1.4. Interim decision in relation to finasteride

1. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #27, June 2019)

Interim decision in relation to finasteride

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision not to amend the current Poisons Standard in relation to finasteride.

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Substance summary | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to amend the Schedule 4 entry for finasteride was considered.

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

The Applicant's main points provided in support of the proposed amendments were as follows:

• Finasteride fulfils the criteria for a Schedule 3 substance and will provide an alternative to topical minoxidil for consumers.
• Consumers can easily identify the symptoms of male pattern hair loss and it can quite easily be verified by the pharmacist to ensure that there is no other reason for the hair loss.
• The product has been on the market for a number of years and pharmacists are well equipped to provide advice to consumers on the adverse effects, interactions and contraindications (in particular, the potential risk to the male foetus if finasteride is handled by pregnant women).
• The risk profile of the medicine is well defined and there are no identified drug interactions of clinical significance.
• There is little risk of misuse, abuse or illicit use as it does not have any effect outside of its use in hair loss or in larger doses for benign prostatic hyperplasia (BPH).

Current scheduling status

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

Scheduling history

In November 1993, finasteride was first considered for scheduling by the National Health and Medical Research Council's, Drugs and Poisons Schedule Standing Committee (DPSSC). The Committee noted that at its 166th meeting, the Australian Drug Evaluation Committee (ADEC) had recommended approval for the registration of finasteride tablets (XXXXXXXXXXX) for the treatment and control of symptomatic BPH in patients who were not candidates for immediate surgery. The Committee agreed that finasteride be included in Schedule 4 of the Poisons Standard.

In May 1998, the Drugs and Poisons Schedule Committee (DPSC) considered information from the 195th ADEC Minutes from February 1998 relating to a new strength finasteride tablet indicated for the treatment of male pattern hair loss (androgenic alopecia) to increase hair growth and prevent hair loss in men aged 18 years or older. The Committee agreed that the existing Schedule 4 classification was appropriate.

In October 2007, finasteride was again considered at the meeting of the National Drugs and Poisons Schedule Committee (NDPSC) for potential inclusion in Appendix D. In May 2007, the National Co-ordinating Committee on Therapeutic Goods identified inconsistencies between the Poisons Standard's Appendix D and Australian Drug Evaluation Committee (ADEC) 'Prescribing Medicines in Pregnancy' booklet with respect to Category X medicines (i.e. medicines that have a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or where there is a possibility of pregnancy). The Committee noted that there was the possibility of off-label use in women for an unapproved indication, although it would only be prescribed by specialist endocrinologists who would be aware of the pregnancy contraindication. However, due to its specialist indication, that it would only be prescribed by a specialist and that there was adequate warning that it was not for use in women, the Committee agreed that finasteride was suitable to remain in Schedule 4 only and did not warrant inclusion in Appendix D.

Australian regulations

• According to the TGA Ingredient Database, finasteride is available for use as an active ingredient in biologicals, export only and prescription medicines and as an excipient in biologicals, devices and prescription medicines. It is not available as an equivalent ingredient in any application.
• There are 29 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[16] that contain finasteride as an active ingredient. All 29 products are prescription medicines, containing finasteride at either 1 mg (13 products) or 5 mg (16 products).
• Finasteride is indicated for the treatment and control of symptomatic BPH in patients who were not candidates for immediate surgery and for the treatment of male pattern hair loss (androgenic alopecia) to increase hair growth and prevent hair loss in men aged 18 years or older.
• Finasteride is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2019^[17].
• The Database of Adverse Event Notifications (DAEN)^[18] contains 222 reports of adverse events for products containing finasteride as an active ingredient, with 203 reports where finasteride was the single suspected medicine. There was one report of death associated with finasteride use.
• There are no products containing finasteride listed on the Public Chemical Registration Information System Search (PUBCRIS)^[19].

International regulations

• Finasteride is included in the Canadian Food and Drug Regulations as a restricted drug.
• The European Chemicals Agency (ECHA) hazard classification for finasteride is, 'Danger... This substance is very toxic to aquatic life with long lasting effects, may damage fertility or the unborn child, causes damage to organs through prolonged or repeated exposure, is harmful if swallowed and is suspected of damaging fertility or the unborn child'.
• In the United States and New Zealand, finasteride is available as a prescription medicine.

Substance summary

Table 1: Chemical information for finasteride

Property	Finasteride
Chemical structure
Molecular formula	C23H36N2O2
Molecular weight	372.55 g/mol
Chemical name	N-(1,1-dimethyethyl)-3-oxo- 4-aza- 5α-androst-1-ene-17β-carboxamide.
CAS number	98319-26-7
IUPAC and/or common and/or other names	(1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-tert-butyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide.

Toxicity

In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in side effects. No specific treatment is recommended for over dosage with finasteride. Finasteride is contraindicated for use in women when they are or may potentially be pregnant. Type II 5α-reductase inhibitors have the ability to inhibit conversion of testosterone to dihydrotestosterone (DHT) in some tissues and as a result, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male foetus when administered to a pregnant woman. Women who are or may potentially be pregnant should not handle crushed or broken tablets of finasteride or handle tablets with wet hands, because of the possibility of absorption of finasteride and the subsequent potential risk to a male foetus. Whole tablets are coated to prevent contact with the active ingredient during normal handling.

Pharmacology: mechanism of action

Finasteride is a competitive and specific inhibitor of type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t1/2 ~ 30 days). Finasteride has no affinity for the androgen receptor and has no androgenic, anti-androgenic, oestrogenic, anti-oestrogenic or progestational effects. Inhibition of this enzyme blocks the peripheral conversion of testosterone to the androgen DHT, resulting in significant decreases in serum and tissue DHT concentrations. Finasteride produces a rapid reduction in serum DHT concentrations, reaching significant suppression within 24 hours of dosing. Hair follicles contain type II 5α-reductase. In men with male pattern hair loss, the balding scalp contains miniaturised hair follicles and increased amounts of DHT and administration of finasteride decreases scalp and serum DHT concentrations in these men. In addition, men with a genetic deficiency of type II 5α-reductase do not suffer from male pattern hair loss. These data and the results of the clinical studies confirm that finasteride inhibits the process responsible for miniaturisation of the scalp hair follicles, leading to reversal of the balding process.

Summary of pre-meeting public submissions

Seven (7) public submissions were received in response to the notice published under regulation 42ZCZK advising of the proposed amendment. One (1) submission was in support, five (5) were opposed and one (1) that provided general comments to the proposed amendment.

The main points in support of the proposed amendment were:

• Finasteride 1 mg meets the scheduling factors for Schedule 3 (Pharmacist Only Medicines).
• Finasteride for androgenetic alopecia would be expected to be used long term. Therefore, it is believed that the pack size for Schedule 3 supply should allow at least one months' supply to adequately support and improve access for patients.
• In view of the safety profile of finasteride 1 mg oral preparations, and to support optimal treatment options for androgenetic alopecia in men, it is appropriate to include finasteride in Appendix H of the Poisons Standard.
• In order to ensure appropriate and safe use of Schedule 3 finasteride, issues will need to be considered and information, guidance and practice support provided to pharmacists, including:
  • Current therapy;
  • Age;
  • Informed choice;
  • Understanding how finasteride might help;
  • Establishing reasonable treatment expectations;
  • Storage and handling of finasteride tablets;
  • Monitoring ongoing treatment;
  • Clarification regarding the existence of 5 mg finasteride which will continue to be a Prescription Only medicine with a different approved indication; and
  • Practice advice around recording or labelling requirements and uploading of information in the patients my health record.
• Specific consideration is warranted on whether an upper limit on age should be stipulated for Schedule 3 use given the range of published information regarding age-related efficacy.

The main points in opposition of the proposed amendment:

• The current Schedule 4 entry for finasteride remains appropriate due to the potential serious health risks associated with the substance, which requires a healthcare professional intervention.
• The ability to differentiate the diagnosis of androgenetic alopecia from other forms of scalp alopecia is not easily made by a non-clinician.
• Down-scheduling introduces a risk of inadequate communication to the patient of known safety issues, most notably those related to the effect of finasteride on the serum prostate-specific antigen (PSA) test and the potential for mechanism-based teratogenic effects of finasteride on a developing male foetus if a pregnant women is exposed to the drug
• Given the controversy around PSA as a marker for prostate cancer, medical management of this and other potential side-effects is essential as well as taking other conditions or co-morbidities into account.
• Potential safety risks associated with finasteride need to be clearly communicated as they significantly outweigh the cosmetic benefits. This is especially important as long term/continued use of the medicine is recommended to obtain maximum benefit.
• It is well documented that when administered to a pregnant woman, finasteride may cause abnormalities of the external genitalia of a male foetus. Therefore, it is contraindicated for women who are or may potentially be pregnant.
• While finasteride is not indicated for women, there is potential for the substance to be misused or for women to be accidentally exposed to it.
• Androgenetic alopecia is common among men and women, and therefore, may not be clear for consumers that the medicine is only indicated for men and that women should not be exposed to it whatsoever.
• Females with androgenetic alopecia could potentially use the product after it is obtained by a male, especially if the product is also advertised directly to consumers.
• Finasteride is classified as a prescription medicine in the United States (U.S.) and European market.
• In recent years, the U.S. Food and Drug Administration (FDA) have included additional safety/risk statements to strengthen the warning labels for finasteride products. New safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer) was introduced. Similar warnings were added into the Australian product information in 2013.
• In 2012, the U.S. FDA announced that product labels for finasteride 1mg require warnings for libido disorders, ejaculation disorders and orgasm disorders that continued after discontinuation of the drug.
• There is potential for finasteride to be misused if it is included in Appendix H. As androgenetic alopecia is common among men and women, from an advertising perspective, the dangers of using finasteride in women will not be clear, especially in a 15 or 30 second commercial.
• It is likely that the convenience of a tablet will influence consumers who currently use topically applied minoxidil over the counter products to switch to finasteride 1mg tablets. It may actually cause confusion that can lead the consumer to believe that they have the similar safety profile. The similarity in indication between the two medications might increase the possibility of women incorrectly acquiring finasteride 1mg for self-use if it became available as a Pharmacist Only Medicine.
• There is potential for finasteride misuse by adolescents who could acquire this drug for self-use from a third party if it were to become available as a Pharmacist Only Medicine
• Post Finasteride Syndrome (PFS) - is a disease that has been reported to occur in some male patients who have taken finasteride. Reports of symptoms include sexual, physical and neurological symptoms that may persist after the patient has stopped taking finasteride
• Rescheduling finasteride to Schedule 3 could expose pharmacists to a significant risk of litigation should it be prescribed incorrectly. This would be difficult for pharmacists to defend in the absence of a documented full consultation.
• The above issues cannot be discussed over the counter at a pharmacy. Pharmacists are not adequately trained to discuss these issues.
• The treatment of hair loss is a highly lucrative and easily abused industry. People seeking help are often highly motivated to find a 'cure' and are easily exploited.

General comments on the proposed amendment:

• Speculation regarding the plausibility of PFS due to the referencing low-quality studies and skewed public discussion. The stance is taken that PFS is a condition not recognised by the scientific community.
• It was questioned that PFS is something that is not based on clinical evidence and may well be an example of mass hysteria by a group of patients who have been self-selected to suffer from this 'debilitating' condition.
• It was also questioned that if PFS was real that the TGA should have already removed finasteride containing products from the ARTG. Due to it not being removed, it would suggest that it is a safe and an efficacious medicine.
• Finasteride does not produce significant side effects in terms of sexual function.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that the scheduling of finasteride 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; and (e) the potential for abuse of a substance.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • The risks are already covered by inclusion in Schedule 4.
   • Can mask the diagnosis of more serious conditions.
2. the purpose for which a substance is to be used and the extent of use:
   • Therapeutic use for hair loss.
3. the toxicity of a substance:
   • Covered under Schedule 4 entry.
   • Does not meet Schedule 3 Scheduling Factors because of issues around PSA, uncertainty surrounding post finasteride syndrome and it is a known teratogen.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Nil.
5. the potential for abuse of a substance:
   • Potential for inappropriate use.
6. any other matters that the Secretary considers necessary to protect public health:
   • Nil.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to finasteride;

• Advisory Committee on Medicines Scheduling's advice;
• The public submissions received before the first closing date;
• Section 52E of the Therapeutic Goods Act 1989, in particular: (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; and (e) the potential for abuse of a substance;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• The Australian Health Ministers' Advisory Council's Scheduling Handbook (V 1.0, January 2018).

Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (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; and (e) the potential for abuse of a substance.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the scheduling factors for Schedule 4 and Schedule 3.

I have made a decision that the scheduling of finasteride remains appropriate under Schedule 4 and I have set out my reasons below.

I am not persuaded by the evidence supplied by the Applicant that there is a public health benefit of down scheduling finasteride to Schedule 3. Whilst the Applicant argues that finasteride 1 mg meets the scheduling factors for Schedule 3, I am not satisfied that these factors would result in a public health benefit that would outweigh my concern that finasteride is a Category X medication. I note there are currently no Category X substances in Schedule 3.

I have considered that there is potential for inappropriate use of finasteride and significant safety issues. In particular, finasteride does not have a well-defined risk profile and can cause irreversible health effects such as the development of breast and prostate cancer and teratogenic effects on a developing male foetus if pregnant women are exposed to the drug. I am not convinced that if finasteride were to be a Schedule 3 substance that a pharmacist would ensure that Prostate-Specific Antigen (PSA) levels are checked before dispensing the medication. I am of the view that this may result in undetected prostate cancer and a delay in seeking treatment.

I have also considered that there is the possibility that finasteride use may result in Post Finasteride Syndrome. However, I note that at present there is limited evidence to support this. On balance, whilst a Schedule 3 status may increase the use of finasteride and provide pharmacists more opportunities to utilise their training, I find there is little benefit to public health and significant risks associated with easing access restrictions to enable cosmetic use. I note also that the majority of public submissions were against the down scheduling of finasteride to Schedule 3.

In considering these factors and the advice obtained from the Committee, I am of the view that down scheduling finasteride to Schedule 3 would set a dangerous precedent for Category X medications, and the potential risks from broader access under Schedule 3 significantly outweigh the benefits.

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