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Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

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1.8. Orphenadrine

Referred scheduling proposal

An application was submitted to amend the Schedule 4 entry and create a new Schedule 3 entry for orphenadrine in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

This was a general application. The applicant’s proposed amendments to the Poisons Standard are:

Schedule 3 – New Entry

ORPHENADRINE in oral preparations containing 35 mg or less of orphenadrine:

  1. when compounded with not more than 500 mg paracetamol for the relief of pain associated with skeletal muscle spasm in adults and children 12 years of age and over; and
  2. in a primary pack containing 24 or less dosage units.

Schedule 4 – Amend Entry

ORPHENADRINE except when included in Schedule 3.

The applicant's reasons for the request are:

  • Orphenadrine is a skeletal muscle relaxant. Its citrate salt is used to relieve pain due to muscle spasm. Paracetamol is an analgesic. The combination of a skeletal muscle relaxant and an analgesic is useful in conditions where pain is associated with muscle spasm. The individual substances relieve the two defining symptoms of the targeted indication (pain and muscle spasm) and contribute to the clinical effect via different modes of action.
  • Orphenadrine containing tablets have been available in Australia as a Schedule 4 medicine for over 40 years, and have a known efficacy and safety profile.
  • The combination of orphenadrine 35 mg and paracetamol 450 mg provides effective relief of pain associated with muscle spasm including painful muscular conditions, musculoskeletal spasm, sports muscle injuries, lower back ache and muscle contraction headaches. It is useful in helping to break the pain-spasm-pain cycle resulting from minor trauma or injury.
  • Painful musculoskeletal conditions are readily recognisable by the consumer. They are generally self-limiting and suitable for short-term treatment under the supervision of a pharmacist.
  • Orphenadrine is an alternative treatment that provides a specific treatment for muscle spasms without the risks associated with low-dose non-steroidal anti-inflammatory drugs (NSAIDs) and codeine.
  • Post codeine up-scheduling, there will be fewer preparations available for pharmacist's to recommend for painful musculoskeletal conditions.
  • Treatment of muscle spasm with a combination of orphenadrine and paracetamol helps avoid undue immobilisation and consequential loss of work/other activities of daily living.
  • Adverse effects associated with the combination are mainly due to the anticholinergic activity of orphenadrine and are more likely to occur at doses higher than proposed for the Schedule 3 entry. The safety of the combination is comparable to that of other anticholinergic medicines. Orphenadrine can potentially cause adverse effects such as dry mouth, palpitations, confusion and dizziness in elderly people. These effects are reversible and are usually mild and self-limiting at the recommended dosage. They can be managed by reducing the dose.
  • The risk-benefit profile for the fixed dose regimen is positively supported with clinical trial evidence of up to 10 weeks treatment and includes comparison with the single actives.
  • There are over 45 years of global post-marketing surveillance with orphenadrine. Its safety profile is comparable to that of other over-the-counter (OTC) medicines with anticholinergic activity. The safety profile of paracetamol is well known and does not appear to be affected by orphenadrine.
  • There is a low level of relative risk associated with the rescheduling of orphenadrine when used in combination with paracetamol. Many products with anticholinergic activity are already available as Schedule 2 medicines for use in adults (e.g. hyoscine or diphenhydramine) and are often used with paracetamol-containing products. Pharmacists are familiar with counselling and educating consumers on the use of such medicines. Additionally, paracetamol is available as a general sales medicine in packs of 20 tablets, with larger packs up to 100 tablets available in pharmacies. Thus, pharmacists are already counselling patients on the use of anticholinergics and analgesics as separate medications. The counselling appropriate for a paracetamol and orphenadrine combination is consistent with that applied for the separate medicines.
  • Strategies to minimise associated risks with a paracetamol and orphenadrine combination are:
    • Pack size restriction;
    • Inclusion of warning and precautionary statements in the product information (PI), consumer medicines information (CMI) and on the carton; and
    • Mandatory intervention by a pharmacist at point of sale to help minimise the potential for adverse effects and misuse.
  • The proposed medicine label for the proposed product will comply with the new TGO92 medicine labelling orders set by the TGA, which will show all active ingredients prominently on the label thereby helping to minimise inadvertent misuse.
  • The proposed product (same formulation as the Australian product) has been available in several countries, although not always concurrently. In South Africa, the proposed product has been an OTC medicine since 1978.
  • The proposed product is a rational combination analgesic product fulfilling the unmet clinical need for an accessible OTC preparation supervised by the pharmacist that:
    • Specifically addresses both pain and muscle spasm;
    • Is without the risks associated with NSAIDs and codeine; and
    • Contains a total daily therapeutic dosage of 2.7 g paracetamol, well under the maximum 4 g recommended daily dosage considered safe by regulatory authorities worldwide and in published literature.
  • The 4 day supply pack of the proposed product limits the amount of paracetamol intake. Pharmacists in their mandatory interventionist role as provider of Schedule 3 medicines will counsel individuals against co-administering other paracetamol containing products while taking the proposed product. This precaution will also appear on the label.
  • The proposed Schedule 3 pack provides a maximum of 4 days treatment for painful musculoskeletal conditions associated with muscle spasm.
  • Orphenadrine has nearly 40 years'; experience in Australia and over 40 years' experience internationally.
  • Safety record supported by longstanding Periodic Safety Update Reports (PSURs) and Database of Adverse Event Notifications (DAEN) data.
  • Dedicated educational support programme for pharmacists by the sponsor and the Pharmaceutical Society of Australia including the best practice clinical protocol for pharmacists.
Current scheduling status

Orphenadrine is currently listed in Schedule 4 of the Poisons Standard as follows:

Schedule 4

ORPHENADRINE.

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

Schedule 2

PARACETAMOL for therapeutic use:

  1. when combined with ibuprofen in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a primary pack containing no more than 12 dosage units per pack; or
  2. in tablets or capsules enclosed in a primary pack containing not more than 100 tablets or capsules; or
  3. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
  4. in individually wrapped powders or sachets of granules enclosed in a primary pack containing not more than 50 wrapped powders or sachets of granules; or
  5. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules intended only as a bulk medicine pack and labelled 'For dispensing only' and 'This pack is not to be supplied to a patient'; or
  6. in other preparations except:
    1. when included in Schedule 3 or 4; or
    2. in individually wrapped powders or sachets of granules each containing 1000 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
      1. enclosed in a primary pack that contains not more than 10 such powders or sachets of granules,
      2. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
      3. not labelled for the treatment of children 6 years of age or less, and
      4. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin; or
    3. in tablets or capsules each containing 500 mg or less of paracetamol as the only therapeutically active constituent (other than caffeine, phenylephrine and/or guaifenesin or when combined with effervescent agents) when:
      1. packed in blister or strip packaging or in a container with a child-resistant closure,
      2. in a primary pack containing not more than 20 tablets or capsules,
      3. compliant with the requirements of the Required Advisory Statements for Medicine Labels,
      4. not labelled for the treatment of children 6 years of age or less, and
      5. not labelled for the treatment of children under 12 years of age when combined with caffeine, phenylephrine and/or guaifenesin.

Schedule 3

PARACETAMOL when combined with ibuprofen in a primary pack containing 30 dosage units or less except when included in Schedule 2.

Schedule 4

PARACETAMOL:

  1. when combined with aspirin or salicylamide or any derivative of these substances except when separately specified in these Schedules;
  2. when combined with ibuprofen in a primary pack containing more than 30 dosage units;
  3. in slow release tablets or capsules containing more than 665 mg paracetamol;
  4. in non-slow release tablets or capsules containing more than 500 mg paracetamol;
  5. in individually wrapped powders or sachets of granules each containing more than 1000 mg paracetamol;
  6. in tablets or capsules enclosed in a primary pack containing more than 100 tablets or capsules except in schedule 2;
  7. in individually wrapped powders or sachets of granules enclosed in a primary pack containing more than 50 wrapped powders or sachets of granules except when included in Schedule 2;
  8. for injection.

It is also included under the entry paracetamol in Appendix F with the following statements:

Appendix F, Part 3

PARACETAMOL

Warning Statements:

  • 97 (Adults: Keep to the recommended dose. Don't take this medicine for longer than a few days at a time unless advised to by a doctor); and/or
  • 98 (Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor); and
  • 99 (If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26; New Zealand 0800 764 766) or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage); and
  • 100 (Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist).
Scheduling history

In February 1987, orphenadrine was first scheduled. Based on a jurisdiction list of sedating drugs, orphenadrine was included in Appendix K by the Drugs and Poisons Scheduling Committee (DPSC).

In November 1987, the DPSC noted that orphenadrine was included in the list of substances requiring a child-resistant closure in TGO 20. The committee agreed this was appropriate, and that it should not be replicated in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).

In June 2011, the ACMS considered a proposal to reschedule orphenadrine in dosage units containing less than 35 mg from Schedule 4 to Schedule 3 when combined with paracetamol in a pack size of 24 dosage units or less. The application was referred to an external evaluator, who recommended that the application be rejected.

In September 2011, the delegate concluded that the recommendations of the ACMS were clear and appropriately supported. The delegate agreed with the recommendations that the scheduling of orphenadrine and paracetamol in Schedule 4 of the Poisons Standard remained appropriate.

Australian regulatory information

The Australian Register of Therapeutic Goods (ARTG) has two entries for products registered containing both orphenadrine and paracetamol. The products differ in container presentation – blister pack vs. tablet bottle.

In the last 30 years there have been 39 reported cases of adverse events related to orphenadrine, and 3237 related to paracetamol in the Database of Adverse Events Notification (DAEN) - Medicines: 21 cases with the single suspected medicine being orphenadrine, and 1244 cases with paracetamol. Of these, no cases reported death as the outcome associated with orphenadrine, compared to 137 cases reported death as an outcome associated with paracetamol over the same 30 year period.

International regulations

Tablets containing orphenadrine citrate 100 mg (as the only active ingredient) are marketed as OTC in Canada.

Both Medsafe New Zealand and the United States of America’s Food and Drug Authorisation classify orphenadrine citrate as a prescription medicine.

Substance summary

Orphenadrine is a congener of diphenhydramine. It is a tertiary amine antimuscarinic agent with weak antihistaminic and local anaesthetic properties. It also inhibits noradrenaline transport and blocks NMDA receptors and voltage-gated sodium channels.

Orphenadrine is a skeletal muscle relaxant. Its citrate salt is used to relieve pain due to muscle spasm. However, efficacy for this indication is not well established.

Paracetamol is an analgesic. The combination of a skeletal muscle relaxant and an analgesic is useful in conditions where pain is associated with muscle spasm. The individual substances relieve the two defining symptoms of the targeted indication (pain and muscle spasm) and contribute to the clinical effect via different modes of action.

Table 1.8.1: Chemical information of orphenadrine and paracetamol
Property Orphenadrine Paracetamol
CAS number 83-98-7 103-90-2
IUPAC and/or common and/or other names

N,N-dimethyl-2-[(2-methylphenyl)-phenylmethoxy]ethanamine (IUPAC);

1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3 (InChI);

Orphenadrine (INN);

N-(4-hydroxyphenyl)acetamide (IUPAC);

1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) (InChI);

Acetaminophen (USP);

Chemical structure
Molecular formula C18H23NO C8H9NO2
Molecular weight 269.4 g/mol 151.2 g/mol
Pre-meeting public submissions

Five (5) public submissions were received, four (4) that oppose and one (1) that supports the scheduling proposal for orphenadrine.

Main points in support:
  • The rescheduling proposal outlined is for short-term therapy. Although anticholinergic effects of orphenadrine may require some caution, the proposed dosage is low and orphenadrine has an overall well-established safety and efficacy profile.
  • The proposed indication for Schedule 3 can be regarded to be recognisable by the patient.
  • A pharmacist will be able to consider the patient's circumstance to discuss whether orphenadrine and paracetamol would be the most appropriate analgesic. The submitter also recognises that pharmacist education and relevant practice tools would be required for the implementation of Schedule 3.
  • The orphenadrine and paracetamol combination product has been available in Australia for many years. However, pharmacists report it is not widely used. This may be due to low level awareness of prescribers since the product is not listed on the Pharmaceutical Benefits Scheme (PBS). Even if the product was an appropriate therapeutic option, patients may prefer other PBS-listed options.
Main points opposed:
  • Orphenadrine is potentially very toxic in overdose.
  • Orphenadrine has very limited role in pain management,[39][40] poor efficacy and patients rapidly develop tolerance to this medicine.
  • Orphenadrine has significant abuse potential and Inclusion in schedule 3 would allow greater access to orphenadrine for inappropriate use.
  • Clinical toxicology and poison information units have experienced an increase in presentations with orphenadrine ingestion in recent years as the management of chronic pain turns its focus onto alternatives to opioids.
    • In the period 6/1/14 to 27/9/17 there have been 45 deliberate self-poisonings, 16 therapeutic errors and 11 accidental exposures involving orphenadrine.
    • Anecdotal recount from a pharmacist who has encountered a patient who had overdosed on orphenadrine resulting in ischaemic bowel and the formation of a stoma.
  • Within the group of anticholinergic medications it appears to have the greatest risk of death as a result of ventricular dysrhythmias, respiratory depression, seizures and hypoglycaemia. [41] Orphenadrine is over represented in deaths when compared to other antimuscarinics or antipsycotics.
    • 71.5 deaths per million prescriptions compared to 0-6.1 deaths per million prescriptions for other anticholinergics.[42]
  • Orphenadrine is not a high volume prescription item, and given that those who would benefit from it have conditions which should require medical management, there is no rationale for a proposal to down schedule.

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

Summary of ACMS advice to the delegates

The committee recommended that the current scheduling of orphenadrine remains appropriate.

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:

  1. the risks and benefits of the use of a substance:
  • Risks: there is significant abuse potential, increased occurrence of abuse episodes, OD-induced deaths, adverse cardiac events, drug-drug interactions, and incompatible pharmacokinetics with other drugs. There is also a lack of efficacy for certain claims for indications.
  • Benefit: There is modest evidence of support as a skeletal muscle relaxant.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • It is not a realistic alternative for those in whom NSAIDs are contraindicated or precautioned (e.g. those over 65) because this same group is also the most sensitive to the anticholinergic adverse effects of orphenadrine.
    • Orphenadrine is claimed to be useful for painful conditions where muscle spasm is a component of the pain, such as sprains and strains, sports muscle injuries, whiplash, lower back ache and tension headaches. It is noted that there are no specific data on efficacy for most of these conditions.
  • the toxicity of a substance:
    • There are documented cases of child poisoning with significant toxicity at doses of 6 tablets, and has been associated with fatalities in overdose (e.g. 80 fatalities in Sweden). For overdose, there is evidence that orphenadrine is more toxic than other anticholinergic drugs (Buckley and McManus 1998), and many fatalities have been reported (Jonsson et al., 2004). Orphenadrine has also caused fatalities in children after accidental ingestion.
    • Orphenadrine contributes to the anticholinergic burden.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Because of the potential toxicity for children of orphenadrine products, these products need to be presented in child-resistant packing.
    • The evaluator noted the applicant’s statement that ingestion of 24 tablets as a single dose would have minimal potential for harm was incorrect, as 10.8 g of paracetamol could lead to serious or fatal hepatotoxicity, even in adults.
    • The total content of 840 mg orphenadrine could cause serious problems in children (Van Herrewhege et al., Intensive Care Med 1999; Garza et al., Pediatr Emerg Care 2000).
  • the potential for abuse of a substance:
    • There are some case reports of dependency and abuse (Shariatmadari, BMJ1975; Schifano et al., South Med J 1988; Mugglestone, Lancet 1985), but it does not appear to be a commonly abused substance. With wider use, if there were greater ease of access, this may change.
  • any other matters that the Secretary considers necessary to protect public health
    • The product has not been fully evaluated based on contemporary standards.
    Delegate's considerations

    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)
    Delegate's interim decision

    The delegate’s interim decision is that the current scheduling of orphenadrine remains appropriate.

    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; (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 recommendation comprised the following:

    1. the risks and benefits of the use of a substance:
    • Risks: there is significant abuse potential, increased occurrence of abuse episodes, OD-induced deaths, adverse cardiac events, drug-drug interactions, and incompatible pharmacokinetics with other drugs. There is also a lack of efficacy for certain claims for indications.
    • Benefit: There is modest evidence of support as a skeletal muscle relaxant.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • It is not a realistic alternative for those in whom NSAIDs are contraindicated or precautioned (e.g. those over 65) because this same group is also the most sensitive to the anticholinergic adverse effects of orphenadrine.
    • Orphenadrine is claimed to be useful for painful conditions where muscle spasm is a component of the pain, such as sprains and strains, sports muscle injuries, whiplash, lower back ache and tension headaches. It is noted that there are no specific data on efficacy for most of these conditions.
  • the toxicity of a substance:
    • There are documented cases of child poisoning with significant toxicity at doses of 6 tablets, and has been associated with fatalities in overdose (e.g. 80 fatalities in Sweden). For overdose, there is evidence that orphenadrine is more toxic than other anticholinergic drugs (Buckley and McManus 1998), and many fatalities have been reported (Jonsson et al., 2004). Orphenadrine has also caused fatalities in children after accidental ingestion.
    • Orphenadrine contributes to the anticholinergic burden.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Because of the potential toxicity for children of orphenadrine products, these products need to be presented in child-resistant packing.
    • The evaluator noted the applicant’s statement that ingestion of 24 tablets as a single dose would have minimal potential for harm was incorrect, as 10.8 g of paracetamol could lead to serious or fatal hepatotoxicity, even in adults.
    • The total content of 840 mg orphenadrine could cause serious problems in children (Van Herrewhege et al., Intensive Care Med 1999; Garza et al., Pediatr Emerg Care 2000).
  • the potential for abuse of a substance:
    • There are some case reports of dependency and abuse (Shariatmadari, BMJ1975; Schifano et al., South Med J 1988; Mugglestone, Lancet 1985), but it does not appear to be a commonly abused substance. With wider use, if there were greater ease of access, this may change.
  • any other matters that the Secretary considers necessary to protect public health
    • The product has not been fully evaluated based on contemporary standards.

    Footnotes

    1. Chou R, Peterson K, Helfand M. (2004). Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. Aug;28(2):140-75
    2. Richards BL, Whittle SL, Buchbinder R. (2012). Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. Jan 18;1:CD008922
    3. Dawson AH. Antimuscarinic drugs in Dart RC (ed). Medical Toxicology 3rd Ed.
    4. Buckley and McManus (1998) ‘Fatal toxicity of drugs used in the treatment of psychotic illnesses’, Br J Psychiatry, 172, 461

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