1.1 Nabiximols

Part A - Interim decisions on matters referred to an expert advisory committee (November 2018)

1. Advisory Committee on Medicines Scheduling (ACMS #25)

1.1 Nabiximols

On this page: Delegate's interim decision | Materials considered | Scheduling proposal | Background information for nabiximols

Delegate's interim decision

Materials considered

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

• The application to amend the current Poisons Standard with respect to nabiximols;
• The advice from the Advisory Committee on Medicines Scheduling (ACMS #25);
• The public submissions 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; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal for nabiximols was published on the TGA website on 31 August 2018 at Consultation: Proposed amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS/ACMS meetings, November 2018.

Background information for nabiximols

In this section: Delegate's referral to ACMS | Applicant's scheduling proposal and reasons | Current scheduling status | Scheduling history | Australian regulations | International regulations | Substance summary | Current use pattern in Australia | Pharmacodynamic properties | Pharmacokinetic properties | Pre-meeting public submissions | Joint ACMS-ACCS advice

Delegate's referral to ACMS

An application was submitted to amend the Poisons Standard with respect to nabiximols. The application proposed to delete the Schedule 8 and Appendix D entries for nabiximols and create a new entry for nabiximols in Schedule 4.

Applicant's scheduling proposal and reasons

The applicant's proposed amendments to the Poison Standard are:

The applicant's reasons for the proposal are:

• Nabiximols is regulated as an approved medicine and controlled under a Risk Management Plan in Australia by the TGA.
• Nabiximols at established therapeutic dosage levels does not produce dependency or have a high propensity for misuse, abuse, or illicit use.
• Nabiximols is currently available as a prescription medicine in 26 other countries with scheduling that is similar to Schedule 4 in Australia. This level of control has not led to abuse, diversion, dependence or use for illegal purposes of nabiximols.
• As of 26th June 2018 there have been no post-marketing reports of abuse or diversion reported spontaneously from healthcare professionals in the global safety database.
• Nabiximols meet the Scheduling Policy Framework criteria for Schedule 4.
• It is estimated that there have been 82060 patient years of exposure to nabiximols from post-marketing and compassionate use. There are no important interactions considered to be a safety concern, or emergent in the post-market data. The potential for interactions is managed in the current wording of the PI and monitored as part of the RMP and ASA through Pharmacovigilance.
• The risk profile of the nabiximols product is considered to be well defined.

Current scheduling status

Nabiximols is in Schedule 8 of the Poisons Standard as follows:

Scheduling history

Scheduling of cannabinoids has been considered on several occasions over the last 30 years. Since 1984, nabilone, dronabinol (synthetic delta-9-tetrahydrocannabinol), cannabidiol and nabiximols have been listed in Schedules 8 or 4, to enable access for therapeutic use for specific medical conditions.

The scheduling of cannabis and its extracts has been considered by the National Drugs and Poisons Scheduling Committee (NDPSC) on a number of occasions. Currently, cannabis is a Schedule 9 substance, i.e., a prohibited substance which may be abused or misused and the manufacture, possession, sale or use of which is prohibited by law. An exemption exists for cannabinoid substances listed in lower schedules, and for processed hemp fibre and its products containing 0.1 percent or less of tetrahydrocannabinol.

Dronabinol (delta-9-tetrahydrocanabinol) was considered by the NDPSC in 1994 following a recommendation that it be included in Schedule 8 of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), for use in patients with advanced HIV disease with irreversible weight loss. At the time the NDSPC agreed to include dronabinol in Schedule 8 for therapeutic use.

Nabilone was considered at the July 1984 NDPSC meeting and included in Schedule 8 following that meeting. It is used as an anti-emetic in the treatment of nausea and vomiting caused by chemotherapy, primarily for patients who are not responsive to conventional anti-emetic treatments.

In February 2009, cannabidiol (CBD) was discussed by the National Drug and Poisons Scheduling Committee (NDPSC) as a part of a consideration of THC and the product [REDACTED] which led to the creation of the nabiximols entry (June and October 2009).

While the focus of the February 2009 meeting item was on the classification of THC, a number of public submissions received were regarding the availability of [REDACTED] which contains both THC and CBD. It was noted that it was difficult to give approval to special access scheme (SAS) applications for medications containing CBD as it was considered a Schedule 9 substance. However, access would be granted if CBD was placed in Schedule 8 for therapeutic use. This scheduling consideration was to be discussed at the June 2009 meeting.

In June 2009 the NDPSC considered scheduling requirements for the product [REDACTED], which contained CBD and small amounts of other cannabinoids, and its access under jurisdictional laws and the Special Access Scheme (SAS). Members agreed that it was appropriate to allow access to nabiximols and suggested that a pragmatic approach would be to create a Schedule 8 entry (listing the individual cannabinols and restricting its presentation to buccal sprays for therapeutic use) for this specific formulation, in conjunction with an Appendix D, paragraph 3 listing to facilitate its use within the various jurisdictions.

In October 2009, the NDPSC considered the scheduling of nabiximols after it was established that the United States of America Adopted Names Council had designated 'nabiximols' as the approved non-proprietary name for an extract of Cannabis sativa. This extract contained THC and CBD as major components and related cannabinoids and non-cannabinoid components alpha- and trans-caryophyllenes as minor components (i.e. the specific THC and CBD formulation considered appropriate for inclusion in Schedule 8 by the June 2009 meeting). The Cannabis sativa extract Schedule 8 entry was amended to nabiximols.

In May 2010, nabiximols was included in Schedule 8 and Appendices D and K. The Appendix D, Part 3 entry was made to limit access through the SAS. The Appendix K entry was agreed due to its sedating effects.

In March 2013, the committee advised that a change in the Appendix D entry for nabiximols from Paragraph 3 to Paragraph 1would be appropriate noting the requirement for specialist oversight for safe prescribing of the drug.

In November 2014, the ACMS considered the scheduling of cannabidiol. The committee recommended to the scheduling delegate that cannabidiol, including extracts of Cannabis sativa, and including preparations of up to 2% of cannabinoids, including cannabidivarin (CBDV) for therapeutic use, be included in Schedule 4. The reasons for the recommendation included:

• The condition that cannabidiol treats (the therapeutic use) requires diagnosis, management and monitoring under an appropriate medical practitioner.
• Cannabidiol has a safety profile which is consistent with a Schedule 4 listing.
• There is low risk of misuse or abuse as cannabidiol does not possess psychoactive properties.

In May 2016, after extensive consultation, the scheduling delegate agreed with the committee recommendations and provided further reasons and clarification of the decision that included:

• The schedule entry needs to acknowledge that there is no pure form of cannabidiol currently available. However, low levels of impurities found in some cannabidiol products are not clinically significant and the scheduling entry should reflect this by allowing cannabinoids up to 2 %.
• The entry allows for, but does not specify, any particular non-active cannabis impurity/ies to be within the 'up to 2%'.
• The substances that comprise the 'up to 2%' must be substances found in cannabis. They cannot be synthetic cannabinoids.
• The entry does not preclude the cannabidiol and/or any other cannabinoids being derived from natural sources or made artificially, consistent with the interpretation of the schedules.
• Appendix D is not supported as the criteria are not met. It is considered that it is the medical condition for which CBD may be used which requires treatment by a specialist. Cannabidiol itself has no particular attributes that require it to be included in Appendix D. Scope of practice will ensure the appropriate prescribing of cannabidiol, rather than scheduling.

As a result, a Schedule 4 entry for cannabidiol was created, and the Schedule 9 entry for THC and their alkyl homologues was amended to exempt the new Schedule 4 entry for cannabidiol.

In November 2016, the Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS) further considered cannabidiol to improve the clarity of the entry with regards to the component cannabinoids found in cannabis. A final decision was made to improve the clarity of the cannabidiol entry on 31 May 2017, by including the word 'total' in relation to the other cannabinoids found in cannabis.

In March 2018, the ACMS provided advice to the delegate on a proposal to amend the Schedule 4 entry of cannabidiol, Schedule 8 entry of THCs and the Appendix K entries of cannabis and THCs to clarify the meaning of the cannabidiol Schedule 4 entry. On 7 June 2018 the delegate made an interim decision to amend the Schedule 4 entry for cannabidiol, and the Schedule 8 and Appendix K entries for tetrahydrocannabinols and cannabis in the Poisons Standard. A final decision on this proposal, has been published on the TGA web site on 28 September 2018, which

• Further clarifies that 'any cannabinoids, other than cannabidiol, must be only those naturally found in cannabis and comprise 2 per cent or less of the total cannabinoid content of the preparation';
• Clarifies the wording of the Schedule 8 entry references to cannabidiol in the tetrahydrocannabinols and cannabis entries; and
• Deletes references to hemp seed oil in the Schedule 8 entries for tetrahydrocannabinols and for cannabis because hemp seed oil is adequately controlled by the Schedule 9 entries for these substances.

In June 2018, the ACMS provided advice to the delegate on a further proposal to amend the Schedule entries for cannabidiol and tetrahydrocannabinols. An interim decision not to amend the Schedule entries for cannabidiol and tetrahydrocannabinols as proposed was published on 10 September 2018.

Australian regulations

There is one registered medicine currently active on the Australian Register of Therapeutic Goods (ARTG) that contains nabiximols ([REDACTED]) and one product containing cannabidiol which has been approved for export only.

According to the TGA Ingredient Database, cannabidiol is available for use as an active ingredient in Export Only and Prescription Medicines, and there is no reference to cannabis or THC.

In the last 30 years, in the Database of Adverse Events Notification (DAEN) - Medicines:

• There have been 2 reported cases of adverse events related to cannabidiol: 1 case with a single suspected medicine and no cases where death was a reported outcome;
• There have been 77 reported cases of adverse events related to cannabis: 77 cases with a single suspected medicine and 1 case where death was a reported outcome; and
• There have been no reported cases of adverse events related to THC.

International regulations

The following is an excerpt from the current application:

Substance summary

Nabiximols is a specific extract of Cannabis sativa which contains a range of cannabinoids, of which tetrahydrocannabinols and cannabidiol in approximately equal proportions comprise not less than 90% of the total cannabinoid content. Nabiximols are registered for use in Australia as a buccal spray preparation ([REDACTED]) as an adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis in adults.

Nabiximols is comprised of two Botanical Drug Substances (BDS). These are:

• delta-9-tetrahydrocannabinol BDS (THC BDS)
• cannabidiol BDS (CBD BDS)).

The BDSs are whole extracts of Cannabis sativa L.

According to the approved Product Information document each mL Sativex oromucosal spray contains:

80 mg of extracts (nabiximols) from Cannabis sativa L., folium cum flore (Cannabis leaf and flower), corresponding to 27 mg delta-9-tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD) and lesser amounts of other cannabinoids (56 mg total cannabinoids).

Tetrahydrocannabinol

THC is one of at least 113 cannabinoids identified in cannabis and is the principal psychoactive constituent of cannabis.

The THC effects result from its partial agonist activity at the cannabinoid receptor CB1 located mainly in the central nervous system, and the CB2 receptor mainly expressed in cells of the immune system. The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.

Table 1: Chemical information

Property	Delta-9-tetrahydrocannabinol
Chemical structure
Molecular formula	C21H30O2
CAS numbers	1972-08-3
IUPAC and/or common and/or other names	(−)-(6aR,10aR)-6,6,9-trimethyl- 3-pentyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen-1-ol; Dronabinol; Tetrahydrocannabinol; THC
Property	Delta-9-tetrahydrocannabinol
Chemical structure	(−)-(6aR,10aR)-6,6,9-trimethyl- 3-pentyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen-1-ol; Dronabinol; Tetrahydrocannabinol; THC

Cannabidiol

Cannabidiol is a cannabinoid compound which occurs naturally in Cannabis sativa plants. The pharmacology of cannabidiol is complex and has been well characterised in in vitro environments.

Some cannabinoid compounds work by binding to the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) receptors in the brain. Cannabidiol does not activate CB1 and CB2 receptors directly. However, it has effects on many other 'signalling' systems and can be considered a 'multi-target' drug. Some of the effects of cannabidiol may be attributed to inhibition of the inactivation of endocannabinoids, such as anandamide. Other effects may be related to the chemical properties of the compound as opposed to pharmacodynamic effects. For example, it is thought that the presence of two hydroxyl groups enables cannabidiol to have an anti-oxidant action.

There is evidence that cannabidiol affects serotonin receptors (5HT1A), adenosine uptake, nuclear receptors of the peroxisome proliferator-activated receptors (PPAR) family and other pharmacological targets. The pharmacological targets of cannabidiol include receptors, ion channels, enzymes and cellular uptake processes.

There are reports that cannabidiol possesses anti-proliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion. Evidence is also accumulating that there are positive effects of cannabidiol in the vasculature, where cannabidiol may induce vasorelaxation.

Information about the pharmacokinetics of the substance in humans is also accumulating. Oral absorption is slow and unpredictable relative to other routes of administration, possibly due to the chemical's poor water solubility. There is significant first pass metabolism where the concentration of ingested cannabidiol is greatly reduced before it is absorbed into systemic circulation, and the overall oral bioavailability may be as low as 6%. Other sources suggest an oral bioavailability of between 12 and 19%. Oromucosal and sublingual delivery, through sprays and lozenges, results in less variability with similar overall bioavailability.

The distribution of cannabidiol is governed by its high lipophilicity and there is rapid distribution to the brain, adipose tissue and other organs. It is also highly protein bound.

Like most cannabinoids, cannabidiol is extensively metabolised in the liver by cytochrome P450 enzymes, predominantly the CYP3A and CYP2C series. The terminal half-life is estimated to be 18-32 hours, although earlier work suggested a much shorter half-life of only 9 hours.

Table 1.2: Chemical information for Cannabidiol

Property	Cannabidiol
Chemical structure
Molecular formula	C21H30O2
CAS numbers	13956-29-1
IUPAC and/or common and/or other names	2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (IUPAC)

Current use pattern in Australia

The only presentation of nabiximols currently available in Australia is [REDACTED] oromucosal spray, which is an ARTG-registered medicine for human use with the TGA approved indication:

"Treatment for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy."

Additional Therapeutic Indications Approved outside of Australia:

• For relief of neuropathic pain in patients with multiple sclerosis (MS).^[2][3][4]
• For relief of persistent background pain in patients with cancer.^[5][6]

Nabiximols is currently approved and regulated in Australia under the brand name of [REDACTED] as an oromucosal spray containing 80 mg/mL nabiximols in a pump-actuated metered dose (AUST R 181978, CAS Number 1972-08-3).

Nabiximols is a botanical drug product developed for the treatment of spasticity in multiple sclerosis. According to the AusPAR for nabiximols^[7], the active ingredient is a highly characterised botanical extract of defined chemotypes of Cannabis sativa L., containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the major constituents, together with other cannabinoid and non-cannabinoid components. These are dissolved in a vehicle of ethanol and propylene glycol, with peppermint oil. The two principal cannabinoids, THC and CBD are present at concentrations of 27 mg/mL and 25 mg/mL respectively. In addition to these two main cannabinoids, nabiximols also contains a range of minor cannabinoids and plant-based materials, such as terpenes, plant sterols, carotenoids and triglycerides. The spray is administered via a metered dose pump giving a spray volume of 100 µL per spray. Hence each 100 μL spray is equivalent to 2.7 mg THC and 2.5 mg CBD. The dose required for effective relief is patient dependent and a titration regime is used to establish the individual dose. The cannabis plants are propagated through cuttings and are grown under managed indoor conditions in glasshouses to assure their genetic reproducibility and consistent quality of the extracts.

As part of the human endocannabinoid system (ECS), cannabinoid (CB) receptors, CB1 and CB2 receptors are found predominantly at nerve terminals where they have a role in retrograde regulation of synaptic function. THC acts as a partial agonist at both CB1 and CB2 receptors, mimicking the effects of the endocannabinoids, which may modulate the effects of neurotransmitters (e.g. reduce effects of excitatory neurotransmitters such as glutamate).

In animal models of MS and spasticity CB receptor agonists have been shown to ameliorate limb stiffness and improve motor function. These effects are prevented by CB antagonists, and CB1 knockout mice show more severe spasticity. In the chronic relapsing experimental autoimmune encephalomyelitis mouse model, nabiximols produced a dose-related reduction in the hind limb stiffness.

Pharmacodynamic properties

Anatomical Therapeutic Chemical (ATC) Code: NO2BG10

The endocannabinoid system comprises of cannabinoid receptors, endogenous cannabinoids (endocannabinoids) and their synthetic and degradative enzymes. There have been two cannabinoid (CB) receptors (CB1 and CB2) isolated and cloned to date, both are members of the super-family of G-protein coupled receptors.^[8] In addition to these established CB receptors, there are several proposed novel cannabinoid receptors including (but not limited to) the endothelial anandamide receptor and GRP55.^[9] CB1 receptors are highly expressed in neuronal tissue, where they predominantly inhibit neurotransmitter release at nerve terminals. CB1 receptors are also expressed in non-neuronal tissues such as the liver and adipose tissue, as well as the cardiovascular, urinary and reproductive systems.^[10] In contrast, CB2 receptors are expressed mainly by immune tissues, such as the spleen and thymus as well as in circulating/resident immune cells. However, recent publications have indicated that CB2 receptors are functionally active in brain neurons and pain pathways.^[11] The endocannabinoid system is thought to act as a fine-tuning system regulating and maintaining body homeostasis.

The first endocannabinoids identified were N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl glycerol (2-AG).^[12] These transmitters are not stored and released like classical neurotransmitters, but are synthesised on demand in response to elevations of intracellular calcium. Once released, the endocannabinoid activates CB receptors and the biological actions are then terminated by cellular reuptake via the putative endocannabinoid transporter.^[11] Termination of endocannabinoid signalling is initiated by two hydrolytic enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). FAAH predominantly degrades anandamide into fatty acids and ethanolamine, whereas MAGL is thought to be the major 2-AG degrading enzyme.^[11]11

THC binds to the CB1 and CB2 receptors with nanomolar affinity and acts as a partial agonist13. In contrast, CBD binds to CB1 and CB2 receptors with micromolar affinity and does not appear to activate CB receptors.^[13] However, the effects of CBD can be antagonised by pharmacological blockade of the CB1 or CB2 receptors; this may be due to inhibitory actions of CBD at very high doses at FAAH, which would act to increase local anandamide levels which may then indirectly activate CB receptors.^[14] In addition to activating CB receptors which are negatively coupled to adenylate cyclase (GI) and positively coupled to mitogen activated protein, THC and CBD can act on other biological targets, these include allosteric modulation of receptors for serotonin, glutamate and noradrenaline, modulation of various ion channels, enzymes and neurotransmitter transporters.^[7][14]

The principal pharmacological actions of THC include analgesia, anti-inflammatory actions, neuroprotection, reduced GI motility and secretion, tachycardia and hypotension, reduced intra-ocular pressure, relief from muscle spasm, anti-emetic properties, appetite stimulation and psychoactive effects such as elevation of mood, altered perception and cognition.^[14] CBD has similar properties where analgesia, anti-inflammatory actions, neuroprotective and antiemetic properties are observed. In addition to these actions, CBD is also reported to act as an anxiolytic drug and possess anticonvulsant properties.^[14] An important difference between the pharmacological properties of CBD and THC is that CBD lacks the central psychoactive effects of THC. When CBD is co-administered with THC, it can both enhance and reduce the effects of THC depending on the experimental or clinical conditions.^[14]

Pharmacokinetic properties

Absorption

There is a high degree of variability between patients in pharmacokinetic parameters.

Distribution

Following a single oromucosal administration, maximum plasma concentrations of both CBD and THC typically occur within two hours. When [REDACTED] is administered oromucosally, plasma levels of THC and other cannabinoids are lower compared with the levels achieved following inhalation of cannabinoids at a similar dose. A dose of 6.65 mg of vaporised THC extract, administered by inhalation resulted in mean plasma C_max of more than 100 ng/mL within minutes of administration, with significant psychoactivity. With [REDACTED], a mean C_max of about 4 ng/mL was reached some 45-120 minutes after a single dose administration of 10.8 mg (THC) dose, and was generally well tolerated with little evidence of significant psychoactivity.^[16] The resultant concentrations in the blood are lower than those obtained by inhaling the same dose because absorption is slower and redistribution into fatty tissues is rapid. Additionally, some of the THC undergoes hepatic first pass metabolism to 11-OHTHC, the first metabolite of THC, which then undergoes further oxidation to 11-nor-9-COOH-THC, the most abundant metabolite of THC.

Metabolism

THC and CBD are metabolised in the liver. Human hepatic cytochrome P450-2C9 isozyme catalyses the formation of 11-OH-THC, the primary metabolite, which is further metabolised by the liver to other compounds including 11-nor-carboxy-delta-9-THC (THC-COOH), the most abundant metabolite in human plasma and urine. The cytochrome P450-3A sub-family catalyse the formation of other hydroxylated minor metabolites. CBD is extensively metabolised and more than 33 metabolites have been identified in urine. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups. The major oxidized metabolite identified was CBD-7-oic acid containing a hydroxyethyl side chain.

Protein binding of THC is high (~97%). THC and CBD may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream, then metabolised and excreted via the urine and faeces.

Elimination

From clinical studies with [REDACTED, a non-compartmental PK analysis shows that the first order terminal elimination half-life from plasma is 1.94, 3.72 and 5.25 hours for THC and 5.28, 6.39 and 9.36 for CBD following the administration of 2, 4 and 8 sprays respectively. From the literature, elimination of oral cannabinoids from plasma is bi-phasic with an initial half-life of approximately four hours, and the terminal elimination half-lives are of the order of 24 to 36 hours or longer. Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life.

Pre-clinical safety data

The following information is taken from the Australian approved Product Information for Sativex.

Effects in nonclinical toxicity and safety pharmacology studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Sativex or a mixture of its component extracts was not genotoxic in in vitro tests for bacterial reverse mutation and in vivo micronucleus tests for clastogenicity in mice and rats, or in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes. No consistent genotoxicity was seen in an in vitro test for forward mutation in mouse L5178Y cells.

Fertility in rats was unaffected by oral treatment with a 1:1 mixture of THC BDS and CBD BDS, at doses up to 12.5 mg/kg/day or each active component. This dose resulted in estimated exposures that were well in excess of that expected in humans with the maximum recommended dose (>300 fold based on AUC). Effects on various male reproductive parameters have been reported with cannabinoids in some animal studies, but findings were inconsistent or observed at high/toxic doses and their clinical significance is uncertain.

There was no evidence for teratogenicity in rats and rabbits treated with oral doses of a 1:1 THC BDS and CBD BDS mixture of up to 12.5 mg/kg/day of each active component. This dose resulted in respective THC and BDS exposures (based on AUC) that were approximately 490 and 320 fold (rats) or 12.5 and 3 fold (rabbits) those expected in humans with the maximum recommended dose. The highest dose was maternotoxic in rabbits and resulted in a slightly lower fetal weight and impaired skeletal ossification. Reduced fetal weights and increased incidences of skeletal variants were seen in rabbits, associated with maternal toxicity which was apparent with all doses tested.

Oral treatment of rats with 4 mg/kg/day of a 1:1 THC BDS and CBD BDS mixture from the time of implantation to weaning of the offspring resulted in a lower pup body weight gain and slightly impaired righting reflex on day 5 of lactation. The NOEL for these findings (2 mg/kg/day) was below the maximum recommended human dose in terms of body surface area.

In studies with animals, as expected, due to the lipophilic nature of cannabinoids, considerable levels of cannabinoids were found in the maternal breast milk. Following repeat dosing, cannabinoids are concentrated in breast milk (40 to 60 times the plasma level). Doses in excess of normal clinical doses may affect growth rates of breast-fed infants.

Pre-meeting public submissions

Six public submissions were received before the first closing date in response to an invitation published on 31 August 2018 under regulation 42ZCZK of the Regulations. Three of the submissions were in support of the proposal while three were opposed.

The main points in support of the applicant's proposal:

• Nabiximols meet the Scheduling Policy Framework and the criteria under Section 52(e) for inclusion in Schedule 4 on the basis of its overall safety profile and characteristics including low potential for physical or psychological dependence, misuse and abuse.
• Intoxication effects following use of nabiximols are reported to be low so dependence on nabiximols is suggested to be unlikely.
• The characteristics of nabiximols with respect to the potential for abuse meet the scheduling factor for Schedule 4 ('The use of the substance at therapeutic dosage levels may produce dependency but has a moderate propensity for misuse, abuse or illicit use.')
• Adverse effects most commonly reported are mild or moderate dizziness, fatigue or fainting, which are most frequent in the first few weeks of therapy and resolve without discontinuation.
• Nabiximols is not widely used and is only approved for use by a subset of a particular patient population. As the product is not listed on the Pharmaceutical Benefits Scheme it would only be accessed by patients with multiple sclerosis willing to pay privately.
• Patient factors would be assessed by the relevant prescriber when considering initiation of treatment with nabiximols, and responses to treatment can be managed through monitoring of patients, particularly with regards to adverse effects of initial doses.
• The down scheduling of nabiximols and deletion of the Appendix D entry will make the prescribing, storing, transporting and distribution of nabiximols easier, resulting in potential cost savings for consumers particularly as nabiximols is not currently listed on the PBS.
• The storage requirements for nabiximols as a Schedule 8 medicine are challenging for pharmacists.
• The particular formulation of this product requires refrigeration which is difficult as most jurisdictions require Schedule 8 medicines to be stored in a Controlled Drugs safe. In NSW new storage requirements for Schedule 8 medicines that require refrigeration for community pharmacies, pharmacies in a public hospital, or pharmacies in a private hospital. This presents challenges at present for pharmacists in meeting storage requirements for Schedule 8 medicines. For a product such as [REDACTED] that meets all the scheduling factors for Schedule 4, it would appear unnecessary to make an exemption for refrigerated Schedule 8s when these products are more suited to Schedule 4.
• Nabiximols has made a valuable addition to the repertoire of medications available to people with MS and their healthcare teams. It allows for an appropriate treatment choice to be made according to the efficacy and possible side-effects in relation to an individual's circumstances and, with these further amendments to scheduling, has the potential to help alleviate the economic cost of MS to individuals, their families and the broader community.
• Easy-to-use medications for MS such as [REDACTED] are of great benefit for people living with MS in rural and regional settings where the need for hospital and clinic visits can be minimised or not needed at all.

The main points against the applicant's scheduling proposal include:

• The proposed scheduling change is inconsistent with the current scheduling requirements for cannabis and tetrahydrocannabinols.
• No evidence was provided that the specific properties of the [REDACTED] formulation confer a degree of safety distinct from any other formulation containing both CBD and THC.
• The proposal is aimed at a particular product, while the Poisons Standard considers the scheduling of 'substances'.
• It is timely for the committee to consider whether there is a need for a separate scheduling entry for nabiximols in the Poisons Standard.
• There is potential for harm, including serious adverse effects, from
  • known interactions (induction or inhibition of drug metabolising enzymes, additive CNS depressant effects with sedatives, hypnotics and alcohol) and
  • potentially from others not previously elucidated
  • Additive muscle relaxant effects and subsequent falls risk.
• As nabiximols contains the psychoactive cannabinoid THC, there is potential for misuse, abuse, illegal use or diversion, particularly in light of the illicit market for street cannabis. The applicant's assertion of a lack of spontaneous reporting of such is not indicative of its absence.
• Down-scheduling would potentially lead to prescribing by practitioners with limited knowledge of appropriate indications, contraindications and drug interactions, and may lead to patient pressure on practitioners to prescribe.
• The delivery mechanism - a spray - has a similar effect to giving the medicine intravenously. This is an important contraindication for its down-scheduling to a less controlled category of medicine.
• Further research is needed investigating incidence of cannabis dependency with supra-therapeutic use.
• Down-scheduling of nabiximols would reduce the potential for monitoring adverse effects.
• The AMA is not aware of any difficulties experienced by medical practitioners who wish to appropriately prescribe this medicine to their patients under the current scheduling arrangements, nor of patients having difficulty in accessing the medicine appropriately.
• It would introduce inconsistency within the Poisons Standard given that the NABIXIMOLS entry provides for the spray (dose form is explicit in the entry) to contain no more than 30mg of tetrahydrocannabinols per millilitre, together with approximately equal proportions of cannabidiol. This would place the entry in conflict with the listings for CANNABIDIOL.
• The claim by the applicant that the scheduling of nabiximols in 26 other countries is similar to Schedule 4 in Australia is questionable.
• There are unique regulatory structures underlying the scheduling of cannabis in other countries and there is also a paucity of longitudinal outcome data related to potential for abuse, diversion, dependence or use for illegal purposes.
• There are inherent limitations of post-marketing reporting in the global safety database, as this is reliant upon spontaneous reporting. Reliance upon data derived via spontaneous reporting is likely to underreport any potential public health risk signals.

Joint ACMS-ACCS advice

The committee recommended that the current scheduling of nabiximols remains appropriate and no changes to the Poison Standard were proposed.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 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 advice included:

1. the risks and benefits of the use of a substance:
   • There is an emerging evidence base regarding the use of cannabinoids in multiple sclerosis.
   • Recent reviews consider the evidence for the use of cannabinoids for symptoms of multiple sclerosis and pain, and find modest effects (generally small effect sizes, and for pain, around 20 patients needing to receive cannabinoids for one to benefit).
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • [REDACTED] is indicated as a treatment for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy.
   • Off-label use for other conditions have been explored (e.g. other pain conditions, and for the treatment of cannabis dependence).
   • Nabiximols has therapeutic use and therefore Schedule 8 is applicable, rather than Schedule 9.
3. the toxicity of a substance:
   • In clinical trials, adverse effects occur at a higher rate in the cannabinoid groups than placebo groups.
   • Most adverse effects are considered 'mild' to 'moderate'.
   • In early clinical studies, 3/41 patients taking a high dose (18 sprays twice a day) in phase 1 studies experienced a toxic psychosis (resolved spontaneously), 0/41 reported toxic psychosis at 12 sprays twice a day. Side effects also include cognitive impairment.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Nabiximols is a highly characterised botanical extract of defined chemotypes of Cannabis sativa L., containing delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) as the major constituents, together with other cannabinoid and non-cannabinoid components. These are dissolved in a vehicle of ethanol and propylene glycol, with peppermint oil. The two principal cannabinoids, THC and CBD are present at concentrations of 27 mg/mL and 25 mg/mL respectively. In addition to these two main cannabinoids, [REDACTED] also contains a range of minor cannabinoids and plant-based materials, such as terpenes, plant sterols, carotenoids and triglycerides.
   • The spray is administered via a metered dose pump giving a spray volume of 100 µL per spray. Hence each 100 μL spray is equivalent to 2.7 mg THC and 2.5 mg CBD.
   • The dose required for effective relief is patient dependent and a titration regime is used to establish the individual dose.
   • The cannabis plants are propagated through cuttings and are grown under managed indoor conditions in glasshouses to assure their genetic reproducibility and consistent quality of the extracts.
5. the potential for abuse of a substance
   • A randomized, double-blind, placebo-controlled, crossover study to evaluate the abuse potential of [REDACTED] in subjects with a history of recreational marijuana use found that abuse liability was broadly comparable to oral THC, particularly at higher doses within the therapeutic dose range.
   • Well-conducted research indicates that oral THC has a lower abuse liability that smoked THC.
   • THC has a well-established abuse liability when used outside therapeutic contexts. Around one in ten people using cannabis regularly are reported to develop dependence.
   • Evidence is currently limited, but indicates there is potential for misuse and abuse.
6. any other matters that the Secretary considers necessary to protect public health
   • This listing for a specific ratio of THC:CBD may require review - to date, little evidence has explored differing ratios. It is likely that as studies that explore differing ratios emerge, and the role of cannabidiol in different clinical conditions becomes clearer, that we will start to see products with a range of ratios.
   • Other THC/CBD combination preparations are included in Schedule 8.  Nabiximols could be described as an extract of cannabis. Extracts of cannabis are in Schedule I of the UN Single Convention on Narcotic Drugs. The Scheduling Factors for Schedule 8 require Schedule I and II substances to be included in Schedule 8.
   • States and territories have enacted mechanisms to allow convenient storage of S8 refrigerated products.