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Scheduling delegate's final decisions, March 2017

Scheduling medicines and poisons

23 March 2017

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3.4 Vardenafil

Part A - Final decisions on matters referred to an expert advisory committee

3. Advisory Committee on Medicines Scheduling (ACMS #19)

3.4 Vardenafil

Referred scheduling proposal

An application was submitted to reschedule vardenafil in oral preparations containing up to 10 mg in Schedule 3.

Scheduling application

This was a general application. The Applicant’s proposed amendment to the Poisons Standard is as follows:

Schedule 4 – Proposed Amended Entry

VARDENAFIL except when included in Schedule 3.

Schedule 3 – Proposed New Entry

VARDENAFIL in oral preparations containing 10 mg or less of vardenafil per dosage unit in packs containing not more than 8 dosage units.

The applicant’s reasons for the request are:

  • To improve access to an effective treatment of verified pharmaceutical quality for an appropriate cohort of adult males suffering from erectile dysfunction (ED), who may not have otherwise consulted a doctor regarding their ED symptoms;
  • ED affects at least 20% of Australian men >40 years, with the odds of ED increasing up to 10 times in >70 year-olds. However, the reported prevalence of ED is likely to represent an underestimate because of the general reluctance of men to seek medical advice, the social implication of admitting the condition, and the embarrassment their discussion will cause.
  • Improved management of ED may have a potential for public benefit beyond men’s sexual health.
  • Although ED is rarely the first sign of other emerging medical conditions, it has been correlated with other health conditions; thus opportunities to encourage men reticent to consult a health professional about ED are valuable.
  • Of particular concern is the variety of internet-sourced, unapproved ED products that may pose safety risks due to unevaluated ingredients, containing undeclared PDE5 inhibitors or other substances, or are falsely manufactured, packed or advertised counterfeit versions. The scale of the risk these products pose to Australia men appears to be significant (25% of all 2015 TGA safety alerts) and is expected to increase based on 2016 TGA safety alerts to date.
  • For ED sufferers who are aware of treatment options, are comfortable enough to discuss their symptoms with a HCP and can afford adequate healthcare, the General Practitioner (GP) is another access option to treatment. However, as men commonly delay or avoid consulting their GP generally and in particular regarding ED, safe, alternative options to access effective treatments such as PDE5 inhibitors appear warranted.
  • Vardenafil has a well-characterised and favourable benefit-risk profile. The safety of vardenafil has been well established through clinical trials in more than 52,000 subjects and post-marketing experience since 2003 (up to 107 countries as of 2016) from more than 2.2 Mio patient-years.
  • Rescheduling vardenafil up to 10 mg in distinctively labelled packs of up to 8 dosage units as Schedule 3 medicines, when supplied by trained and accredited pharmacists according to a strict screening protocol will provide better access to effective treatment for men with ED and a low risk CV status. More broadly, the proposed treatment algorithm could be seen as patient screening programme focused on CV risk indicators that can identify at-risk patients earlier and thus improve health management and well-being for Australian men.
Current scheduling status

Vardenafil is currently listed in Schedule 4 of the Poisons Standard as follows:

Schedule 4


Relevant scheduling history

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.

Australian regulatory information

In Australia, vardenafil 5, 10, and 20 mg tablets and vardenafil 10 mg dispersible tablets were registered as Prescription Only Medicines on the ARTG in April 2003.

International regulatory information

Internationally (Canada and USA), vardenafil appears to be classified as prescription medicine.

Substance summary

Vardenafil is present in oral dosage forms as vardenafil hydrochloride trihydrate, which is nearly colourless, very slightly soluble in water, soluble in dilute hydrochloric acid and soluble in ethanol.

Vardenafil inhibits the most prominent phosphodiesterase (PDE) in the corpus cavernosum, the enzyme phosphodiesterase type 5 (PDE5), which specifically hydrolyses cGMP. By preventing the breakdown of cGMP, vardenafil allows the male to reach and maintain an erection when sexually stimulated to produce nitric oxide.

The maximum recommended dose is one orodispersible tablet daily (10 mg vardenafil) - Australian Public Assessment Report for Vardenafil.

Table 3.4: Chemical information
Property Vardenafil
CAS No. 330808-88-3 (hydrochloride trihydrate), 224785-91-5 (anhydrous)
Chemical structure Chemical structure for vardenafil
Chemical name 2-[2-Ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one hydrochloride.
AAN Vardenafil hydrochloride trihydrate (INNM) and vardenafil (INN)
Molecular formula C23H32N6O4S·HCl·3H2O (hydrochloride trihydrate)
Molecular weight 579.1 g/mol (hydrochloride trihydrate)
Pre-meeting public submissions

Seven (7) public submissions were received. Six (6) submissions supported the proposal and one (1) opposed the proposal.

The main points in support were:

  • Erectile dysfunction is closely correlated with a number of chronic conditions involving compromised vascular function, such as coronary artery disease, hypertension, diabetes, and hypercholesterolemia. As men with erectile dysfunction are likely to have or to develop cardiovascular risk factors it is important that they seek assistance from a health care professional at the earliest opportunity. In many cases erectile dysfunction is an early sign of cardiovascular risk development and is a potential indicator for adverse cardiovascular events. Therefore enabling a discussion between men with erectile dysfunction and trained health professionals will go some way to help address the health concern of male cardiovascular risk.
  • There are several classes of prescription drugs contribute to sexual dysfunction in men. These include antihypertensives, antidepressants and antipsychotics. Patients who develop drug-induced sexual dysfunction are more likely to be non-adherent to their medicine regimens. Therefore pharmacists have an important role to play in screening and risk assessment of patients who may be suffering from sexual dysfunction caused by a medical condition or the use of a medicine.
  • As males traditionally do not engage to the same extent as females with medical practitioners, Pharmacist Only vardenafil represents an opportunity for men who would otherwise not seek primary care support to be assessed by a pharmacist and appropriately referred to a medical practitioner for assessment of their health conditions/comorbidities.
  • Availability of Pharmacist Only vardenafil provides an avenue for men to access proven, registered treatments for erectile dysfunction and have related health conditions initially screened by a pharmacist and appropriately referred. An overseas study showed pharmacists can accurately use screening tools to identify erectile dysfunction in their practice.
  • Men without a GP will welcome the opportunity to access information and pharmacist screening services for erectile dysfunction.
  • Many men suffer in silence and are reluctant to get professional help for their sexual concerns and often do not continue treatment. Men turn to online unregistered and unsafe options for erectile dysfunction which may pose significant safety risks. Many men, in the absence of an easily accessible face-to-face pharmacy erectile dysfunction service, access internet-sourced unregistered erectile dysfunction options. These unregistered erectile dysfunction options have been found to contain undisclosed Schedule 4 medicines with the potential for causing adverse drug reactions and drug interactions if not provided with counselling from a health professional. Increased primary care intervention (by pharmacists) including erectile dysfunction assessment and referral of men who may otherwise choose unregistered medicines via the internet appears significant. Rescheduling vardenafil to an Schedule 3 medicine would reduce the likelihood that men will resort to internet-sourced unregistered options, which are fraught with counterfeiting and variable quality assurance standards, thereby improving safety.
  • Vardenafil is generally well tolerated has a well-established safety profile. The risk profile and potential for side effects of the proposed Schedule 3 entry (vardenafil 10 mg – 8 dosage units) is low.
  • Several professional bodies indicated that pharmacist training is needed, as this is a new area of practice and there are no similar medications in Schedule 3. Relevant stakeholders need to ensure rigorous, consistent and user-friendly professional education and practice support tools can be developed for the pharmacy profession. Symptoms of erectile dysfunction can be identified by patients and managed by appropriately trained pharmacists with referral to a GP where necessary. Some pharmaceutical professional bodies have developed protocols and training for pharmacists to use to screen/risk assess patients who self-report the symptoms of erectile dysfunction. The protocol was developed in consultation with a range of expert health professionals including urologists, cardiologist and pharmacists, to ensure only low risk patients are supplied vardenafil and all patients with risk factors are referred. A similar scheduling arrangement to that proposed already exists in New Zealand (albeit with sildenafil) and the results there have been positive.
  • The proposed Schedule 3 dosage strength of 10 mg and small pack size would limit potential for overdose.
  • Researchers at Cancer Council NSW have estimated that by 2017 there will be 200,000 Australian men living post diagnosis and treatment for prostate cancer. Of those who have been treated by the main treatment modalities (radical prostatectomy, radiotherapy and androgen deprivation therapy), some 70% will experience persistent erectile dysfunction. Rescheduling vardenafil to an Schedule 3 medicine would greatly benefit men suffering from erectile dysfunction following treatment for prostate cancer. It would improve access to an effective registered treatment in a self-care controlled environment, thereby increasing the number of men who seek professional help for their sexual concerns.
  • Vardenafil has undergone a full evaluation on registration in Australia no new information that may alter the clinical safety and efficacy profile of this medicine is known.
  • The key considerations around whether this rescheduling proposal is acceptable to health professionals and safe for consumers will depend heavily on implementation issues e.g.
    • Screening needed by pharmacists on appropriateness of medicine for consumer
    • Clear criteria for when immediate (or conditional) referral to a medical practitioner is warranted and for these to be clearly highlighted for pharmacists
    • Appropriate communication with prescribers (e.g. consumer’s GP, other prescribers in the area)
  • A change to Schedule 3 would encourage more men to discuss erectile dysfunction by increasing the availability of treatment options. Pharmacists can play in assessing and providing this medication in a responsible manner, improve accessibility, giving professional advice and support from healthcare professionals.
  • Several health risks were identified: risk of arrhythmia; use in patients with hepatic impairment; use in older patients; and potential interaction with other medications. Several professional bodies suggested managing the risks by: additional pharmacist training, use of questionnaires, and limitations on the dosage and maximum pack size allowable in Schedule 3, as proposed by the applicant.
  • An appropriate questionnaire and pharmacist training should be mandated as part of any considerations to create a Schedule 3 listing for vardenafil. Mandating or recommending requirements would ultimately be a matter for the States and Territories and the Pharmacy Board of Australia.
  • In New Zealand sildenafil (a vardenafil analogue) has been available without a prescription from pharmacists that have completed training endorsed by the Pharmaceutical Society of New Zealand. Arguments presented in New Zealand were:
    • men rarely make an appointment to see the doctor about erectile dysfunction as they often think the problem is too trivial from a medical point of view.
    • it is possible for pharmacists to be trained to screen for, and deal with erectile dysfunction that has a purely psychological origin.
    • the proposed substantial cardiovascular risk screening to be performed by pharmacists would mean that patients could receive not only timely access to sildenafil, but also early cardiovascular disease detection.
    • the improved convenience of obtaining sildenafil from a pharmacist would reduce the number of men attempting to import the medicine from overseas via the internet. In Australia, the TGA regularly publishes safety advisories on products that can be bought from overseas websites that have been registered on the Australian Register of Therapeutic Goods (ARTG). These products often contain undeclared active ingredients such as sildenafil and have not been tested for safety, quality and efficacy.

The main points opposed was:

  • If a new Schedule 3 entry is created for vardenafil, the inclusion of vardenafil in Appendix H at this time was not supported given the lack of experience as a Schedule 3 medicine.
  • Vardenafil can prolong cardiology QT intervals and increase the risk of arrhythmias, and its use is also cautioned in the setting of hepatic impairment. Community pharmacies do not have adequate resources to screen for these risks.
Summary of ACMS advice to the delegate

The Committee advised that the current scheduling of vardenafil remains appropriate.

The Committee recommended adding this issue to the SPF review – Schedule 3/Schedule 4 boundary for ‘switch’ products. The Committee also recommended providing feedback to the applicant.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee 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; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the advice comprised the following:

  • 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. 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.
  • PDE5 inhibitors are commonly misused, often in combination with other drugs such as MDMA (ecstasy/methamphetamines). The rescheduling of vardenafil would most likely not reduce internet purchasing and access to overseas supply of vardenafil.
  • The application was predicated on the both pharmacist training and a supply protocol. However, additional pharmacist training and use of a specific supply protocol cannot be mandated for the supply of pharmacist-only Schedule 3 medicines.
Delegate’s considerations

The delegate considered the following in regards to this application:

  • Scheduling proposal
  • Public submissions received
  • ACMS advice
  • 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 delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee’s advice.
  • Although vardenafil has a good toxicological profile and is well-tolerated, the aetiology of the medical condition should first be assessed by a medical practitioner. Erectile dysfunction can be a marker of an underlying cardiovascular disease, diabetes or endocrine disorder.
  • PDE5 inhibitors are commonly misused, often in combination with other drugs such as MDMA (ecstasy/methamphetamines). The rescheduling of vardenafil would most likely not reduce internet purchasing and access to overseas supply of vardenafil.
  • The application was predicated on the both pharmacist training and a supply protocol. However, additional pharmacist training and use of a specific supply protocol cannot be mandated for the supply of pharmacist-only Schedule 3 medicines.
Public submissions on the interim decision

Two (2) public submissions were received that opposed the interim decision. The main points were:

  • Schedule 3 availability of vardenafil has led to an increase in discussions between men and their healthcare providers in New Zealand. This could be mirrored in Australia if vardenafil is changed to Schedule 3.
  • The submission suggests that the rescheduling of vardenafil and the availability of safe, high quality and regulated products may reduce internet purchases of unsafe products. Risk mitigation of illicit use of vardenafil proposed by the submission include, recording vardenafil sales, label warnings, limited Schedule 3 pack sizes and specific counselling against misuse in combination with recreational illicit drugs.
  • Pharmacists are involved in Schedule 3 transactions and are able to recommend appropriate products tailored to each specific patient’s circumstance. This protocol makes mandating ‘additional pharmacist training and use of a specific supply protocol… for the supply of pharmacist-only Schedule 3 medicines’ unnecessary.
  • The TGA’s existing authority could be utilised in order to mandate risk mitigation activities (E.g. Risk Management Plans (RMPs)) as a condition for approval for Schedule 3 medicines, thus overcoming the delegate’s concerns regarding pharmacist practices and training. The submission asserts that existing tools are available to support pharmacist recommendations for medical referral, such as the Pharmacy Society of Australia’s (PSA’s) clinical intervention standard template ‘referral letter’ from dispensing software.
  • Schedule 3 supply of vardenafil could be provided only to patients who, on pharmacist screening, do not have medication contraindications, medical conditions (or family histories of medical conditions) such as cardiovascular (CV) disease, diabetes or endocrine disorders. Such interactions with a pharmacist will prompt men to consider engaging with a medical practitioner to investigate potential cause of their erectile dysfunction (ED) in addition to providing a new opportunity for blood pressure (BP) checks, other elements of CV screening and pharmacist counselling that otherwise would not have occurred. This protocol is in alignment with existing pharmacy frameworks to provide continued professional training, best pharmacy practices for supply of any new and all existing Schedule 3 medicines, and the PSA’s standard for the provision of Schedule 3 medicines as follows:
    • Determine if the patient’s symptoms are caused by other conditions and/or
    • Refer the patient to the doctor where required, in accordance with any pharmacy protocol for the medicine in question.
  • Current consumer, pharmacist and broader healthcare network attitudes and behaviours in relation to ED have the potential to be impacted by the Schedule 3 availability of vardenafil and the consequential promotional and educational investment in ED medicines.
Delegate’s final decision

The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is that the current scheduling of vardenafil remains appropriate.

Reasons for the final decision additional to those provided from the interim decision include:

  • As there are currently no risk management plans for Schedule 3 medicines it is premature to down schedule vardenafil where there are no mandated requirements to minimise the risk relating to underlying medical conditions. The delegate will raise this suggestion with the appropriate TGA area as robust RMPs might assist in assessing down-scheduling applications.
  • The delegate also notes that no other PDE5 inhibitors have been down-scheduled.

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