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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017

Scheduling medicines and poisons

17 May 2017

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1.1. Dihydrocodeine

1. Advisory Committee on Medicines Scheduling (ACMS #20)

1.1. Dihydrocodeine

Referred scheduling proposal

A delegate from the TGA has referred the substance dihydrocodeine for consideration for the appropriateness of the Schedule 2 and Schedule 3 entries, noting the recent up-scheduling of codeine.

Current scheduling status

Dihydrocodeine is currently listed in Schedules 8, 4, 3 and 2 of the Poisons Standard as follows:

Schedule 8

DIHYDROCODEINE except when included in Schedule 2, 3 or 4.

Schedule 4

DIHYDROCODEINE when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing not more than 100 mg of dihydrocodeine per dosage unit; or
  2. in undivided preparations with a concentration of not more than 2.5 per cent of dihydrocodeine,

except when included in Schedule 2 or 3.

Schedule 3

DIHYDROCODEINE when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing 10 mg or less of dihydrocodeine per dosage unit and with a recommended dose not exceeding 15 mg of dihydrocodeine; or
  2. in undivided preparations containing 0.25 per cent or less of dihydrocodeine with a recommended dose not exceeding 15 mg of dihydrocodeine,

except when included in Schedule 2.

Schedule 2

DIHYDROCODEINE when compounded with aspirin and no other therapeutically active substance in divided preparations:

  1. containing 5 mg or less of dihydrocodeine per dosage unit;
  2. packed in blister or strip packaging or in a container with a child-resistant closure;
  3. enclosed in primary packs containing 25 or less dosage units; and
  4. labelled with a recommended dose not exceeding 10 mg of dihydrocodeine.

The related substance acetyldihydrocodeine is in Schedule 8.

Scheduling history

In December 2016, the delegate made a decision to up-schedule codeine from Schedules 2 and 3 to Schedule 4. The decision and reasons are on the TGA website at: Scheduling delegate's final decision: codeine, December 2016

In November 1979 - June 1980, the Poisons Schedule Committee (PSC) reviewed the scheduling of dihydrocodeine in certain preparations following evidence of abuse. The committee discussed the desirability of placing uncompounded preparations containing less than 1% dihydrocodeine in Schedule 4, and considered that uncompounded preparations currently available in Schedule 2 should be classified in Schedule 8. Two manufacturers sought the committee's concurrence that inclusion of sorbitol (40 g/100 mL) in their products would remove the need for Schedule 2 status of their products. Members agreed to take no further action.

Between August 1985 and July 1987, the PSC and Drugs and Poisons Schedule Committee (DPSC) reviewed the scheduling of dihydrocodeine, following potency concerns raised by WA regarding the inclusion of dihydrocodeine tartrate in Schedule 2 as this allowed a higher limit than codeine, which was reported to be equipotent. At the November 1986 meeting the Committee foreshadowed a recommendation to alter the Schedule 2 entries for opiates (except dihydrocodeine) and other substances with regard to a specific quantity per dosage unit in divided preparations, a percentage limit for undivided preparations and an upper dose limit recommended for both divided and undivided preparations. Members agreed to delete dihydrocodeine from Schedule 2 and enter it into Schedule 3 in February 1987. Following this, the committee received further information about the decision to delete Schedule 2 and create a new Schedule 3 entry. The committee noted a potency equivalence of 5 mg dihydrocodeine to 10 mg of codeine and agreed to a new Schedule 2 entry for dihydrocodeine. A new Schedule 2 entry was also made for dihydrocodeine when in combination with aspirin.

In April 1994, the National Drugs and Poisons Scheduling Committee (NDPSC) considered a request from the Australian Pharmaceutical Advisory Council (APAC) to review the scheduling of dihydrocodeine combined with paracetamol, in view of the fact that dihydrocodeine with aspirin is Schedule 2. Members were not aware of a registered OTC product containing paracetamol and dihydrocodeine or of a detailed technical submission supporting such a change, or was there any response to the Gazettal invitation for public comment. Accordingly the Committee was unable to accede to the request.

In June 2010 - September 2011, the NDPSC and ACMS, considered a TGA request to reschedule several medicines, following a TGA review of the safety, efficacy, availability and packaging of all OTC cough and cold medicines. The review concluded that there was a lack of evidence of efficacy and potential safety concerns associated with use in children, especially those aged less than 6 years, and stated that the current scheduling of codeine, dihydrocodeine and pseudoephedrine was appropriate. Members noted that, of the 22 substances identified in the TGA review, a number were recommended for exemption from the proposed cascade as it was considered that either existing controls were sufficient (codeine, dihydrocodeine and pseudoephedrine) or that scheduling was not necessary (ammonia). Members noted that for some substances the current scheduling may in fact be more restrictive than the proposed cascade (e.g., pseudoephedrine) as this was the basis for the TGA Panel recommending that existing controls were sufficient for codeine, dihydrocodeine and pseudoephedrine and did not need to be rescheduled. The committee agreed that the use of certain substances in preparations for treating cough and cold be rescheduled to:

  • Schedule 4 for use in children less than 2 years of age.
  • Schedule 3 for use in children aged from 2 to 6 years of age.
  • Schedule 2 for use in adults and children above 6 years of age.

However, the delegate decided that the scheduling of dihydrocodeine and another 14 substances (including codeine) in cough and cold preparations remained appropriate.

Scheduling application

This was a delegate initiated application made in response to the scheduling changes of codeine where from 1 February 2018, the Schedule 2 and 3 entries for codeine will be deleted.

Australian regulatory information

There are currently 7 ARTG products containing dihydrocodeine tartrate that are included on the ARTG.

International regulations
Japan

In Japan, dihydrocodeine is available without a prescription; used in cough medicines. Medicines in Japan containing dihydrocodeine are combined with caffeine to offset the sedative effects and discourage recreational use. Sale is limited by quantity and restricted by age.

UK

In the UK and other countries, 30 mg tablets containing only dihydrocodeine as the active ingredient are available; 40 mg dihydrocodeine tablets are also available in the UK. Dihydrocodeine is considered to be a Class B drug in the UK, but is available OTC in small amounts (less than 8 mg), when combined with paracetamol.

Dihydrocodeine is listed in Schedule 5 of the Misuse of Drugs Regulations 2001, exempting it from prohibition of possession provided that it is in the form of a single preparation not designed for injection and less than 100 mg (as free base) or with a total concentration less than 2.5% (as free base).

New Zealand

The NZ database of Medicine Classifications states that dihydrocodeine (or drocode) is a prescription medicine.[1] It is also conditionally classed as a C2 and C6 Controlled drug (drugs that pose a moderate risk of harm to individuals, or to society, by its misuse):[2]

Acetyldihydrocodeine is also a Class C2 controlled drug in NZ.

United States of America

In the USA, dihydrocodeine is a Schedule II controlled substance.

Preparations containing small amounts of dihydrocodeine are classified as Schedule III or V, depending on the concentration of dihydrocodeine relative to other active constituents, such as paracetamol (acetaminophen). The USA currently has 2 combination products registered and available as prescription medicines containing paracetamol (acetaminophen) or aspirin with caffeine and dihydrocodeine tartrate (dihydrocodeine bitartrate).[3]

Substance summary

Dihydrocodeine (CAS number 125-28-0) is a semi-synthetic phenanthrene opioid receptor agonist analgesic with a molecular weight of 301.4, C18H23NO3 (molecular weight for the tartrate is 451.5, molecular formula C22H29NO9, CAS number for the tartrate is 5965-13-9). Dihydrocodeine is a chemical derivative of codeine and is an opioid pain reliever that produces similar effects to codeine, prepared by codeine or neopine (Merck Index). The chemical name for dihydrocodeine is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol. Dihydrocodeine is a white or almost white, crystalline powder, freely soluble in water, sparingly soluble in alcohol and practically insoluble in cyclohexane. Martindale[4], indicates that dihydrocodeine is available as both tartrate and phosphate salts.

Figure 1.1: Structure of dihydrocodeine tartrate

Figure 1.1: Structure of dihydrocodeine tartrate

Abuse

As with other opioids, tolerance and physical and psychological dependence develop with repeated use of dihydrocodeine. Martindale indicates that dihydrocodeine has been reported to be widely abused by opiate addicts.[5]

Pharmacokinetics

Dihydrocodeine is converted by cytochrome P450 isoenzyme CYP2D6 in the liver to the primary active metabolite dihydromorphine[6]. Oral bioavailability is approximately 20%. Dihydromorphine has potent analgesic activity, although the analgesic effect of dihydrocodeine appears to be mainly due to the parent compound. Dihydrocodeine is excreted in urine as unchanged drug and metabolites, including glucuronide conjugates. Elimination half-life ranges from 3.5 - 5 h. Martindale reports that the peak plasma concentration for dihydrocodeine is delayed and the area under the plasma concentration-time curve is greater in subjects with renal impairment compared with healthy subjects.

Pre-meeting public submissions

Five (5) public submissions were received.

Three (3) submissions supported the scheduling proposal. The main points were:

  • Cases of misuse/abuse of dihydrocodeine reported to the NSW Poisons Information Centre have increased in recent years.
  • Acknowledge no reason to have different scheduling compared with codeine, but also supports deleting Schedule 2 and amending Schedule 3 and Schedule 4 pack sizes.

Two (2) submissions did not support the scheduling proposal. The main points were:

  • Schedule 3 is appropriate for dihydrocodeine in low doses when indicated as a cough suppressant. There have been no reported events related to abuse or dependence of OTC dihydrocodeine products on the ARTG in the past 6 years. Undivided preparations of dihydrocodeine in conjunction with sorbitol are not seen as candidates for abuse or misuse.
  • An additional safety measure of a mandatory warning label about the potential for addiction was proposed as an alternative.
  • As there are no products on the ARTG containing any aspirin or other analgesic preparation co-formulated with dihydrocodeine for the treatment of pain, there is no opposition to the removal of dihydrocodeine from Schedule 2 of the SUSMP.
  • There are already control measures in place in the pharmacy for dispensing Schedule 3 medicines. There is also a longstanding status of Schedule 3 medicines for the treatment of cough. Removal of dihydrocodeine from Schedule 3 would limit the availability of treatment options for stubborn cough available without a prescription. This would necessitate the consumer visiting the doctor for a prescription. This provides an added cost to the consumer.
  • Dihydrocodeine is an efficacious cough-suppressant.
  • There are minimal side effects with dihydrocodeine.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee advised that the Schedule 2 entry for dihydrocodeine be deleted and the Schedule 8, 4 and 3 entries be amended as follows:

Schedule 8 - Amend Entry

DIHYDROCODEINE except when included in Schedule 2, 3 or 4.

Schedule 4 - Amend Entry

DIHYDROCODEINE when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing not more than 100 mg of dihydrocodeine per dosage unit; or
  2. in undivided preparations with a concentration of not more than 2.5 per cent of dihydrocodeine,

except when included in Schedule 2 or 3.

Schedule 3 - Amend Entry

DIHYDROCODEINE when indicated for cough suppression and compounded with one or more other therapeutically active substances:

  1. in divided preparations containing 10 mg or less of dihydrocodeine per dosage unit and with a recommended dose not exceeding 15 mg of dihydrocodeine; or
  2. in undivided preparations containing 0.25 per cent or less of dihydrocodeine with a recommended dose not exceeding 15 mg of dihydrocodeine,

except when included in Schedule 2.

Schedule 2 - Delete Entry

DIHYDROCODEINE when compounded with aspirin and no other therapeutically active substance in divided preparations:

  1. containing 5 mg or less of dihydrocodeine per dosage unit;
  2. packed in blister or strip packaging or in a container with a child-resistant closure;
  3. enclosed in primary packs containing 25 or less dosage units; and
  4. labelled with a recommended dose not exceeding 10 mg of dihydrocodeine.

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; (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 comprised the following:

  • Dihydrocodeine is effective for stubborn, unproductive cough.
  • Dihydrocodeine has a known potential for abuse, but misuse is uncommon with the current formulation, and overdose, although possible, doesn't appear to be common.
  • There is a single product available which is indicated for stubborn, unproductive cough.
  • There is limited evidence of respiratory depression in overdose, and potential toxicity in high doses. Reports of overdose were largely from the UK where dihydrocodeine is used in the context of addiction treatment, and the product used is in tablet form.
  • Dihydrocodeine can produce euphoria and has a known potential for abuse. The potential for abuse is limited by the formulation, indication, Poisons Schedule and potential cost.
  • Consideration should be given to monitoring adverse events and additional safeguards to prevent misuse in light of the changed access to non-prescription codeine from February 2018.
  • There is a lack of evidence of abuse of the current product to justify removing it from Schedule 3, however the Schedule 3 entry should be limited to products used for cough suppression.
Delegate's considerations

The delegate considered the following in regards to this 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 for dihydrocodeine and amend the Schedule 8, 4 and 3 entries. The proposed Schedule entry is as follows:

Schedule 8 - Amend Entry

DIHYDROCODEINE except when included in Schedule 3 or 4.

Schedule 4 - Amend Entry

DIHYDROCODEINE when compounded with one or more other therapeutically active substances:

  1. in divided preparations containing not more than 100 mg of dihydrocodeine per dosage unit; or
  2. in undivided preparations with a concentration of not more than 2.5 per cent of dihydrocodeine,

except when included in Schedule 3.

Schedule 3 - Amend Entry

DIHYDROCODEINE when indicated for cough suppression and compounded with one or more other therapeutically active substances:

  1. in divided preparations containing 10 mg or less of dihydrocodeine per dosage unit and with a recommended dose not exceeding 15 mg of dihydrocodeine; or
  2. in undivided preparations containing 0.25 per cent or less of dihydrocodeine with a recommended dose not exceeding 15 mg of dihydrocodeine.

Schedule 2 - Delete Entry

The proposed implementation date 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; (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 interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • There is data indicating dihydrocodeine is an efficacious cough suppressant.
  • There are lower blood levels of its metabolites compared to codeine.
  • Dihydrocodeine has a known potential for abuse, but misuse is uncommon with the current formulation, and overdose, although possible, doesn't appear to be common.
  • There is a single Schedule 3 product available which is indicated for stubborn, unproductive cough.
  • There is limited evidence of respiratory depression in overdose, and potential toxicity in high doses. Reports of overdose were largely from the UK where dihydrocodeine is used in the context of addiction treatment, and the product used is in tablet form.
  • Dihydrocodeine can produce euphoria and has a known potential for abuse. The potential for abuse is limited by the formulation, indication, Poisons Schedule and potential cost.
  • Consideration should be given to monitoring adverse events and additional safeguards to prevent misuse in light of the changed access to non-prescription codeine from February 2018.
  • There is a lack of evidence of abuse of the current product to justify removing it from Schedule 3, however the Schedule 3 entry should be limited to products used for cough suppression. Restricting its Schedule 3 indication to cough suppression only will restrict products and use.
  • There needs to be consideration on whether a 200mL Schedule 3 product is appropriate.
  • There are no Schedule 2 products on the ARTG.

Footnotes

  1. Database of Medicine Classifications
  2. Schedule 3 Class C controlled drugs
  3. Drugs@FDA: FDA Approved Drug Products
  4. Dihydrocodeine
  5. Swadi H, et al. Misuse of dihydrocodeine tartrate (DF 118) among opiate addicts. BMJ 1990; 300: 1313; Robertson JR, et al. Misuse of dihydrocodeine tartrate (DF 118) among opiate addicts. BMJ 1990; 301: 119; Strang J, et al. Misuse of dihydrocodeine tartrate (DF 118) among opiate addicts. BMJ 1990; 301: 119; Seymour A, et al. The role of dihydrocodeine in causing death among drug users in the west of Scotland. Scott Med J 2001; 46: 143–6
  6. Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing Wilder-Smith CH, et al. The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine: a cross-over study with extensive and quinidine-induced poor metabolizers. Br J Clin Pharmacol 1998; 45: 575–81

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