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Scheduling delegate's final decisions, June 2017
Scheduling medicines and poisons
Part A - Final decisions on matters referred to an expert advisory committee
Advisory Committee on Medicines Scheduling (ACMS #20)
Referred scheduling proposal
An application was submitted to exempt penciclovir from scheduling in preparations containing 1 per cent or less of penciclovir for the treatment of herpes labialis in packs containing 10 g or less.
Current scheduling status
Penciclovir is currently included in Schedules 4 and 2 of the Poisons Standard as follows:
PENCICLOVIR except when included in Schedule 2.
PENCICLOVIR for external use for the treatment of herpes labialis.
In August 1996, the NDPSC considered a proposal to include penciclovir in Schedule 3 after registration approval was granted. It was noted that while penciclovir and aciclovir were related drugs and few adverse effects would be expected to be associated with the use of penciclovir, there was no data on adverse effects resulting from the widespread use of penciclovir in topical form. In addition, it did not appear to be more efficacious than aciclovir and a public need for this particular product had not been demonstrated. The committee considered that Schedule 4 for penciclovir was appropriate, in view of the lack of post-marketing experience with the topical preparation in Australia and the availability of other preparations of similar efficacy and well documented post-marketing history.
In May 1998, the NDPSC considered proposal to reschedule penciclovir from Schedule 4 to Schedule 2 in preparations for the treatment of cold sores (herpes labialis) in preparations containing 1% of penciclovir. The committee agreed that on the basis of market history, another product for treatment of herpes labialis already being in Schedule 2 and the low concern for possible unknown side effects of penciclovir (the active metabolite of famciclovir) that Schedule 2 was appropriate.
In August 1998, the NDPSC agreed that Schedule 2 was appropriate for dermal preparations containing penciclovir. The committee did not consider that there was sufficient justification to require Warning Statement 64 on either aciclovir or penciclovir cold sore creams. Warning statement 64 was recommended to be removed from Appendix F, part 3 for penciclovir and aciclovir at the February 1999 NDPSC meeting.
Relevant scheduling history for related substance, aciclovir
Current scheduling of aciclovir:
ACICLOVIR except in preparations containing 5 per cent or less of aciclovir for the treatment of herpes labialis in packs containing 10 g or less.
When compounded with hydrocortisone, aciclovir is Schedule 3 at 5% w/w or less in adults and adolescents (12 years of age and older).
In August 1984, the Poisons Scheduling Standing Committee agreed to place aciclovir in Schedule 4.
In May 1993, the committee considered a request for a change of topical aciclovir scheduling from Schedule 4 to Schedule 3, for an OTC indication, without the product or indication having already been approved by the TGA. The committee declined to consider the application for a drug product which it believed should be evaluated through the appropriate channels.
In May 1996, the NDPSC considered a submission in support of a change from Schedule 4 to Schedule 2 for aciclovir cold sore cream (5% w/w, 2g). The committee noted that when the sponsor had applied for ADEC approval for the indication for "the treatment of herpes simplex viral infection of the lips" that committee had agreed to the indication. The committee agreed to waive the "2 year rule" in view of the fact that aciclovir has been used for many years as an eye ointment in Australia and had been available overseas for many years as a cold sore non-prescription preparation, without giving rise to public health concerns
In August 1997, the NDPSC noted the Australian Approved Name (AAN) change from acyclovir to aciclovir.
In February 1999, the NDPSC endorsed amendment of the Schedule 2 entry to read: 'ACICLOVIR FOR EXTERNAL USE FOR THE TREATMENT OF HERPES LABIALIS'.
In 2001 – February 2002, the NDPSC considered the proposal to exempt preparations containing 5% or less of aciclovir for dermal use from the requirements of scheduling. The committee agreed to exempt dermal preparations containing aciclovir for use in the treatment of cold sores from the requirements of scheduling with appropriate pack size restriction which accommodated existing Schedule 2 products.
In November 2001, the NDPSC agreed to exempt preparations containing 5 per cent or less of aciclovir for the treatment of herpes labialis in packs containing 10 g or less, on the grounds that herpes labialis was a short-term and self-limiting condition, appropriate for self-diagnosis and management by consumers. In addition, the product was simple to use and increased access to such a product would be beneficial to public health.
In October 2002, the NDPSC considered the NZ MCC recommendations to harmonise aciclovir and decided that it should remain unharmonised and be placed on the 2-year review list of unharmonised substances.
In March 2015, the ACMS reconsidered the scheduling of hydrocortisone when compounded with aciclovir, in relation to a proposed Schedule 3 amendment and Appendix H listing. The committee recommended that it was not necessary to include aciclovir in Appendix H as topical aciclovir has been exempt from scheduling for over a decade without signals indicating significant risk at this scheduling level. The Schedule 3 entry for hydrocortisone and hydrocortisone acetate was amended in October 2015 for human therapeutic use containing 1 per cent of hydrocortisone for dermal use in packs containing 2 g or less of such preparations, containing no therapeutically active constituent other than aciclovir (5% w/w or less) in adults and adolescents (12 years of age and older).
Relevant scheduling history for related substance, famciclovir
Current scheduling of famciclovir:
FAMCICLOVIR except when included in Schedule 3.
FAMCICLOVIR for oral use, in divided preparations containing a total dose of 1500 mg or less of famciclovir for the treatment of herpes labialis (cold sores).
The related substance famciclovir is an oral pro-drug that is converted to penciclovir in vivo. In June 1994, ADEC recommended approval for the registration of famciclovir for the treatment of herpes zoster [shingles] infection. In May 1995, the NDPSC agreed to include famciclovir in Schedule 4.
The TGA approved famciclovir for the treatment of recurrent herpes labialis (cold sores) in January 2007. The approved dosage was 1500 mg administered orally either as a single dose or 750 mg twice daily at 12 hourly intervals (to a total dose of 1500 mg per episode). Famciclovir is also indicated in immune compromised patients for the treatment of uncomplicated herpes zoster (shingles), and treatment and prophylaxis of herpes labialis.
In February 2009, the NDPSC considered a submission to down-schedule famciclovir (oral use, single dose) for the treatment of herpes labialis in immunocompetent patients from Schedule 4 to Schedule 3 and inclusion in Appendix H. The NDPSC noted the potential risk of generating resistance in the community and thus putting immunocompetent patients at risk. Also noted that in immunocompetent patients, the condition was self-resolving and the benefit of oral treatment over topical therapy was not significant. Overall, the NDPSC was of the opinion that the risks associated with down-scheduling outweighed the benefits, and agreed that the current scheduling remained appropriate.
The same rescheduling proposal was considered at the October 2009 NDPSC meeting. The applicant provided additional data that showed absence of evidence of resistance developed by immune compromised patients. The application also provided a draft pharmacist treatment algorithm and discussed some educational initiatives. The NDPSC noted that a lack of evidence of resistance was not the same as evidence proving that over the counter (OTC) use of famciclovir orally would not lead to resistance. The NDPSC decided that the current Schedule 4 remained appropriate.
In May 2009, the New Zealand MCC rejected a submission to reclassify famciclovir 500 mg tablets from prescription medicine to restricted (pharmacist only) medicine. Subsequently, at its November 2009 meeting, the MCC reconsidered the submission with further information on warnings and training material relating to use in immunocompromised patients. The MCC agreed to reclassify famciclovir 500 mg tablets to restricted (pharmacist only) medicine in packs of 3 tablets for the treatment of recurrent herpes labialis.
In February 2010, the NDPSC considered whether to harmonise with the MCC's November 2009 decision in reclassifying famciclovir to restricted (pharmacist only) medicine. The NDPSC contended that the MCC's decision to reclassify famciclovir was dependent on a number of NZ specific requirements, and argued that Australian jurisdictions may not be able to enforce these requirements to a similar degree. The NDPSC recommended to not harmonise with NZ.
In October 2011 the ACMS again considered a proposal to down-schedule famciclovir to Schedule 3. The committee noted that the potential for development of resistance had been sufficiently addressed, since famciclovir is not activated into penciclovir until taken into cells infected with the virus. The proposed single (divided) oral dose was considered acceptable and would be beneficial when the use of topical formulation would not be appropriate (i.e. around the eyes). The committee agreed to down-schedule famciclovir to Schedule 3 for oral use, in divided preparations, containing a total dose of 1500 mg or less of famciclovir for the treatment of herpes labialis (cold sores). This was implemented in 2012.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 4 – Proposed Amendment
included in Schedule 2 in preparations containing 1 per cent or less of penciclovir for the treatment of herpes labialis in packs containing 10 g or less.
Schedule 2 – Delete entry
PENCICLOVIR for external use for the treatment of herpes labialis.
Index – Proposed Amendment
The applicant's reasons for the request are:
- It is estimated that up to a third of the world's population are affected by herpes simplex at some stage in their life, with the majority of infections presenting as repeated vesicular eruptions, herpes labialis within the general community. While herpes labialis is self-limiting and will generally resolve within 7-8 days, it can significantly decrease quality of life of those with active or recurrent infections as it can be painful, emotionally distressing and highly contagious. Historically, penciclovir has been used to treat herpes labialis topically, successfully promoting faster resolutions and a reduction in pain.
- Topical cold sore treatments are commonly used by consumers after self-diagnoses of their condition, as already occurs with topical aciclovir. Penciclovir, an alternate option for recurrent cold sore sufferers, is in many respects similar to aciclovir, with benefits in improved healing time and associated pain. As a major difference with aciclovir, available as a 5% topical formulation, penciclovir topical products are formulated at 1%, and although less concentrated they still retain an effective therapeutic outcome due to their greater activity, exclusive towards infected cells
- Penciclovir is indicated only for short term topical use. The product is intended to be applied at two hourly intervals, at least six times a day for up to four days as stated on labelling and packaging. The nature of the product indication is self-limiting. The mean duration of recurrences is 7–8 days, but individual episodes of up to 15 days have been reported. As for aciclovir, it has a low risk of masking a serious disease, compromising the medical management of a disease, or resulting in a consumer mistaking a cold sore for a more serious condition. With an indicated time frame for product use of 4 days, any misdiagnosis would not significantly delay any referral to a healthcare professional. In addition to an excellent well-defined safety profile, penciclovir is a topical application with no known risk of misuse and abuse; it has high selectivity to viral cells; and low bioavailability / toxicity to human cells, making this medicine a good candidate for reclassification in line with aciclovir topical products
- Reclassification of penciclovir topical would increase the availability of the product to the general community, and act as an alternative to aciclovir topical allowing consumers a greater freedom of choice. Reclassification would also be beneficial for immediate and early access to treatment, since penciclovir is effective at every stage of herpes labialis cycle, from tingle, to blister, to providing potential for early symptom relief regardless of the stage of the condition. With greater access and quicker healing, the virus will be less likely to be transmitted to others, potentially reducing spread and minimising frequency of occurrence.
- Aciclovir, a similar anti-viral agent indicated for the same condition, was reclassified in 2002 from Schedule 2 to Unscheduled, on the basis that the product was safe, simple to use and increased access would be beneficial to the general public. Since aciclovir is no longer a scheduled product when used topically for herpes labialis, it would be logical for both penciclovir and aciclovir to be similarly scheduled and equally accessible to the consumer.
Australian regulatory information
There is one registered product in Australia that contains penciclovir which is indicated for the treatment of recurrent cold sores (herpes labialis) in adults and children aged 12 years and over.
In New Zealand penciclovir is considered Prescription, except for external use for the treatment of herpes labialis, and it is a pharmacy only medicine for external use for the treatment of herpes labialis. The NDPSC was advised in November 1996 that penciclovir cream was given a Schedule 2 classification in New Zealand.
In the USA, penciclovir is marketed as a prescription 1% topical cream.
In Canada, penciclovir is marketed as a prescription 1% topical cream.
No reference to penciclovir has been provided for in S26BB, as penciclovir is a scheduled ingredient and not eligible for use in listed medicines.
Penciclovir is a synthetic guanine derivative, chemically designated as 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine. It is a white to pale yellow crystalline solid with a molecular weight of 253.3 g/mol.
Figure 1.6: Structure of penciclovir
Penciclovir has inhibitory activity against herpes simplex virus (HSV) types 1 and 2. It targets virus-infected cells where it is rapidly converted into penciclovir-triphosphate (mediated via virus-induced thymidine kinase), which inhibits viral DNA polymerase by competition with deoxyguanosine triphosphate and is incorporated into the extending DNA chain, preventing significant chain elongation. Consequently, viral DNA synthesis and therefore viral replication are inhibited
Penciclovir is only readily phosphorylated in virus-infected cells. In uninfected cells treated with penciclovir, concentrations of penciclovir-triphosphate are only barely detectable.
The active penciclovir triphosphate has a half-life of up to 10-20 hours, remaining active in infected cells for up to 12 hours.
Both penciclovir and aciclovir have a similar mechanism of action and a long history of use. Penciclovir has minimal side effects with the majority of adverse effects being at the site of application including, erythema, itching and contact dermatitis.
The applicant noted that the safety profile of aciclovir and penciclovir are fundamentally similar and for more than 20 years aciclovir use has been considered safe and well tolerated regardless of the administration route. A good safety profile of penciclovir cream has been reported in two large clinical trials. Penciclovir is poorly absorbed following oral administration. Systemic absorption is negligible and adverse effects are similar to those observed with placebo.
In the event of accidental oral ingestion or over-dosage, no untoward effects would be expected if the entire contents (2 g) of penciclovir 1% cream were ingested and no specific treatment is necessary. Some irritation of the mouth could occur.
Pre-meeting public submissions
One (1) submission was received, which opposed the scheduling proposal. The main points in the submission were:
- The current scheduling remains appropriate due to best practice being a certain level of professional intervention.
- Broader access to immunocompromised individuals may contribute to drug resistance.
The public submission will be made available on the TGA website.
Summary of ACMS advice to the delegate
The committee advised that the Schedule 2 entry for PENCICLOVIR be deleted and that the Schedule 4 entry be amended as follows:
Schedule 4 –Amend Entry
when included in Schedule 2 in preparations containing 1 per cent or less of penciclovir for the treatment of herpes labialis in packs containing 10 g or less.
Schedule 2 – Delete Entry
PENCICLOVIR for external use for the treatment of herpes labialis.
Index – Amend Entry
The committee also recommended an implementation date of 1 October 2017.
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 (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the advice comprised the following:
- Low toxicity
- Sufficient data available to demonstrate use of the product in its current presentation
- Public health benefit of increased access
- Penciclovir has a similar safety profile and precautions as unscheduled topical aciclovir
The delegate considered the following in regards to 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 to delete the Schedule 2 entry and amend the Schedule 4 entry for penciclovir. The proposed Schedule entry is as follows:
Schedule 4 – Amend Entry
PENCICLOVIR except in preparations containing 1 per cent or less of penciclovir for the treatment of herpes labialis in packs containing 10 g or less.
Schedule 2 – Delete Entry
Index – Amend Entry
The proposed implementation date to amend the Schedule 4 entry is 1 October 2017.
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; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
- The delegate acknowledges the committee's advice.
- Low toxicity.
- Sufficient data available to demonstrate use of the product in its current presentation.
- Public health benefit of increased access.
- Penciclovir has a similar safety profile and precautions as unscheduled topical acyclovir.
Public submissions on the interim decision
No public submissions were received in response to the interim decision for penciclovir.
Delegate's final decision
The delegate notes the submission, and as no new evidence has been received to alter the interim decision; the delegate has confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.
The delegate's final decision is to delete the Schedule 2 entry and amend the Schedule 4 entry for penciclovir. The implementation date is 1 October 2017.