citrate is:

  • Available for use as an Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription Medicines; and
  • Not available as an Equivalent Ingredient in any application.

International regulations

Canada

Health Canada regulates sildenafil as a Prescription Only Medicine. Tablet strengths available include 25 mg, 50 mg and 100 mg, and there is also a 0.8 mg/mL solution of sildenafil registered (as a 10 mg/12.5 mL product) for intravenous use.

New Zealand (NZ)

Medsafe NZ regulate sildenafil as a prescription medicine with the exception of sildenafil for oral use containing 100 mg or less per dose unit sold in the manufacturer's original pack containing not more than 12 dosage units. This is indicated for the treatment of ED in males aged between 35 and 70 years and is provided by a registered pharmacist who has successfully completed a training programme endorsed by the Pharmaceutical Society of NZ.

United States of America (USA)

The USA Food and Drug Administration regulate sildenafil as a Prescription Only Medicine.

United Kingdom (UK)

In November 2017, the UK Medicines and Healthcare products Regulatory Agency (MHRA) formally classified sildenafil 50 mg from a prescription only medicine (POM) to a pharmacy medicine (P). Sildenafil 50 mg could be available without prescription for use by men over 18 who have ED. This decision was made following an assessment of the safety of [REDACTED] advice from the Commission on Human Medicines and a public consultation with positive outcome. Sildenafil 50 mg will be sold in pharmacies following a discussion with the pharmacist. Pharmacists will be able to determine whether treatment is appropriate for the patient and can give advice on ED, usage of the medicine, potential side effects and if further consultation with a general practitioner is required.

[REDACTED] will not be sold to those with severe CVD; at high cardiovascular risk; liver failure; severe kidney failure; or taking certain interacting medicines. Use of [REDACTED] in these groups of men must continue to be under the supervision of a doctor.

European Union (EU)

An application to switch sildenafil from prescription to OTC in the EU in 2008 was withdrawn by the sponsor after the European Medicines Agency (EMA) noted some concerns. The EMA committee expressed concerns that there would be no medical supervision, which could delay diagnosis of possible CVD. The EMA's Committee for Medicinal Products for Human Use (CHMP) was also concerned that availability of sildenafil through pharmacies could lead to an increase in its recreational use, particularly among younger people.

Substance summary

Sildenafil facilitates penile erection by enhancing the relaxant effect of nitric oxide (NO) released in response to sexual stimulation. Sildenafil citrate, a sildenafil salt, is an orally active selective inhibitor of cyclic guanosine monophosphate (cGMP) specificPDE5. Cyclic-GMP PDE5 is the predominant isoenzyme in the human corpora cavernosa responsible for the degradation of cGMP. By inhibiting PDE5, sildenafil causes NO-induced cGMP concentrations to remain elevated in the corpus cavernosum smooth muscle. Elevated cGMP levels signal smooth muscle relaxation, resulting in an inflow of more blood in the corpus cavernosum and subsequent penile erection.[9],[10] To be effective, sexual stimulation is required.

Table 1.1: Chemical properties of sildenafil
Property Sildenafil (as citrate)
CAS number 171599-83-0 (as citrate)
IUPAC and/or common and/or other names 5-[2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d-]pyrimidin-7-one dihydrogen 2-hydroxypropane-1,2,3- tricarboxylic acid.
Chemical structure Chemical structure of sildenafil citrate (sildenafil citrate)
Molecular formula C22H30N6O4S.C6H8O7 (as citrate)
Molecular weight 666.7 g/mol (as citrate)

Pre-meeting public submissions

Eleven (11) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Seven (7) submissions supported the proposed amendment (one did not support the proposed Appendix H entry), and four (4) opposed the proposed amendment.

The main points provided in support of the amendment were:

  • General statements on the proposal:
    • The prevalence of ED reported in Australia and NZ has ranged between 25-40% of men.[11] However, only 14-16% of men sought a medical diagnosis and treatment to manage their condition despite the increase in public awareness and acknowledgement of ED since the development of effective pharmacological treatments such as sildenafil.
    • Australian men are less likely than women to seek treatment from a GP or other health professional. Pharmacists have been repeatedly voted as one of the top three regarded professions in Australia. It is believed that men will be more willing to discuss their health with their pharmacist. Further, appointments with pharmacists are not required.
    • Risk factors such as smoking, hypertension, obesity and high total cholesterol levels all contribute to ED. If risk factors are identified during the consultation/screening, the pharmacist can refer them to a doctor. As a result, more men would enter into the healthcare system. This opportunity can potentially slow or halt the progression of diseases such as CVD.
    • Men with low CVD risk can be readily identified by a pharmacist, can begin ED treatment without further testing and can initiate/resume sexual activity quicker. This will reduce the burden on GPs.
    • The proposal meets the scheduling factors for a Schedule 3 medicine.
    • A lack of an upper age limit in the proposed Schedule 3 entry is not a valid reason for rejection. Men that fall into this category will be identified by the pharmacist and referred to their GP.
    • A similar scheduling arrangement has existed in NZ since 2014 and results have been positive. The UK regulator recently re-classified sildenafil to a Pharmacy Medicine.
    • Allowing sildenafil to be available without a prescription will provide greater opportunities for men to be screened for CVD, be provided health advice and be referred to a doctor if necessary.
  • Proposed Appendix H entry:
    • An Appendix H entry will lead to more men having earlier discussions with a health professional, help raise public awareness of the Schedule 3 availability of sildenafil and deliver a range of benefits to both consumers and pharmacists.
  • Proposed Appendix M entry:
    • The concern from a previous ACMS meeting that 'additional pharmacist training and use of a specific supply protocol cannot be mandated for the supply of pharmacist-only Schedule 3 medicines' has now been addressed through the establishment of Appendix M. Other concerns that were raised by the delegate will also be mitigated by the proposed Appendix M entry and associated mandatory pharmacist training/protocols. This will ensure that Quality Use of Medicines (QUM) principles are met.
    • Community pharmacists have the capacity be trained in the diagnosis and management of ED. This will enable pharmacists to encourage men to seek further medical care if required, increasing the chance of early detection of undiagnosed comorbidities such as CVD, metabolic syndrome and diabetes. This training will also enable pharmacists to educate men, helping them to overcome the stigma of ED and in turn increasing the likelihood that they will seek health advice from their GP.
    • The Schedule 3 protocols will be a systematic, evidence-based procedure that will assist pharmacists to fulfil their professional obligations. Key elements of guidelines will consider similar guidance in NZ and the UK, but would be contextualised for Australian practice. This would provide a robust, evidence-based clinical assessment process to identify men found suitable for supply and expectations for medical referral when not appropriate.
    • Men already diagnosed with type 2 diabetes would be under the care of their GP and would be regularly consulted on the management of their condition. This regular consultation would provide them with the opportunity to discuss any concerns regarding ED. Men with undiagnosed type 2 diabetes will benefit from a pharmacist screening using the protocol as they will be referred to a GP.
    • The risk of men not disclosing contraindications to a pharmacist is mitigated by pharmacists being trained to explain the importance of disclosure. This risk is likely to be the same for pharmacists as it is for doctors.
    • Repeat supplies for sildenafil will require assessment using the protocol to ensure that the patient's condition had not changed. This will provide an opportunity for those men at higher risk to have a full medical investigation.
  • Safety of sildenafil:
    • Sildenafil has a well-established safety profile and is well tolerated. Adverse events of sildenafil are generally transient and mild to moderate in nature. Data from systematic reviews, case reports and pharmacovigilance monitoring systems support the safety and tolerability of PDE5 inhibitors. The TGA's DAEN reports for sildenafil products indicate relatively minor adverse events that mostly align with the PI. Considering the history of sildenafil prescribing in Australia (available for over 20 years), the number of reports is relatively minor.
    • Sildenafil has been extensively studied. Numerous studies have demonstrated the safety of PDE5 inhibitors, including a reduction in all-cause mortality, dose dependent reduced risk of death or heart failure and independent protection against mortality in men with diabetes. The risk of a serious adverse event occurring is extremely low.
    • Sildenafil is not addictive and has a very low abuse potential. MedWatch reported 44 separate warnings of abuse since 2000, most of which reported contamination of herbal products with active drug components.
    • Performance of a CV assessment and collection of medical history is not required prior to commencing treatment with a PDE-5 inhibitor for all men with ED. The Princeton III Consensus states that men deemed to be 'low risk' can initiate or resume sexual activity and begin ED treatment without further testing or evaluation.[12]
  • Drug interactions:
    • Potential drug-drug interactions involving sildenafil are unlikely to be an issue as they will be identified by the pharmacist. The only serious drug-drug interaction is with nitrates and riociguat. Those interactions will be highlighted on the pack. In most cases, sildenafil - nitrate interactions involve transient hypotension and are not associated with serious adverse events leading to incapacitation or hospitalisation.
    • Any patient taking nitrates would have been prescribed these by their GP and would be aware of their clinical diagnosis. It is assumed they would be regularly visiting their GP for this and they would have the opportunity to discuss their suspected ED. In the event that they requested a supply of sildenafil from a pharmacist, these medicines would be identified as part of the protocol and the pharmacist would refer them back to their doctor.
    • Contraindications will be addressed by appropriate labelling.
  • Counterfeit sildenafil:
    • ED medicines are currently the most counterfeited medicines seized by UK customs, suggesting that the market for these drugs is large. ED medicines from uncontrolled sources are often of poor quality, have an unknown amount of active, contain the wrong ingredient and often have no appropriate patient information.
    • There are a growing number of TGA alerts relating to contaminated, adulterated and counterfeit ED products. Men who purchase these products are doing so without the supervision of a healthcare professional. Increased access of sildenafil without a prescription will provide men with a legitimate product and advice from a pharmacist.
    • Access to sildenafil from a pharmacist following a consultation would likely reduce counterfeit purchasing from internet websites. Men consulting their pharmacist are more likely to engage with their doctor if the pharmacist has identified any risk factor.

The main points provided in opposition of the amendment were:

  • The potential benefits of re-scheduling sildenafil to Schedule 3 do not outweigh the potential risks to patient safety. Re-scheduling sildenafil will not help destigmatise ED or lead to improvements in treatment seeking behaviour for chronic medical conditions.
  • The same proposed amendment for sildenafil was made in mid-2017 and a similar proposal for vardenafil was made in the mid-2016. Both applications were subsequently rejected by the ACMS.
  • ED is complex medical condition, is a marker for the state of the blood vessels and should be thoroughly investigated before PDE5 inhibitors are prescribed. This is best investigated by the patient's usual GP where this issue can be teased out and, if appropriate, alternatives discussed. ED may also be caused by many other prescription medicines. It is also crucially important to explore whether there are psychological causes of ED which can be a very significant reason for presentation. These issues cannot be addressed by answering a simple checklist of questions posed by a pharmacist.
  • Pharmacists in the community setting do not have the adequate resources to screen for these risks, irrespective of any Appendix M entry that would mandate the pharmacist to undertake accredited Continuing Professional Development and use a patient assessment tool. The contents of any patient assessment and screening tool must be consulted on and validated by expert clinicians.
  • It is argued that men will be more likely to seek help for ED from a pharmacist rather than make an appointment with their GP. Men who have not attempted to obtain prescription sildenafil from a GP will not be more comfortable obtaining non-prescription sildenafil from a pharmacist. Further, accessing these medicines from a pharmacist does not avoid initiating a conversation about ED. Conversations with men regarding ED can be very difficult to initiate when there is no well-developed therapeutic relationship between doctor and patient. It is most unlikely that a pharmacist delivered checklist will facilitate the confidence, trust and emotional security to entertain such a delicate discussion.
  • Once ED issues are broached, a consultation with a GP will ensure that a full health assessment is undertaken, risk factors are identified and holistic advice is provided. A GP consultation to obtain a sildenafil prescription also provides an opportunity to screen for diabetes mellitus and sexually transmissible infections, as well as undertake unrelated but important health prevention activities.
  • There are potential and serious adverse reactions associated with use of sildenafil including (but not limited to) prolonged QT intervals and an increased risk of arrhythmias. There are also a significant range of contraindications. Identification and management of these contraindications is most appropriately assessed by a GP for the first prescription.
  • Sildenafil has serious interactions with a range of other medicines. While a pharmacist may theoretically know about a patient's usual medicines, a patient's regular GP will also know the full range of medicines currently prescribed, why those particular medicines were prescribed, and be able to discuss safe alternative approaches. A pharmacist identifying a potential adverse drug interaction will, in any event, have to refer the patient to their GP.
  • A pharmacist-administered questionnaire, even if supported by additional training provided by the sponsor, will not mitigate the risks to patient safety or ensure dispensing and use that is consistent with QUM principles.
  • It should be noted that pharmacists will gain financially from the dispensing of these medicines which is an inherent conflict of interest.
  • Data from a poisons line indicates the potential harms and misuse of PDE5 inhibitors such as sildenafil which would be expected to increase with more widespread availability without a prescription. PDE5 inhibitor exposure has a high rate of hospital referral (91%) compared to other pharmaceuticals.

ACMS advice

The committee recommended that the current scheduling of sildenafil remains appropriate.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

  1. risks and benefits of the use of a substance:
    • Sildenafil does not meet the Schedule 3 SPF criteria because:
      • Risk of ED treatment without medical diagnosis or treatment of any underlying serious medical conditions (such as cardiovascular disease and diabetes) outweighs benefit of making sildenafil available as a Schedule 3 medicine.
      • The list of diagnosis tools (including ECG and other cardiac testing) recommended by the Princeton III report is not possible in a pharmacy setting.
    • ED is an independent risk factor of cardiovascular disease.
    • There is no evidence that the patient will consult with their GP at the advice of their pharmacist.
    • There is no evidence that the benefits of improved access for consumers are greatly outweighed by the risk of improper diagnosis or treatment of erectile dysfunction or associated risk factors by a pharmacist.
  2. the purpose for which a substance is to be used and the and extent of use:
    • Although both patients and pharmacists can identify erectile dysfunction, the risk of facilitating ED treatment without appropriate diagnosis or treatment of any underlying serious medical conditions is too great to recommend sildenafil be moved to Schedule 3.
    • Erectile dysfunction - on an 'as necessary' basis
  3. the toxicity of a substance:
    • Although sildenafil has well known side-effects and drug interactions, the risk of facilitating ED treatment without appropriate diagnosis or treatment of any underlying serious medical conditions is too great to recommend sildenafil be moved to Schedule 3.
    • Main risk is hypotension. Sildenafil has a significant adverse effect profile that requires medical monitoring. Drug-drug interactions may potentiate sildenafil toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Limited pack size is considered to not appropriately address risk of harms to consumers brought about by a lack of medical oversight in supply of sildenafil.
  5. the potential for abuse of a substance:
    • Misuse by men without erectile dysfunction is already known to occur, including in combination with illicit drugs such as MDMA.
    • Issues with counterfeit sildenafil are recognised, however increasing consumer access to sildenafil through down scheduling is not considered an appropriate mechanism to address this problem.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Educational campaigns to raise awareness of the association between erectile dysfunction and serious medical conditions and to direct men to discuss their sexual function with their GP can be undertaken, without requiring sildenafil to be down-scheduled.
    • Overcoming stigma with erectile dysfunction and improving treatment rates would be better addressed through consumer education and information.
    • No new relevant evidence supporting the down scheduling to schedule 3 was provided in the submission.
    • No appendix M training and checklist information was provided for the Australian context in managing ED.
    • Questionability of whether appendix M is appropriate for ED and sildenafil treatment given that ED is a symptom of other conditions requiring medical practitioner monitoring and treatment.
    • A public health campaign would be beneficial in raising awareness of ED independently of potential medical treatments or down-scheduling sildenafil.
    • It was suggested by the committee that guidance be developed in relation to the content of Appendix M.
      • There was no proposed appendix M education and checklist material included in the submission so until this was provided, it is difficult to assess whether an Appendix M listing would mitigate the risks of down scheduling. An appendix M listing would need to address:
        • Development of accredited competency-based training for pharmacists by an appropriate accredited training body.
        • Pharmacists are required to have written documentation of their consultation, outlining the clinical assessment they undertook and whether they supplied medication or referred.
        • Well-developed clinical referral pathways for pharmacists that must be adhered to.

Footnotes

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  1. The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018)
  2. Uddin SM, Mirbolouk M, Dardari Z et al. Erectile dysfunction as an independent predictor of future cardiovascular events: the multi-ethnic study of atherosclerosis. Circulation 2018;June 11;[Epub ahead of print]
  3. Nehra et al. (2012) 'The Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease', Mayo Clin Proc, 87(8), 766-778
  4. Andrology Australia Clinical Summary guide 9 - Erectile dysfunction - Diagnosis and Management Update March 2018 found at https://andrologyaustralia.org/wp-content/uploads/clinical-summary-guide-09.pdf (pdf,99kb) (Accessed 25 July 2018)
  5. Nehra et al. (2012) 'The Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease', Mayo Clin Proc, 87(8), 766-778
  6. Andrology Australia Clinical Summary guide 9 - Erectile dysfunction - Diagnoisis and Management Update March 2018 found at https://andrologyaustralia.org/wp-content/uploads/clinical-summary-guide-09.pdf (pdf,99kb) (Accessed 25 July 2018)
  7. Morales AM, Hatzichristou D, Llados JM et al. Community pharmacy detection of erectile dysfunction in men with risk factors or who seek treatment or advice but lack a valid prescription. J Sex Med 2013;10:2303-2311
  8. Braund R et al. Pharmacist supply of sildenafil: pharmacists' experiences and perceptions on training and tools for supply. Int J Clin Pharm. 2018 Jun;40(3):650-658.
  9. Boolell M, Allen MJ, Ballard SA, et al., Sildenafil: An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res1996;8(2):47-52.
  10. Burnett AL. Role of nitric oxide in the physiology of erection. Biol Reprod 1995;52(3):485-9.
  11. Chew, KK, Stuckey B, Bremner A, Earle C, Jamrozik K. Male Erectile Dysfunction: Its Prevalence in Western Australia and Associated Sociodemographic Factors. Journal of Sexual Medicine. 2008; 5(1): 60-69 and Quilter M, Hodges L, Von Hurst P, Borman B, Coad J. Male Sexual Function in New Zealand: A Population-Based Cross-Sectional Survey of the Prevalence of Erectile Dysfunction in Men Aged 40-70 Years. Journal of Sexual Medicine. 2017;14(7): 928-36.
  12. Nehra A, Jackson G, Miner M, et al., The Princeton Ill Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease. Mayo Cli n. Proc. 2012; 87: 766-78.

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