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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017
Scheduling medicines and poisons
Referred scheduling proposal
An application was submitted to create a new Schedule 3 entry for vardenafil in oral preparations containing up to 10 mg per dosage unit in pack containing not more than 8 dosage units.
This was a general application. The applicant's proposed amendments to the Poisons Standard are:
Schedule 3 – New Entry
VARDENAFIL in oral preparations, containing up to 10 mg per dosage unit in packs containing not more than 8 dosage units.
Schedule 4 – Amend Entry
VARDENAFIL except when included in Schedule 3.
The applicant's reasons for the proposal are:
- Following consideration by the ACMS and Scheduling Delegate in 2016, this proposal aims to address the concerns raised by the ACMS and Scheduling Delegate at that time. The primary concerns were:
- The underlying aetiology of the presented erectile dysfunction (ED) requires initial assessment by a medical practitioner;
- PDE5 inhibitors (for example vardenafil) are commonly misused and no data were provided to support a reduction in internet purchasing; and
- The ACMS/Scheduling Delegate has no remit to mandate pharmacist training or a supply protocol and there is currently no TGA requirement for Risk Management Plans for down-scheduled OTC medicines.
- With regards to the need for patient assessment by a medical practitioner, the ongoing professional responsibilities for pharmacists to identify situations where patient symptoms are possibly caused by underlying diseases especially in relation to supply of Schedule 3 medicines, will ensure that appropriate investigation into any potentially underlying disease is investigated where clinically indicated.
- The ACMS/Scheduling Delegate concerns regarding the extent of misuse of PDE5 inhibitors may have been based on the assumption that internet-sourced products are intended for misuse, but available data on the use of illicit substances in Australia does not indicate this. Local social science health research evidence presented in this submission indicates that the level of misuse of PDE5 inhibitors in the general and homosexual/bisexual male population is very low, and concomitant use with 'recreational drugs' lower still. While there is no published evidence to support the contention that the availability of Schedule 3 vardenafil will reduce internet sourcing, statements included herein from pharmacists involved in the non-prescription supply of another PDE5 inhibitor in New Zealand demonstrates that a proportion of internet-sourcing has been converted to pharmacy-sourcing. Furthermore, it is clear that Schedule 3 availability will ensure increased healthcare professional interaction compared to unrestricted internet procurement, and there is most certainly no evidence suggesting that expanded availability will lead to increase internet sourcing. Consequently, the concerns expressed are not supported by the evidence and there remains the real possibility that Schedule 3 vardenafil will result in reduced sourcing of unapproved and unsafe PDE5 inhibitors via the internet.
- The capacity to mandate provision of pharmacist training materials and treatment protocols is considered to already reside with the TGA in their consideration of any Schedule 3 vardenafil 'medicine registration application', under the powers currently vested in the TGA via s3, s25(1)(e), s25(1)(k), s28(b) and/or s28(e) the Therapeutic Goods Act 1989 and associated Regulations. While the current TGA guidelines for over-the-counter (OTC) medicine registration do not specifically cover mandating conditions of registration such as pharmacist training or treatment protocol use, this does not preclude the TGA from invoking such conditions, with regulatory guideline updates following as required in due course. The logistical and administrative particulars of the pharmacist training program and use of the treatment protocol are most pertinent to peak pharmacy bodies and for TGA Schedule 3 product registration applications.
- The current international precedents of non-prescription supply of PDE5 inhibitors in New Zealand and the United Kingdom, and significantly the MHRA's 28 March 2017 view that sildenafil is safe enough to be recommended for reclassification to Pharmacy medicine status. Vardenafil has been acknowledged to be well-tolerated with a good toxicological profile, and provides a safe and effective treatment option for ED.
Current scheduling status and relevant scheduling history
Vardenafil is currently listed in Schedule 4 of the Poisons Standard as follows:
The chemically and pharmacologically similar sildenafil and tadalafil are also in Schedule 4 of the Poisons Standard.
In June 2003, the National Drugs and Poisons Committee (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 reschedule vardenafil in oral preparations containing up to 10 mg in Schedule 3. The committee recommended 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 PDE5 inhibitor treatment. The delegate agreed with the committee's advice that there are currently no risk management plans for Schedule 3 medicines considering it to be 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. The delegate agreed with the committee's advice and decided that the scheduling for vardenafil remained appropriate.
In August 1998, the National Drugs and Poisons Schedule Committee (NDPSC) considered a proposal to schedule sildenafil as a new medicine. The committee decided to list sildenafil in Schedule 4 on the grounds that the committee considered that the contraindications, precautions and drug interactions were such that medical advice was required.
A rescheduling proposal for sildenafil is also being considered at this meeting.
Australian regulatory information
According to the TGA Ingredient Database, vardenafil is available for use as an:
- Active ingredient in biologicals and prescription medicines;
- Excipient in biologicals, devices and prescription medicines; and
- Equivalent ingredient in prescription medicines.
Vardenafil is listed in 4 entries on the Australian Register of Therapeutic Goods (ARTG). The products marketed include a 5 mg, 10 mg and 20 mg film-coated tablet blister pack and a 10 mg orodispersible tablet blister pack registered.
In the last 20 years there have been 34 adverse event reports in the Database of Adverse Events Notification (DAEN) - Medicines: 29 cases with a single suspected medicine and 1 case of death as a reported outcome. Of the cases where vardenafil was the suspected causative medicine, reactions included ataxia, headache, blurred vision, cyanopsia, erythema, muscle rigidity, deafness, dysphagia, dysphonia, urogenital haemorrhage, thrombocytopenia, atrial fibrillation, prostatic specific antigen increased, and prostate cancer.
Health Canada regulates vardenafil as a prescription medicine, in strengths of 5 mg, 10 mg and 20 mg.
Medsafe New Zealand classifies vardenafil and its structural analogues as prescription only medicines.
The US FDA regulates vardenafil as a prescription only medicine, in strengths of 2.5 mg, 5 mg, 10 mg and 20 mg.
In the UK vardenafil is a prescription only medicine.
Vardenafil hydrochloride is a benzenesulfonamide derivative and an inhibitor of phosphodiesterase type 5 (PDE5), the most prominent PDE in the corpus cavernosum of the penis responsible for the hydrolysis of cGMP. By preventing the breakdown of cGMP, vardenafil allows the male to reach and maintain an erection when sexually stimulated. Vardenafil is used to treat erectile dysfunction (ED) in adult males. The maximum recommended dose is one orodispersible tablet daily (10 mg vardenafil).
|CAS number||224785-90-4 (vardenafil)|
(as hydrochloride trihydrate)
|Molecular formula||C23H32N6O4S.HCl.3H2O (as hydrochloride trihydrate)|
|Molecular weight||488.6 g/mol (vardenafil)|
|IUPAC and/or common and/or other names||
2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-imidazo[5,1-f][1,2,4]triazin-4-one hydrochloride (IUPAC);
Pre-meeting public submissions
Six (6) submissions were received, four (4) in support and two (2) opposed.
Main points in support:
- Implementation of the proposed scheduling amendment will encourage men suffering from ED into the healthcare system and provide the opportunity for men to engage in more health-related discussions with their pharmacist.
- Pharmacists are well-placed to ensure the appropriate, judicious, and safe supply of PDE inhibitors.
- The increased accessibility of ED treatment will assist men who see themselves as otherwise healthy interacting with a health professional where they may not have ordinarily. This, in turn, provides the opportunity for cardiovascular risk screening and referral to a GP of those patients who may not currently have a relationship with their GP.
- Sildenafil and vardenafil have been available in Australia for a significant period of time as Schedule 4 medicines. To facilitate Schedule 3 supply, additional information and advice will be provided, based on current available evidence, to offer pharmacists contemporary, realistic and useful guidance to support good decision-making in practice.
- Allowing controlled access to this medicine without a prescription has led to an increase in discussions between men and healthcare providers in New Zealand, where erectile dysfunction medicines are already available for supply by pharmacists under certain conditions.
- British Medicines and Healthcare Products Regulatory Agency is considering an application to re-schedule sildenafil, to make it available over-the-counter in pharmacies.
Main points opposed:
- Vardenafil can prolong the QT interval and increase the risk of arrhythmia. Its use is also cautioned in hepatic impairment.
- Pharmacies in the community setting do not have adequate resources to screen for these risks.
- Erectile dysfunction (ED) is a marker of the state of the blood vessels in other parts of the cardiovascular system and should be thoroughly investigated before phosphodiesterase inhibitors are prescribed. This is best investigated by the patient's usual medical practitioner in a consultation where this issue can be teased out and if appropriate, alternatives discussed.
- Pharmacists may know about a patient's usual medicines. However, a patient's regular general practitioner will know the full range of medicines currently prescribed, why those particular medicines were prescribed, and be able to discuss safe alternative approaches knowing the full medical history of the patient. A pharmacist identifying a potential adverse drug interaction will, in any event, have to refer the patient to their general practitioner.
- A medical practitioner consultation to obtain a prescription for vardenafil also provides an opportunity to screen for diabetes mellitus and sexually transmissible infections, as well as undertake unrelated but important health prevention activities.
The public submissions will be made available on the TGA website.
Summary of ACMS advice to the delegate
The committee recommended that the current scheduling of vardenafil 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 and 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 were:
- Approximately 20% of Australian men greater than 40 years suffer from ED with a significantly increased risk of having CVD. There is evidence to suggest that men who have Type 2 Diabetes and ED have a significantly increased risk of having CVD.3 As a consequence, there is a major risk of the underlying CVD potentially not being identified and subsequently managed.
- Toxicity of vardenafil is low and it is well tolerated. However, the benefits of down-scheduling vardenafil from Schedule 4 to Schedule 3 do not outweigh the risks.
- The proposed vardenafil preparations containing up to 10 mg in a pack size of eight (8) units does not appropriately address the risk of harms brought on by a lack of medical oversight in supply.
- Possible misuse/abuse by men who do not have ED, or by men who take other drugs. The extent in Australia is currently unknown.
- Good clinical practice mandates a cardiovascular assessment and history in all patients presenting with ED, and this is best done by a general practitioner.
The delegate considered the following regarding this proposal:
- Scheduling proposal
- ACMS advice
- Public Submissions received
- Section 52E of the Therapeutic Goods Act 1989
- Scheduling Policy Framework (SPF 2015)
- Other relevant information
Delegate's interim decision
The delegate's interim decision is that the current scheduling of vardenafil remains appropriate.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (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; (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 interim decision are:
- the risks and benefits of the use of a substance:
- Adverse events and drug interactions of vardenafil can be potentially severe. The adverse event profile requires medical monitoring. Drug interactions may potentiate vardenafil toxicity.
- There is a risk of QT prolongation.
- There is increasing evidence of a direct link between erectile dysfunction and cardiovascular disease. Erectile dysfunction is a marker of early atherosclerosis and as an independent predictor of cardiovascular events and all-cause mortality.3
- There is evidence to suggest that the combination of type 2 diabetes and ED with significantly increased risk of cardiovascular disease.3
- Risk of worsened health outcomes is heightened by the possibility of men never going to their doctor for assessments and obtaining repeat supplies from pharmacists.
- Potential for incorrect assessment of ED and lack of screening of underlying and asymptomatic chronic conditions leading to a worsened health outcome due to self-management.
- The proposed warning statements by the applicant actually reinforce the requirement for medical assessment before prescribing.
- Risk it would be used by men who are unfit and/or by those who have contraindications and are not prepared to tell pharmacist.
- Risk is heightened by the possibility of some consumers never going to their doctor for assessment, and obtaining repeat supplies through a pharmacist.
- Any 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.
- the purposes for which a substance is to be used and the extent of use of a substance:
- The proposed Schedule 3 entry is intended for use in men aged 18 years old and older, with no upper age limit.
- Approximately 20% of Australian men greater than 40 years suffer from ED with a significantly increased risk with aging and cardiovascular disease.
- the toxicity of a substance:
- Safety data indicates that NAION and priapism are potential serious AEs, as are interactions with nitrates & some other drugs metabolised via CYP450.
- Vardenafil has a significant AE profile that requires medical monitoring.
- Drug-drug interactions may potentiate vardenafil toxicity.
- the dosage, formulation, labelling, packaging and presentation of a substance:
- Proposed pack size of eight (8) units does not appropriately address the risk of harms brought on by a lack of medical oversight in supply of vardenafil.
- the potential for abuse of a substance:
- Possible misuse and/or abuse by men who do not have ED, or by men who take other drugs.
- any other matters that the Secretary considers necessary to protect public health:
- Good clinical practice mandates a cardiovascular assessment and history in all patients presenting with erectile dysfunction. This is best done by a patient's general practitioner.
- Internet purchasing is recognised, as is counterfeiting, however increased access through down-scheduling is not considered an appropriate mechanism to address this issue.
- Consumer education and information is a better avenue to help overcome the stigma of ED and improve treatment rates.
- Although reticence to speak to GP about ED it not likely to be easier to speak to unknown pharmacists with whom there is no on-going relationship.
- Low public health benefit as access is still outweighed by risks.
- Men do not see GP often anyway, so any opportunity to review for holistic review is good.
- In view of the reasons above the current scheduling of vardenafil is appropriate.