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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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1.1 Sildenafil

Referred scheduling proposal

An application was submitted to create a new entry for sildenafil in Schedule 3 in oral preparations containing 50 mg of sildenafil per dosage unit in packs of not more than 8 dosage units, to include sildenafil in Appendix H and to include additional warning statements in Appendix F for Schedule 3 sildenafil.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

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 F warning statements.

Schedule 4 – Amend Entry

SILDENAFIL except when included in Schedule 3.

Appendix H – New Entry

SILDENAFIL.

Appendix F, Part 3 – New Entry

SILDENAFIL

Warning Statements: 109, 110

Appendix F, Part 1 – New Warning Statements

109: Do not take [this product/name of the product] if you:

  • do not have an erection problem
  • take any nitrate medicine for chest pain or heart failure
  • take riociguat for high blood pressure in the lungs
  • take ritonavir for the treatment of HIV
  • have been advised by your doctor to avoid sexual activity because of a problem with your heart or blood vessels
  • have a severe heart or liver problem
  • have low blood pressure
  • have ever had severe vision loss or a rare inherited eye disease
  • have a deformed penis
  • have an allergy to sildenafil or similar medicines, or to any other ingredient in this product

110: Unless your doctor has told you to, do not take [this product/name of the product] if you:

  • get very breathless or feel chest pain with light or moderate physical activities
  • have a heart problem
  • have high blood pressure that is not controlled
  • take any other medicines listed in the package leaflet
  • take any other treatment for erectile dysfunction
  • ever had a persistent or prolonged erection that lasted for more than 4 hours
  • have a stomach ulcer or bleeding disorder
  • have diagnosed mild to moderate liver problems
  • have diagnosed severe kidney problems

The applicant's reasons for the proposal are:

  • The risks associated with use of non-prescription sildenafil by men with erectile dysfunction (ED) who have underlying aetiology are low, and can be managed within the pharmacy setting. Non-prescription status will not delay diagnosis of underlying aetiology but is expected to encourage treatment-seeking behaviour and access to appropriate advice.
  • The use of sildenafil has been shown to be safe in those with concomitant ED and cardiovascular disease (CVD), including congestive heart failure (CHF) and coronary artery disease (CAD).
  • Men with undiagnosed diabetes would be less likely to obtain satisfactory results with the proposed non-prescription sildenafil dosing regimen, and would be directed by the product labelling or pharmacist to consult a physician.
  • For men who consult a physician about their ED, co-existing conditions are not commonly detected in the initial consultation. The availability of non-prescription sildenafil provides the potential to directly educate men around the causes of ED and bring more men into the healthcare system.
  • Most low-risk patients can initiate or resume sexual activity and begin ED treatment without further testing or evaluation. Data demonstrates that in the majority of cases, men are immediately prescribed a PDE-5 inhibitor (for example, sildenafil) without a physical examination or diagnostic testing.
  • The availability of non-prescription sildenafil 50 mg, and increased awareness of ED and its association with other medical conditions, will facilitate dialogue between those men not currently seeking medical assistance or a pharmacist around sexual function. This could lead to earlier assessment of medical conditions associated with ED.
  • A maximum of 8 tablets is proposed for Schedule 3 sildenafil, with only one pack provided per consultation. Accessing each pack would require a man to actively engage with the pharmacist and for the pharmacist to undertake appropriate assessment and counselling. Men who have not been given the product will be advised to see the doctor, and those that are provided the product will be advised to see a doctor within 6 months of receiving sildenafil. The frequent interaction with a pharmacist provides repeated opportunities for the pharmacist to recommend seeing a doctor for further assessment.

Current scheduling status and relevant scheduling history

Sildenafil is currently listed 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.

Sildenafil

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.

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 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.

Australian regulatory information

According to the TGA Ingredient Database, sildenafil is available for use as an:

  • Active ingredient in biologicals, export only and prescription medicines;
  • Excipient ingredient in biologicals, devices and prescription medicines; and
  • Equivalent ingredient in prescription medicines.

Sildenafil is listed in 102 registered products on the Australian Register of Therapeutic Goods (ARTG). These include 25 mg, 50 mg and 100 mg tablets.

In the last 20 years there have been 1075 adverse event reports in the Database of Adverse Events Notification (DAEN) - Medicines: 967 cases with a single suspected medicine and 39 cases of death as a reported outcome. Of the cases where sildenafil was suspected, reactions include dyspepsia, dizziness, headache, insomnia, urinary tract infection, diarrhoea, flushing and nausea.

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

Medsafe New Zealand 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 erectile dysfunction in males aged 35-70 years and is provided by a registered pharmacist who has successfully completed a training programme endorsed by the Pharmaceutical Society of New Zealand.

USA

The US FDA regulates sildenafil as a prescription medicine. It was first registered in March 1998.

Substance summary

Sildenafil citrate, a sildenafil salt, is an orally active selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5). CGMP PDE5 is the predominant isoenzyme in the human corpora cavernosa responsible for the degradation of cGMP. With sildenafil acting as a potent inhibitor, there is an increased level of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and allowing an inflow of blood to the area.

Table 1.1.1: Chemical properties of sildenafil
Property Sildenafil
CAS number 171599-83-0 (as citrate)
Chemical structure chemical structure of sildenafil(free sildenafil)
Molecular formula C28H38N6O11S (sildenafil)
Molecular weight 666.7 g/mol (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.

PDE-5 inhibitors are a class of medicines for the treatment of erectile dysfunction (ED). They work by helping to relax the blood vessels in the penis, allowing blood flow to the penis when sexually excited. To be effective, sexual stimulation is required.

Sildenafil facilitates penile erection by enhancing the relaxant effect of nitric oxide (NO) released in response to sexual stimulation. By inhibiting PDE-5, the enzyme responsible for cGMP catabolism, 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.[1] [2]

Pre-meeting public submissions

Eight (8) submissions were received, six (6) in support and two (2) opposed.

Main points in support:

  • The key issue facing men with erectile dysfunction (ED) is related to their reluctance to engage with their doctor. It is well known that the vast majority of men with ED have this condition due to vascular issues and have the same risk factors (such as hypertension, dyslipidemia, smoking and diabetes) that are associated with the development of atherosclerotic cardiovascular disease.
  • Enabling access to an over-the-counter (OTC) PDE-5 inhibitor (supported with learning and educational materials) would encourage awareness of cardiovascular risk factors and will open discussions between the patient and their pharmacist about necessary tests, leading to an early diagnosis.
  • ED medicines are currently the most counterfeited medicines seized by European Union customs. Having a TGA-approved product available through an easy accessible healthcare professional could reduce the number of counterfeit medicines purchased online.
  • PDE-5 inhibitors are generally regarded as safe, well-tolerated medicines with a good toxicological profile that exert a beneficial cardio-protective effect in men with cardiovascular disease.
  • Pharmacists are able to offer point of care testing in the pharmacy in relation to blood pressure, cholesterol and blood glucose tests to accompany the sale of OTC PDE-5 inhibitors, and provide appropriate lifestyle advice.
  • The pack size proposed for inclusion in Schedule 3 is consistent with the starting dose of this substance. With a recommended maximum dose of 1 tablet in 24 hours, the pack represents 8 days' supply. This reflects the proposal currently being considered in the UK. In New Zealand, pharmacists are able to supply an original manufacturer's pack containing not more than 12 dosage units.
  • While there may be a level of non-therapeutic use of PDE-5 inhibitors, there is no data to support the notion that this class of medicines is 'commonly misused'.

Main points opposed:

  • Sildenafil 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 of sildenafil 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 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 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:

  • 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.
  • There is evidence to suggest that the combination of type 2 diabetes and ED with significantly increased risk of cardiovascular disease.[3]
  • Adverse events and drug interactions of sildenafil can be potentially severe. The adverse event profile requires medical monitoring. Drug interactions may potentiate sildenafil toxicity.
  • Possible misuse and/or abuse by men who do not have ED, or by men who take other drugs.
  • 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.
  • The proposed Schedule 3 entry is intended for use in men aged 18 years old and older, with no upper age limit.
  • 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 sildenafil.
  • 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.

Delegate's considerations

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 sildenafil 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:

  1. the risks and benefits of the use of a substance:
    • Adverse events and drug interactions of sildenafil can be potentially severe. The adverse event profile requires medical monitoring. Drug interactions may potentiate sildenafil toxicity.
    • 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.
    • 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.
  2. 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.
  3. 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.
    • Sildenafil has a significant AE profile that requires medical monitoring.
    • Drug-drug interactions may potentiate sildenafil toxicity.
  4. 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 sildenafil.
    • Sildenafil has a wide therapeutic index and the proposed 50 mg dose is the recommended starting dose, 1 hour before sexual activity. The PI states that 100 mg is the maximum dose.
  5. 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.
  6. 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 sildenafil is appropriate.

Footnotes

  1. Boolell M, et al., 1996 Sildenafil: An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int, J, Impot, Res., 8(2), 47-52.
  2. Burnett A.L., 1995 Role of nitric oxide in the physiology of erection. Biol, Reprod, 52(3), 485-9.
  3. Kouidrat, Y et al., 2017 'Systematic Review of Meta-analysis: High prevalence of erectile dysfunction in diabetes: a systematic review and meta-analysis of 145 studies' Diabetic Medicine, 1464-5491.

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