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Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

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4.2 Fexofenadine

Part A - Final decisions on matters referred to an expert advisory committee

4. Scheduling proposals referred to the July 2016 meeting of the Advisory Committee on Medicines Scheduling (ACMS#18)

4.2 Fexofenadine

Note

  • Red strikethrough text indicates text that has been deleted.
  • Green italicised text indicates text that has been added.
Referred scheduling proposal

An application was submitted to increase the pack size of unscheduled fexofenadine when in divided preparations for the treatment of seasonal allergic rhinitis (SAR) in adults and children 12 years of age and over when labelled with a recommended daily dose not exceeding 120 mg of fexofenadine from not more than 5 days' supply to not more than 10 days' supply.

Scheduling application

General application.

The applicant's proposed amendments to the SUSMP are as follows:

Schedule 4 - Amend Entry

FEXOFENADINE except:

  1. when included in Schedule 2; or
  2. in divided preparations for oral use for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
    1. in a primary pack containing 10 20 dosage units or less and not more than 5 10 days' supply; and
    2. labelled with a recommended daily dose not exceeding 120 mg of fexofenadine.

Schedule 2 - Amend Entry

FEXOFENADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:

  1. in a primary pack containing 10 20 dosage units or less and not more than 5 10 days' supply; and
  2. labelled with a recommended daily dose not exceeding 120 mg of fexofenadine.

The applicant's reasons for the request are:

  • With a well-defined risk profile, fexofenadine has been made available through grocery channels in many markets including Australia, UK, USA and NZ for a number of years;
  • In other markets including the USA, both larger pack sizes and higher strengths (180mg) of fexofenadine are available through grocery channels with no evidence of any impact on the overall benefit/risk profile;
  • This supports the proposal to revise the scheduling exemption conditions in Australia to allow consumers to benefit from the flexibility and convenience of access to larger packs, noting the proposed pack size still remains small;
  • The benefits of a larger pack include having a more portable pack size for travel or work purposes as a 'top up' or to be 'on hand' to be able to relieve symptoms immediately exposure to a trigger is experienced; supporting treatment for multiple family members or for those sufferers experiencing intermittent episodes over a longer period;
  • Larger pack sizes also help to decrease the economic burden of SAR considering sufferers can be exposed to allergens that trigger symptoms throughout the season and require ongoing relief; and
  • A benefit-risk profile for unscheduled fexofenadine was completed which confirmed that the proposed increase in pack size had no impact on the existing favourable benefit-risk profile for unscheduled fexofenadine.
Substance summary

Fexofenadine hydrochloride is an equimolar mixture of two enantiomers. A summary of its chemical properties are described below in Table 4.2 and its structure is shown in Figure 4.2.

Table 4.2: General information for fexofenadine
INN/BAN Fexofenadine hydrochloride
Chemical name benzeneacetic acid, 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1- piperidinyl]butyl]-a, a-dimethyl-, hydrochloride
Molecular formula C32H39N04 HCl
Molecular Weight 538.12
CAS No. 153439-40-8

Figure 4.2: Structure of fexofenadine

Figure 4.2: Structure of fexofenadine

Fexofenadine is an orally active non-sedating antihistamine with selective peripheral H1-receptor antagonist activity. It is a pharmacologically active carboxylic acid metabolite of terfenadine. Both enantiomers of fexofenadine hydrochloride display approximately equipotent antihistaminic effects. It has a rapid onset and long duration of action after oral administration. Further information on the pharmacology and mechanism of action of fexofenadine is included in the approved Product Information.

Specific questions raised by the delegate

The delegate asked the committee whether it is appropriate to increase the pack size of unscheduled fexofenadine to allow a maximum of 10 days' supply and whether there are increased benefits compared with risks with increasing the pack size.

Current scheduling status

Fexofenadine is currently listed in Schedules 4 and 2.

Schedule 4

FEXOFENADINE except:

  1. when included in Schedule 2; or
  2. in divided preparations for oral use for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
    1. in a primary pack containing 10 dosage units or less and not more than 5 days' supply; and
    2. labelled with a recommended daily dose not exceeding 120 mg of fexofenadine.
Schedule 2

FEXOFENADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:

  1. in a primary pack containing 10 dosage units or less and not more than 5 days' supply; and
  2. labelled with a recommended daily dose not exceeding 120 mg of fexofenadine.

It is also included under the entry for antihistamines in Appendix F as follows:

Appendix F, Part 3

ANTIHISTAMINES not separately specified in this Appendix except:

  1. dermal, ocular, parenteral and paediatric preparations;
  2. oral preparations of astemizole, desloratadine, fexofenadine, loratadine or terfenadine;
  3. nasal preparations of azelastine; or
  4. preparations for the treatment of animals

Warning statements: 39 (This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.) or 40 (This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a motor vehicle or operate machinery).

Relevant scheduling history
National Drugs and Poisons Schedule Committee: May & August 1996

In May and August 1996, the NDPSC considered a request to initially schedule fexofenadine as per terfenadine (Schedule 3). It was agreed that as there was insufficient evidence to make a decision in regard to the toxicity of fexofenadine, a Schedule 4 entry was appropriate at that time. This scheduling was reconsidered in November 1996, where the NDPSC noted additional safety data, and decided that oral divided preparations of fexofenadine should be included in Schedule 3.

National Drugs and Poisons Schedule Committee: February 1997

In February 1997, the NDPSC considered a post-meeting request for a temporary Schedule 4 entry for all pack sizes so that the initial availability of fexofenadine would be under greater control. However, the NDPSC noted that a major reason for its November 1996 Schedule 3 decision was that it had been satisfied that the available evidence indicated that fexofenadine was a safer drug than the prodrug, terfenadine. The NDPSC agreed that the decision to include fexofenadine as Schedule 3 remained appropriate.

National Drugs and Poisons Schedule Committee: August 1998

In August 1998, the NDPSC agreed that it was appropriate for fexofenadine to be included in Appendix H.

National Drugs and Poisons Schedule Committee: November 1998 & February 1999

In November 1998 and February 1999, following recommendations from the Trans-Tasman Harmonisation Working Party, the NDPSC agreed to reschedule fexofenadine from Schedule 3 to Schedule 2. The New Zealand and Australian entries for fexofenadine were then harmonised in November 1999.

National Drugs and Poisons Schedule Committee: October 2009 & February 2010

In October 2009, the NDPSC considered a request to exempt oral fexofenadine from scheduling for the short term treatment of SAR. The NDPSC decided that the current scheduling of oral fexofenadine (Schedule 2) remained appropriate. In February 2010, the NDPSC considered the same request referred from the NZ Medicine Classification Committee along with pre-meeting submissions and again decided that the current scheduling of fexofenadine remained appropriate.

Advisory Committee on Medicines Scheduling: February 2011

In February 2011, the ACMS considered a submission for exemption from scheduling requirements for oral fexofenadine (maximum 10 dosage units) when used for the short-term symptomatic relief (maximum 5 days of therapy) of SAR)\ in adults and children 12 years and over, with a maximum daily dose of 120 mg. The committee recommended that fexofenadine be exempt from scheduling when for the short-term symptomatic relief of SAR in adults and children 12 years of age and over when sold in small packs of 10 dosage units or less (i.e. not more than 5 days’ supply at the current maximum recommended dose) with a maximum daily dose of 120 mg.

Pre-meeting public submissions

Three (3) public submissions were received.

One submission supported the proposal. The main points were:

  • Given fexofenadine is used for the treatment of SAR, a patient could benefit from the proposal to increase pack size, as SAR typically can last up to 10 days. If SAR is left untreated, the patient’s quality of life may be reduced;
  • From a public health benefit perspective, it is logical that the pack size increases from a 5 day supply to a 10 day supply (containing 20 units or less) for unscheduled fexofenadine, as typically SAR can last up to 10 days;
  • Patients already have an awareness of their allergic conditions (particularly with SAR) and/or knowledge of how to manage these allergies with little help or counselling from a pharmacist or doctor;
  • Second generation antihistamines including fexofenadine, loratadine and cetirizine are a class of medicines that have been deemed safe and effective. They are considered low risk, have similar safety and efficacy profiles, similar indications and are well tolerated. Consideration should also be given to all other second generation antihistamines where pack sizes are limited to a 5 day supply, e.g. 10 mg cetirizine;
  • While cetirizine includes a sedation warning according RASML and fexofenadine does not, it is well known that the sedation effect of cetirizine is mild to moderate;
  • In New Zealand and Canada, cetirizine is considered to be non-drowsy at a maximum daily dose of 10 mg and have acknowledged that fexofenadine, loratadine and cetirizine 10 mg warrant the same labelling warnings with respect to sedation;
  • Since cetirizine was down-scheduled to general sale, there has been no evidence to inappropriate or unsafe use. The submission believes this to be the same for other second generation antihistamines. Based on the pharmacology of the molecules in this class of medicine, it is assessed to have a very low abuse potential and is not expected to increase with a pack size increase; and
  • The inclusion of appropriate warnings in the labelling of all second generation antihistamines prevents consumers from using it in clinical settings where such use is not advised.

Two (2) submissions opposed the proposal. The main points were:

  • The current availability of small packs sufficiently accommodates the needs of consumers who may require rapid and short term relief and an increase is not warranted from a perspective of good clinical practice and optimal therapeutic outcomes;
  • Irrespective of fexofenadine's reasonable safety profile, there are still public risks associated with its use; and
  • It is not in the public interest to further increase the scheduling exemption to allow longer doses of fexofenadine to be available in general retail where there is no access to health professional advice.

The public submissions are available on the TGA website.

Summary of ACCS advice to the delegate

The committee advised that the proposal to down-schedule fexofenadine was appropriate.

The ACMS advised an implementation date of 1 February 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.

The reasons for the advice included:

  • Lack of sedative effects. Low abuse potential. Ease of accessibility, consumer preference. Increase in pack size will support sufferers of seasonal allergic rhinitis (SAR) requiring more accessible, flexible and convenient pack size to self-manage their condition;
  • Non-use of alternative treatments, misdiagnosis, potential use for other allergic disorders;
  • Seasonal allergic rhinitis (SAR) can last up to 10 days;
  • Fexofenadine has a wide therapeutic index and well-established toxicity profile. Has been shown to be safe at dosages of 800mg/day, which is six times the dose recommended for treatment of SAR;
  • Current dosage, formulation, labelling and packaging for unscheduled fexofenadine remains unchanged except for the increase in pack size;
  • The proposed increase pack size of fexofenadine would retain the statement to seek medical advice if symptoms persist after 5 days to ensure any consumers who may not be experienced users or who have not previously used it to mitigate the potential for misdiagnosis of any underlying serious symptoms;
  • Seasonal allergic rhinitis (SAR) is a common, easily identified condition that is appropriate for self-management. Non treatment of SAR can affect a sufferer's quality of life; and
  • The number of adverse events recorded on the TGA's Database of Adverse Event Notifications for the period before and after the availability of unscheduled fexofenadine show an unchanged safety profile.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015); and
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, the ACMS advice and reasons to amend the Schedule 4 and Schedule 2 entries for fexofenadine. Seasonal allergic rhinitis (SAR) is a common, easily identified condition that is appropriate for self-management where non treatment can affect a sufferer's quality of life. Given fexofenadine’s lack of sedative effects and low abuse potential, the increase in pack size will support sufferers of SAR who require more accessible, flexible and convenient pack size to self-manage their condition.

The proposed implementation date is 1 February 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; (d) the dosage, formulation, labelling, packaging and presentation of a substance.

Schedule 4 - Amend Entry

FEXOFENADINE except:

  1. when included in Schedule 2; or
  2. in divided preparations for oral use for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
    1. in a primary pack containing 20 dosage units or less and not more than 10 days' supply; and
    2. labelled with a recommended daily dose not exceeding 120 mg of fexofenadine.
Schedule 2 - Amend Entry

FEXOFENADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:

  1. in a primary pack containing 20 dosage units or less and not more than 10 days' supply; and
  2. labelled with a recommended daily dose not exceeding 120 mg of fexofenadine.
Public submissions on the interim decision

No public submissions were received regarding the interim decision for fexofenadine.

Delegate's final decision

The delegate has confirmed the interim decision as no new evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.

The implementation date is 1 February 2017.

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