2.4 Astodrimer sodium

2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)

On this page: Delegate's interim decision | Delegate's considerations | Scheduling proposal | Background information for astodrimer sodium

Delegate's interim decision

Delegate's considerations

The delegate considered the following in regards to this interim decision:

• The advice received from the Joint Advisory Committees on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19);
• the public submission received before the first closing date;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Section 52E of the Therapeutic Goods Act 1989, in particular (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; and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for astodrimer sodium

In this section: Delegate's referral to ACCS/ACMS | Applicant's scheduling proposal and reasons | Current scheduling status and relevant history | Australian regulations | International regulations | Substance summary | Pre-meeting public submissions | Joint ACMS-ACCS advice

Delegate's referral to ACCS/ACMS

A delegate of the Secretary of the Department of Health proposed an amendment to the Poisons Standard by creating a new Schedule 4 entry for astodrimer sodium.

Applicant's scheduling proposal and reasons

The proposed amendments to the Poisons Standard that were referred to the Joint ACMS-ACCS #19 for advice are reflected below:

The reasons for the proposal were:

• Astodrimer sodium is a topical microbicide that is used in a class 2A medical device for the treatment of bacterial vaginosis (BV), and for prevention of sexually transmitted diseases as a condom lubricant.
• BV requires medical diagnosis, management and monitoring before astodrimer sodium is used in alignment with Schedule 4 scheduling factors of the Scheduling Policy Framework (2018).

Current scheduling status and relevant history

Astodrimer sodium is not scheduled in the Poisons Standard and has not been previously considered for scheduling. Therefore, a scheduling history is not available.

Australian regulations

The Australian Register of Therapeutic Goods (ARTG) has two products that contain astodrimer sodium (one condom lubricant and one vaginal gel). The sponsor successfully argued, based on the mechanism of action, that the vaginal gel is a medical device. The vaginal gel was approved on 24 October 2017, and is a Class IIA medical device.

Astodrimer sodium is not in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018.

In the last 2 years there have been no reported cases of adverse events related to condoms containing astodrimer sodium in the Database of Adverse Events Notification (DAEN) - Devices.

According to the TGA Ingredient Database, astodrimer sodium is:

• Available for use as an Active Ingredient in Devices;
• Available for use as an Excipient Ingredient in Devices; and
• Not available as an Equivalent Ingredient in any application.

International regulations

The product in a gel formulation indicated for management of BV and sexually transmitted disease prevention, was not available for sale in any countries at the end of 2017. According to information on the sponsor's website, the vaginal gel product has been granted regulatory approval in the European Union for the treatment and symptomatic relief of BV. It is being considered for regulatory approval in the United States of America and other jurisdictions. The condom product, coated in a lubricant containing 0.5% astodrimer sodium, is currently available for purchase in Australia and Canada.

Substance summary

Table 2.4: Chemical information for astodrimer sodium

Property	Astodrimer sodium
CAS number	676271-69-5
IUPAC and/or common and/or other names	Astodrimer sodium (INN, USAN); 2, 6-Bis-{(1-napthalenyl-3,6-disulfonic acid)-oxyacetamido}-2,6-bis-2,6-bis-2,6-bis-(2,6-diamino-hexanoylamino)-2,6-diamino-hexanoic acid (diphenylmethyl)-amide, polysodium salt; Tetrahexacontasodium N2,N6-bis{N2,N6-bis[N2,N6-bis(N2,N6-bis{N2,N6-bis[(3,6-disulfonatonaphthalen-1-yloxy)acetyl]-l-lysyl}-l-lysyl)-l-lysyl]-l-lysyl}-N1-(diphenylmethyl)-l-lysinamide; SPL7013
Chemical structure
Molecular formula	C583H577N63Na64O287S64
Molecular weight	16581.57 Da

Astodrimer sodium is being investigated for its potential to prevent sexual transmission of genital herpes (HSV-2), human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) including human papillomavirus (HPV), the causative agent of cervical cancer.

Mechanism of action

Astodrimer sodium is a polyanionic, polysulfonate compound that blocks the formation and disrupts pre-formed bacterial biofilms, which are important in the pathogenesis of BV.

The polyanionic surface of the highly-branched dendrimer molecule attaches to targets on viruses, thus blocking viral attachment and/or adsorption to cells to prevent infection. In standard in vitro assays, astodrimer sodium had antiviral activity against HIV-1, HSV-2 and HPV strains. Reduced efficacy was evident in the presence of biological fluids. Astodrimer sodium may have some antiviral activity in the cervicovaginal region but it is expected to have minimal antiviral activity in semen during use, and resistance may develop with prolonged use. In mouse and guinea pig models of genital herpes and in a macaque HIV model, astodrimer sodium prevented vaginal viral transmission in some animals at doses/concentrations exceeding those expected with the condom lubricant formulation. Astodrimer sodium gel had no impact on the vaginal or rectal flora of the southern pig-tailed monkey.

The dermal bioavailability of drug-related material in rats was 1.5% following vaginal dosing with the astodrimer sodium gel.

Acute toxicity

The no-observed-adverse-effect-level (NOAEL) and maximum non-lethal dose was 25 mg/kg intravenous (IV) in rats and rabbits. Following IV dosing, similar effects were seen in rats and rabbits with deaths, clinical signs of decreased activity and evidence of haemorrhages seen at necropsy (red discolouration of the kidneys, stomach and heart). All of these effects may be attributed to thromboembolic events. No adverse effects were seen in rats given high oral doses (≤1600 mg/kg). No adverse effects were seen in single dose toxicity studies in rats or rabbits following vaginal dosing of 5% astodrimer sodium gel.

Repeat-dose toxicity

Repeat-dose toxicity studies of up to 3 months duration were performed in mice, 6 months in rats, 2 weeks in rabbits and 39 weeks in dogs using the vaginal route. Toxicity via the rectal, oral and IV routes was also examined in rats. Only limited observations were included in the IV and oral studies.

Findings in the vaginal and rectal studies were largely restricted to local reactions at the site of application. Findings associated with a gel formulation of astodrimer sodium included anal and vaginal inflammatory reactions and reductions in anal and vaginal pH (to ˜4.5). Astodrimer sodium-associated findings included ovarian abscesses in mice (a no observable effect level (NOEL) was not established) and vaginal irritation, oedema, erosion/ulcer and/or haemorrhage in rabbits and dogs. A NOEL was not established in rabbits, while there was no evidence of vaginal irritation in dogs at concentrations ≤3% gel. Species differences noted in local effects of vaginal dosing with the gel was attributed to differences in vaginal structure.

Systemic effects following repeated vaginal dosing were only seen in rabbits – thrombosis in the vagina with thrombi evident in multiple organs of animals that died prematurely. These systemic effects are likely a result of severe local (vaginal) irritation and damage. Rabbits are generally more sensitive to vaginal irritants than human subjects. The NOEL for systemic effects in rabbits was 1% astodrimer sodium gel (2.9 mg/kg/day) suggesting thrombosis may not be seen in human subjects.

Astodrimer sodium is considered to have a low genotoxic potential. No treatment-related increase in tumour incidence was observed in mice or rats in 2-year vaginal carcinogenicity studies at very high doses.

No adverse effects on female fertility, embryofetal development or pre/postnatal development were evident in rats following vaginal dosing. In the rabbit embryofetal development study there was an increased incidence of abortions and early delivery with the 1% astodrimer sodium gel. These effects were considered to be secondary to maternotoxicity (vaginal irritation and thrombosis) rather than a direct drug-related effect.

There was no evidence of delayed contact hypersensitivity in a standard assay in guinea-pigs using 4% astodrimer sodium in the induction phase (3 × oh occluded dermal applications) and challenging with 2% astodrimer sodium 14 days after induction. No gross indications of penile irritation were seen in male dogs following exposure to 3% astodrimer sodium gel.

Pre-meeting public submissions

One (1) public submission was received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. The submission opposed the proposal.

The main points provided in opposition of the amendment were:

• The proposal to create a new schedule 4 entry for astodrimer sodium does not relate to any risk of poisoning, misuse, and abuse for astodrimer sodium, or other relevant scheduling factors.
• Systemically absorbed antibiotics are currently the only available therapy for BV. Antibiotics are prescription medicines that require medical management due to the potential development of resistant bacteria. In contrast, astodrimer sodium has a unique non-antibiotic mechanism of action, it is not absorbed into the bloodstream, has a very benign safety profile, and does not cause spontaneous development of resistant bacteria. Astodrimer sodium provides a low-risk, non-antibiotic, and non-prescription alternative for women to treat their BV.
• BV is an imbalance in the normal vaginal flora and not an infection caused by a specific pathogen. It is usually a non-serious condition, and treatment of asymptomatic BV is typically not required. BV does not require medical diagnosis, management and monitoring. The need for a woman with BV to be treated via involvement of a doctor is because there are no non-antibiotic treatments.
• Self-treatment of BV does not pose a risk of masking another more serious condition and there is no scientific evidence that repeat episodes of BV are caused by an underlying condition (e.g. diabetes).
• Non-prescription treatments for the more complex vaginal yeast infection are currently available in Australia. Vaginal yeast infection (candidiasis) is an infection caused by Candida albicans. Vaginal candidiasis has the potential to be misdiagnosed, and repeated episodes of candidiasis may be indicative of a more serious condition, such as diabetes or compromised immunity.
• Research indicates that only a small proportion of women with BV are attending general practitioners (GPs) or specialists. Patients with BV prefer to present to pharmacies as an initial point of contact, and there is a large degree of dissatisfaction with currently available therapies.
• Many women's experiences with the clinical management of BV through primary care providers (GPs) are negative; research shows that clinicians frequently fail to diagnose or misdiagnose BV, and are often insensitive when treating patients with the condition.
• Toxicity
  • The clinical safety and efficacy of astodrimer sodium has been investigated in 11 completed clinical studies involving more than 2000 patients, including four global Phase 3 studies.
  • Astodrimer sodium is not systemically absorbed following topical, e.g. vaginal, application. Given this lack of absorption, the product represents a negligible risk of systemic side effects or interaction with food, alcohol, or other medical products, and very low to non-existent risk of dependency, misuse, abuse or illicit use.
  • There was no evidence of any teratogenic, mutagenic or carcinogenic effects of astodrimer sodium.
• Astodrimer sodium is also used as an ingredient in the lubricant of a condom product where its intended purpose is to inactivate viruses that may be sexually transmitted. The condom product with astodrimer sodium has been sold in Australia since 2014 and Canada since 2017. There have been no complaints or safety issues associated with use of astodrimer sodium in the condom product. Further, there is no risk of confusing the condom product containing astodrimer sodium with the gel product for BV.
• Access
  • A decision to create a Schedule 4 entry for astodrimer sodium based on the requirement that BV needs medical diagnosis and intervention would be inconsistent with the way vaginal candidiasis is currently treated by the regulator and managed in practice. It would create a precedent for women that any future product for BV, regardless of the risk/benefit profile of a particular product, must also be Schedule 4 and require a visit to a medical practitioner to obtain a prescription, where proper examination and correct diagnosis are not always guaranteed, and patient satisfaction is low.
  • Creating a new Schedule 4 entry for astodrimer sodium would deny women's preference to access treatment for BV without a doctor's visit, and deprive Australian women of the ability to effectively manage this embarrassing and recurring condition.
  • While women may inaccurately self-diagnose in some cases, this risk must be considered in the context of and given equal weight as published research showing that physicians misdiagnosed BV in 61.3% of cases, and that the rate of misdiagnosis of vaginal candidiasis was even higher (77.1%).^[51] In addition, studies have shown that women with recurrent BV commonly reported primary care providers had often confused BV for candidiasis, with a number indicating they had been diagnosed and treated for candidiasis without further testing, or had been tested and/or treated for chlamydia or other sexually transmitted infections (STIs) without being tested for BV.^[52]
• The available evidence on women's preferences and practices as reported in the scientific literature, and overseas experiences with BV products sold direct-to-consumers without prescription in comparable markets such as the UK, confirm the ability of women to self-select treatment in the absence of harm.
• Women are capable of being informed and self-selecting products, which have appropriate labelling, packaging and the opportunity for point of sale advice, for the treatment of BV. Recent TGA-approval of restricted advertising representations for the product containing astodrimer sodium is consistent with this view.
• Mistreatment
  • The potential for astodrimer sodium to be used to treat a condition other than BV is mitigated by the recently approved restricted representations and required advisory statements for the gel product, including the requirement for an accurate description of BV in the product packaging and instructions for use.
  • The benign safety profile of astodrimer sodium, there is no added risk of harm from exposure to the product for women who may not have BV.
  • Research shows that women with BV are already treating with over-the-counter therapy for candidiasis because it is a therapy that is readily available without prescription.52 The availability of a product specifically for BV will reduce the potential for off-label treatment with an inappropriate product to occur.
  • The consequence of inaccurate self-diagnosis and use of astodrimer sodium would be that a woman treats a condition that is not BV, and delays treatment of another condition for a short period of time. Women who have shown health-seeking behaviour by choosing a therapy for the condition are likely to seek further treatment if their condition is not resolved, minimising the delay in treatment.
• Schedule 2 is more appropriate (unscheduled preferred) with appropriate reference to Appendix F statements (E.g. 64).

Joint ACMS-ACCS advice

The committee recommended that new Schedule 3 and Appendix F entries be created for astodrimer sodium as follows:

The committee also recommended an implementation date of 1 February 2019.

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 extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • Minimal risk. Low toxicity. Evidence of efficacy.
   • The risks of remaining unscheduled are the potential for self-treatment without health professional assessment to exclude STI.
   • Benefits of product are a non-antibiotic option for the treatment of bacterial vaginosis. Side effects are minimal and so compliance is expected to increase for successful treatment.
2. the purpose for which a substance is to be used and the extent of use:
   • Bacterial Vaginosis (BV).
   • Bacterial vaginosis is a very common condition in women, with prevalence estimates of 10-50%. It commonly recurs after treatment. Symptoms of such a medical condition require health professional assessment.
3. the toxicity of a substance:
   • Low.
   • Minimal systemic toxicity risk, local irritant/inflammatory effects.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Vaginal gel. A number of mandatory labels have been proposed including the requirement for an accurate description of BV in the product packaging and instructions for use.
5. any other matters that the Secretary considers necessary to protect public health:
   • Improved public awareness of condition if available OTC but very recently launched product worldwide with no post-marketing surveillance. May be suitable for future Schedule 2 listing but needs further evaluation and better data on consumer diagnostic accuracy/missed diagnosis of STI and access to diagnostic self-testing.
   • Advertising appropriate in alignment with vaginal fungal treatments.