Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, November 2016
Scheduling medicines and poisons
Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)
3. Advisory Committee on Medicines Scheduling (ACMS #19)
Referred scheduling proposal
An application was submitted to include a new entry for tianeptine in Schedule 4.
This was a delegate-initiated application.
The delegate's proposed amendments to the Poisons Standard are as follows:
Schedule 4 - Proposed New Entry
The reason for the request is that tianeptine is currently being sold as a product name Stablon on at least one Australian website in powder form. Safety concerns have been raised that tianeptine is being abused, and poses a public health risk, requiring restrictions on its use.
Australian regulatory information
There have been several requests for special access of tianeptine in the past 10 years in Australia through the Special Access Scheme for Category B patients. Administration is usually by tablet, 37.5 mg - 75 mg daily, orally for twelve months.
Tianeptine is not an active in any products listed on the ARTG.
International regulatory information
Tianeptine is marketed as Stablon in 15 European Union countries (France, Luxembourg, Portugal, Bulgaria, Romania, Slovakia, Poland, Malta, Hungary, Lithuania, Slovenia, Czech Republic, Austria, Latvia, and Estonia) and in 66 countries throughout the world.
France: Authorised for marketing in February 1987. Tianeptine is included in List I, for prescription duration restricted to 28 days with overlap prescription prohibited except on the express instruction of the prescriber written on the prescription. Further conditions apply on pharmacist where a copy of the prescription is to be held for 3 years. It is also included on the list of medicines refundable by National Health Insurance.
Singapore: Stablon (tablet 12.5 mg tianeptine sodium) is a prescription-only drug under Licence No. SIN11182P. It is included in the First Schedule (special restrictions under Rule 10 apply) and the Third Schedule (substances required by Rule 15 (Additional Restrictions on sale of certain poisons) to be sold upon a prescription given by a medical practitioner, dentist or veterinary surgeons) of the Poisons Act.
Bahrain: The Drug Control Directorate has classified tianeptine sodium under the 'special-drugs under-controlled prescriptions' category due to increasing reports of misuse and abuse by patients.
No information could be located for US, Canada or New Zealand regulation for tianeptine.
Tianeptine is a tricyclic compound with psycho-stimulant, anti-ulcer and anti-emetic properties. Tianeptine is considered as an anti-depressive agent and is used for treatment of major depressive disorder. Unlike other traditional anti-depressants that are selective serotonin reuptake inhibitors (SSRIs), tianeptine acts by increasing the presynaptic reuptake of serotonin and has indirect effects on alteration of glutamatergic receptors (AMDA and NMDA) activity.
Martindale states that tianeptine is given in oral doses of 12.5 mg, three times daily in treatment of depression. Doses should be reduced to a total of 25 mg daily in elderly patients. Isolated cases of hepatitis have been reported during treatment with tianeptine. Martindale also states that tianeptine has been reported to improve symptoms in patients with asthma. Martindale refers to reported misuse of tianeptine.
Tianeptine (Figure 3.6A) has one chiral centre and is present at the racemate. The stereocentre is at the C-11 position in the central thiazepinyl ring. Tianeptine differs chemically to other antidepressants by the presence of a sulphonamide function in the central nucleus and a lateral amino acid chain (see Table 3.6 for additional chemical information).
Figure 3.6: Structures of tianeptine (A) and tianeptine sodium (B)
|Property||Tianeptine (free acid)||Tianeptine sodium|
|British Approved Name (BAN)||N/A||Sodium 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl]amino]heptanoate S,S-dioxide|
6981-73-5 (online websites and Martindale)
72797-41-2 (Merck Index and SciFinder)
|30123-17-2 (BP monograph and SciFinder)|
|Chemical name||7-[(3-chloro-6,11-dihydro-6-methyl-5,5-dioxidodibenzo[c,f][1,2]thiazepin-11-yl)amino]-heptanoic acid||7-[(3-chloro-6,11-dihydro-6-methyl-5,5-dioxidodibenzo[c,f][1,2]thiazepin-11-yl)amino]-heptanoic acid monosodium salt (9CI)|
|Molecular Weight||436.9 g/mol||458.9 g/mol|
|Form||White solid||White or yellowish powder|
|Melting Point||129 - 131°C||180°C|
|International trade names||Stablon; Coaxil; Tatiniol; Tianeurax; and Zinosal.|
|WHO ATC Classification||
N - Central nervous system
N06 - Psychoanaleptics
N06A - Anti-depressants
N06AX - Other Anti-depressants
N06AX14 - Tianeptine
Tianeptine is hygroscopic, and freely soluble in water. Tianeptine is amphoteric with two pKa values, 4.4 (acidic) and 6.86 (basic), and is weakly lipophilic (log P at pH 7.4 = 1.06).
Literature reports that absorption of tianeptine from tablet form is rapid and complete following oral administration to fasting healthy subjects. The mean Cmax of tianeptine is 334 +/- 79 ng/mL. Tmax is 0.94 +/- 0.47 h following oral administration. Absolute bioavailability is 99 +/- 29%. Tianeptine is rapidly and completely absorbed in the tablet form and is not subject to first-pass effect. Distribution of tianeptine in the body is characterized by the following: its rapidity, the mean distribution half-life being about 0.7 h; its limited extent, the apparent volume of distribution being about 0.8 L/kg (0.77 +/- 0.31 L/kg); and protein binding, which averages 93.8 +/- 2.4%. Elimination of tianeptine is characterized by a short mean half-life of 2 h 30 min (2.5 +/- 1.1 h) and by renal excretion of 0.4 ml/min (0.4 +/- 0.4 mL/min). Tianeptine is extensively metabolized. Major metabolites are analogues of tianeptine with a C5 and C3 lateral chain and an N-demethylated derivative. Studies have shown negligible influence on pharmacokinetic parameters of chronic alcoholism even in case of hepatic cirrhosis.
There is a BP/EP 2016 harmonised monograph for tianeptine sodium (Figure 3.6B). There are no current USP monographs for Tianeptine or the Tianeptine Sodium Online websites refer to both a sulfate and a sodium salt. The BP monograph for tianeptine sodium is transparent in relation to 4 impurities.
Pre-meeting public submissions
No pre-meeting submissions were received for tianeptine.
Summary of ACMS advice to the delegate
The committee advised that tianeptine should be added to Schedule 4 and Appendix D Item 5.
The recommended wording for the entry is as follows:
Schedule 4 - New Entry
Appendix D, Item 5 - New Entry
The ACMS advised an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee 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.
The reasons for the advice comprised the following:
- Clinical data suggest tianeptine as an effective antidepressant. It is used in 66 countries, but not in NZ, Canada, UK or US. In Singapore, tianeptine is only prescribed by psychiatrists. It is not registered or marketed in Australia. It is not in any products listed on ARTG and is not listed in Therapeutic Goods (permissible ingredients) Determination. Tianeptine is however freely available in Australia via websites where it is reportedly advertised as bulk powder.
- Tianeptine has a short half-life requiring 3 times daily dosing, so its use is likely to be very limited in a well-saturated market of once-a-day antidepressants. Glutamatergic pathways, in which tianeptine acts, may become important in future as research for cognitive enhancement and when neuroprotection develops. These pathways may also become an alternative antidepressant target for special populations (e.g. treatment resistant populations). Tianeptine has a wide therapeutic margin with minimal toxicity reported at very high doses.
- The benefits of tianeptine include its use as an antidepressant with other potential medical uses.
- The risks include misuse. It is apparently relatively uncommon and is apparently used for anxiolytic effect.
- In relation to potential for abuse, there are reports of opioid-like euphoria effects (from mu-agonist activity) at high doses (much higher than antidepressant effect e.g. 300-500 mg/day). There are some reports of abuse potential overseas and reports of 'doctor-shopping' in France, where 28 days' supply restrictions apply. Given this, tianeptine is recommended to have an Appendix D, Item 5 listing.
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 that a new Schedule 4 entry for tianeptine with an Appendix D item 5 entry is appropriate.
The proposed Schedule entry is as follows:
Schedule 4 - New Entry
Appendix D item 5 - New Entry
The proposed implementation date is 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; and e) the potential for abuse of a substance.
The reasons for the recommendation comprised the following:
- The delegate acknowledges the committee's advice.
- The benefits outweigh the risks.
- Tianeptine has a short half-life requiring 3 times daily dosing, so its use is likely to be very limited in a well-saturated market of once-a-day antidepressants. Tianeptine has a wide therapeutic margin with minimal toxicity reported at very high doses.
- Tianeptine is an antidepressant available in Australia via websites where it is reportedly advertised as bulk powder. The risks of misuse are apparently relatively uncommon.
- There are reports of opioid-like euphoria effects (from mu-agonist activity) at high doses (much higher than antidepressant effect e.g. 300-500 mg/day). There are some reports of abuse potential overseas and 'doctor-shopping'. Given this, tianeptine is recommended to have an Appendix D, Item 5 listing.
- Royer, R.J. et al., Pharmacokinetics and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors. Clin Neuropharmacol 1988, 11 Suppl 2:S90-6