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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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1.7. Loratadine

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

1.7. Loratadine

Referred scheduling proposal

An application was submitted to exempt loratadine from scheduling when10 mg or less in divided preparations for oral use in packs containing not more than 5 dosage units when used in children 6 -12 years of age for the treatment of seasonal allergic rhinitis.

Current scheduling status

Loratadine is in Schedules 4 and 2, and in Appendix F, Part 3 of the Poisons Standard as follows:

Schedule 4

LORATADINE 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
    2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.

Schedule 2

LORATADINE 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
  2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.

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).

Scheduling history

At the May 1992 NDPSC meeting, the Committee recommended Loratadine be included in Schedule 4.

In November 1992 the NDPSC declined to down schedule loratadine to Schedule 3 due to concerns about cardiac side effects.

In April 1994, the NDPSC rescheduled loratadine tablets to Schedule 3.

In November 1995, the NDPSC rescheduled loratadine syrup to Schedule 3.

In May 1997, the NDPSC deferred a down-scheduling application for loratadine from Schedule 3 to Schedule 2, due to an article that was published in the Lancet, raising concerns of cardiovascular safety.

In August 1997 meeting, the NDPSC confirmed the current Schedule 3 entry.

Loratadine, cetirizine and fexofenadine were included in Appendix H in August 1998.

In February 1999, the NDPSC considered the rescheduling of loratadine from Schedule 3 to Schedule 2. The NDPSC agreed that loratadine in preparations for oral use should be rescheduled, and that the restriction to 'only therapeutically active ingredient' should no longer apply.

In November 1999, the NDPSC supported a recommendation from the Trans-Tasman Harmonisation Working Party (TTHWP) that on the grounds of harmonisation cetirizine in preparations for oral use be rescheduled from Schedule 3 to Schedule 2. As a consequence of the deletion of the Schedule 3 entry was the deletion of the Appendix H (Schedule 3 Poisons permitted to be advertised) entry.

In October 2005, the NDPSC agreed to alter the wording of Appendix F Part 3 and remove cetirizine for oral use (except when included in Schedule 2) from Appendix K of the Poisons Standard. As the balance of current evidence indicates that cetirizine is no more sedating than loratadine.

In February 2012, the Advisory Committee of Medicines Scheduling recommended exempting from scheduling oral preparations containing 10 mg or less of loratadine in packs containing not more than five dosage units for the treatment of seasonal allergic rhinitis in adults and children over the age of 12 years. The scheduling delegate agreed with the ACMS advice, and implemented this decision on 22 November 2012.

In July 2013, the ACMS considered a proposal to reschedule loratadine from Schedule 2 to unscheduled in oral preparations containing 10 mg or less in packs containing not more than 5 daily doses for the treatment of seasonal allergic rhinitis in adults and children 6 years of age and over, with a warning label recommending a daily dose not exceeding 10 mg loratadine for adults and children with body weight over 30 kg, or recommended daily dose not exceeding 5 mg loratadine for children with body weight 30 kg and under. The Committee recommended that the current scheduling of loratadine remained appropriate, due to the risk of inappropriate use and delay in correct diagnosis, the lack of data on adverse effects/experiences/poisoning in Australia, no substantial public health benefit in exempting from schedules and a complicated dosage regimen with risk of inappropriate dosing.

In March 2016, the ACMS considered the proposal to amend the schedule entries to increase the pack size of exempted loratadine from five dosage units to 10 dosage units. The scheduling delegate agreed with the advice from the ACMS and set an implementation date of 1 October 2016.

Scheduling application

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

LORATADINE 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 for children 12 years and over; or
    2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.
  3. in a primary pack containing 5 dosage units or less when labelled for children 6-12 years; and
    1. labelled with a recommended daily dose not exceeding 10 mg loratadine for adults and children over 9 years of age, and
    2. labelled with a recommended daily dose not exceeding 5 mg

Schedule 2 - Proposed Amendment

LORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis when:

  1. in a primary pack containing 10 dosage units or less when labelled for children 12 years and over; and or
  2. labelled with a recommended daily dose not exceeding 10 mg of loratadine in a primary pack containing 5 dosage units or less when labelled for children 6-12 years; and
    1. labelled with a recommended daily dose not exceeding 10 mg of loratadine for adults and children over 9 years of age, and
    2. labelled with a recommended daily dose not exceeding 5 mg loratadine for children 6-9 years of age.

The applicant's reasons for the request are:

  • Allergic rhinitis is a symptomatic disorder of the nose induced by inflammation, with symptoms of nasal drainage, nasal congestion, sneezing and/or nasal itching. Allergic rhinitis is a common condition affecting children. In Australia, about 12-20% of children aged 6-14 years are affected and the prevalence could be up to 35-47% in some areas. Allergic rhinitis significantly impacts the health and quality of life in children and their carers. It reduces school attendance, impairs cognitive functioning and reduces learning ability and represents a large public health burden associated with significant healthcare costs.
  • Allergic rhinitis is readily self-diagnosed by consumers and can be seasonal or perennial. SAR is caused by an IgE-mediated reaction to seasonal aeroallergens such as pollens. This reaction leads to typical symptoms such as sneezing and nasal congestion and is readily able to be identified. Most Australian adults now self-medicate for allergic rhinitis. The diagnosis and treatment of allergic rhinitis in children follows essentially the same pattern as that in adults other than in children younger than 2 years who may be referred to an allergist/immunologist for diagnosis and subsequent management. An April 2015 XXXX consumer study shows that Australian consumers purchase loratadine products for self-treatment including parents and carers who buy products for children.
  • Second generation non-sedating antihistamines including loratadine, fexofenadine and cetirizine have been proven efficacious and safe for the control of SAR and are recommended as first line treatment for mild to moderate allergic rhinitis in both adults and children. To date in Australia, second generation non-sedating antihistamines are only available for children 12 years and over outside of pharmacies. This leaves an entire class of efficacious and safe medications unavailable for children under 12 years of age other than via pharmacy. This is in contrast to similar countries such as the UK and the USA where these medications have been freely accessible outside of pharmacies for children 2 years and over for more than 10 years.
  • Loratadine is one of the leading second generation non-sedating antihistamines and is widely regarded as a safe and efficacious treatment for the symptoms of allergic rhinitis in children 12 months of age and over. Loratadine as an effective first line treatment for the symptoms of seasonal allergic rhinitis has been available for children 12 months and over in Australia since 1992, and it has been available as an unscheduled medicine in small packs of 5 tablets and capsules for children 12 years and over since 2012. With a long history of use in young children in Australia, access to loratadine only via pharmacy for children under 12 years of age presents a gap in access for affected children and their carers.
  • Access to medicines can be restricted in terms of location and opening hours of community pharmacies in Australia. Non-pharmacy outlets such as supermarkets and local convenience stores are generally more accessible as there are many more outlets available, and they generally operate over longer trading hours. It is convenient for consumers to purchase a product suitable for their minor health condition from supermarkets or other convenience stores rather than only in pharmacies, especially for fast relief of symptoms. Increased access of a second generation non-sedating antihistamine like loratadine for children under 12 years of age outside of pharmacies will assist parents and carers and improve public health outcomes.
  • The symptoms of SAR typically appear during the hayfever season when aeroallergens are abundant. The length of seasonal exposure to these aeroallergens is dependent on geographic location and climatic conditions, and can last for several months of the year in Australia. The flexibility of the antihistamine treatment loratadine which is used on an 'as needed' basis provides convenient self-medication during the hayfever season, especially for those with episodic or intermittent symptoms which may be triggered by the aeroallergens at any time during the season and last for weeks. Loratadine, with minimal toxicity compared to other medications, is an ideal candidate for rescheduling to an unscheduled medicine in a small pack of 5 dosage units for episodic treatment of symptoms in younger children during the hayfever season.
  • The symptoms of SAR are easily recognised because of the rapid and reproducible onset and offset in association with pollen exposure, which are not likely to be indicative of a more serious underlying diagnosis. The seasonal nature of the symptoms leads to easy recognition by sufferers and carers, largely negating the need for professional advice. The rescheduling of loratadine from Schedule 2 to unscheduled in 2012 has shown that the risks of misdiagnosis or masking of underlying diseases are minimal. The proposed unscheduled loratadine products for children 6-12 years of age will retain the same label statements as the existing loratadine unscheduled product for use in children 12 years and over and will contain the same medical and safety information to ensure the safe use of the medication outside of pharmacies is continued in this age group. XXXX also proposes to include an additional label statement to the effect of 'Do not use this product when experiencing first-time hayfever symptoms without advice from a healthcare professional' to minimise any potential risk of misdiagnosis or delay in diagnosis in this particular age group.
  • Loratadine is considered to be a 'second generation non-sedating antihistamine' with an excellent safety profile. The toxicity and safety of loratadine has been well established with over more than 20 years of use in Australia and internationally including use in children as young as 12 months of age.
  • Loratadine has a safety profile similar to that of placebo, does not potentiate the CNS effects of alcohol or diazepam and there have been no reports of clinically significant interactions between loratadine and drugs such as erythromycin, cimetidine and ketoconazole. Loratadine has a similar safety profile in children; the incidence of loratadine associated adverse effects in children appears to be similar to placebo.
  • Loratadine has a wide therapeutic index with no unusual neurological symptoms or signs of toxicity in cases of accidental overdose. In volunteer studies, single doses of loratadine up to 160 mg were administered without any untoward effects. Loratadine is not associated with cardiovascular toxicity. Children who accidentally ingest large quantities of loratadine (up to 40 mg) have tolerated this well and can be adequately managed at home.
  • Loratadine is generally safe for use in children 12 months of age and older. The types and frequencies of adverse events reported in children are consistent with those reported in adults with no increased risks identified in children. Only a few adverse events in children have been reported in Australia. The availability of unscheduled loratadine products in Australia since 2012 has not resulted in any safety concerns, providing confidence that the quality use of loratadine for children 6-12 years purchased in non-pharmacy outlets in small packs can be achieved by appropriate labelling and packaging.
  • A simple age-based dosing instruction for children is proposed to ensure easy administration to children without healthcare professional advice. Current Schedule 2 loratadine medicines marketed for children in the age group of 6-12 years has an age and body weight based dosing instruction (10 mg for children 2 years and over with a body weight over 30 kg, and 5 mg for children 2-12 years of age with a body weight up to 30 kg). In a previous submission to the ACMS in July 2013, this age and body weight dosing regime was deemed too complicated for self-medication without healthcare professional assistance. Age-only dosing instructions, which are based on the evidence that the average Australian child with a body weight of 30 kg is around 9.5 years of age is proposed to ensure that the dosing is effective and safe and dosing instructions are clear and can be followed by parents and carers easily without professional advice. Proposed dosage instructions are as follows: Children 6-9 years: 1 tablet once daily as necessary Children 9-12 years and Adults: 2 tablets once daily as necessary. The proposed labelling will also state "Do not use more than the recommended dose".
  • Given the evidence that loratadine has a well-established safety profile, and the risk of misuse and inappropriate use is rare, it is considered that an unscheduled pack size containing 5 dosage units of loratadine for children 6-12 years of age presents minimal risk to children while increasing the availability of an efficacious second generation non-sedating antihistamine.
  • In countries with a similar regulatory system to Australia such as the UK and the USA, loratadine has been available for many years for children as an unscheduled medicine at a much younger age (2 years and over) with wider therapeutic indications SAR, perennial allergic rhinitis and chronic urticaria) with either no pack size restrictions or in larger pack sizes than in Australia. In the USA, loratadine in both solid and liquid forms is approved in OTC medications (equivalent to unscheduled medicines in Australia) for children 2 years and over without any pack size limitations. In the UK both solid and liquid forms of loratadine have been approved for children 2 years and over in large pack sizes (tablets 30 packs; liquids 70 mg) since 2012.
Australian regulatory information

The Australian Register of Therapeutic Goods (ARTG[28]) has fifty (50) entries for products containing loratadine listed. The products are marketed towards both adults and children's use and come in a range of dosage forms including, 1 mg/1 mL liquid (flavoured), 10 mg tablets and capsules, 5 mg chewable tablets, 10 mg orally disintegrating tablet and 10 mg liquid capsules. In addition there are combination products such as loratadine 5 mg with 120 mg pseudoephedrine sulphate.

A search on the Database of Adverse Event Notifications list (DAEN) for dates between January 1992 and August 2016 returned 815 reported cases of adverse events related to loratadine. 710 of the cases were from a single suspected medicine. Four (4) cases were reported to have resulted in death from cardiac arrest (1), hypoxia (1), haematuria (1), and electrocardiogram abnormal (1)[29].

No reference to loratadine has been provided for in S26BB, as loratadine is a scheduled ingredient and not eligible for use in listed medicines.[30]

International regulations

Globally, loratadine-containing products are marketed in over 110 countries as a safe and effective non-sedating antihistamine for the treatment of allergic rhinitis and allergic skin disorders for adults and children.

Loratadine is available OTC in many countries. In 2 countries (Italy and Czech Republic) there is a pack size limit of 7 days' supply while in others the pack size limit is 10, 14, 30, 70 or unlimited.

In the UK, loratadine tablets have been available as an unscheduled medicine since 2002 in packs containing 7 dosage units for the symptomatic relief and treatment of seasonal allergic rhinitis, perennial allergic rhinitis and chronic urticaria in adults and children. The current unscheduled pack size limit for loratadine tablets is 30 dosage units when used for the symptomatic relief and treatment of seasonal allergic rhinitis, perennial allergic rhinitis and chronic urticaria in adults and children 2 years and over and weighing more than 30 kg. Liquid dosage forms are also available unscheduled for children 2 years and over with a pack size limit of 70 mg.

In the USA, loratadine was first approved for OTC use (equivalent to unscheduled in Australia) in 2002 in tablet (including orally disintegrating tablets) and syrup forms for children 2 years and over for hayfever or other upper respiratory allergies without pack size limitations. In 2006, loratadine in chewable tablets and orally disintegrating tablets (5 mg) was further approved for OTC use for when used in children 2 years and over for the symptoms of hayfever or other upper respiratory allergies without pack size limitation.

Health Canada list 17 loratadine products in various dose rapid dissolve 5mg, 10 mg liquid capsule, tablets, capsules and 0.5 mg / mL oral syrup[31].

The New Zealand Medicines Classification Committee (MCC) at its November 2011 meeting recommended that loratadine be reclassified as a general sale (exempt from scheduling). Medsafe New Zealand regulates loratadine[32] in 10 mg oral divided solid dosage forms as general sale in pack sizes under 10 day supply, other oral dose forms are pharmacy medicines containing not more than 10 day supply. Products outside these restrictions are prescription products.

Substance summary

Loratadine is a white to off-white crystalline powder. It is freely soluble in methanol, ethanol and chloroform, soluble in ether and practically insoluble in water. The molecular weight of loratadine is 352.9, molecular formula C22H23ClN2O2.

Figure 1.7: Structure of loratadine

Figure 1.7: Structure of loratadine

Loratadine is a potent, long-acting tricyclic antihistamine with selective peripheral H1-receptor antagonistic activity. Its efficacy as a first line treatment for the symptomatic treatment of allergic rhinitis and allergic skin conditions such as urticaria (hives) has long been established. This once a day treatment for effective control of allergic rhinitis has been available in Australia and globally for more than 20 years. Loratadine has a rapid onset of action after oral administration, usually within one hour. Loratadine is well absorbed with peak plasma levels occurring at approximately 1-2 hours after dosing, and undergoes extensive first-pass metabolism to the active metabolite desloratadine and is then excreted in urine (~40%) and faeces (42%) in a 10 day period. Renal impairment has no significant effect on loratadine clearance.

Loratadine exhibits greater affinity for peripheral H1-receptors than for central H1-receptors, and loratadine and its metabolites do not readily cross the blood-brain barrier. These properties account for its lack of sedation compared to first generation antihistamines.

Once daily administration of loratadine at therapeutic doses, with or without erythromycin, does not induce adverse cardiac effects in children 5-12 years. No regulatory action has been taken world-wide since the launch of loratadine due to safety concerns. Safety data contained in Periodic Safety Update Reports (PSURs) demonstrates the overall benefit-risk balance for loratadine in children continues to be positive.

Pre-meeting public submissions

Three (3) submissions were received.

One (1) supported the scheduling proposal. Main points:

  • Loratadine has safety profile consistent with other similar substances on the market.

Two (2) did not support the scheduling proposal. Main points:

  • The proposition is not in the public interest for loratadine to be used in children under general retail availability.
  • Loratadine can have sedative-like effects. With the use of higher-than-recommended doses, there is an increased risk of impaired acuity and drowsiness, particularly in young children. Inappropriate use may result without professional advice.
  • The availability of different pack sizes based on age may cause confusion to consumers.

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

Summary of ACMS advice to the delegate

The committee advised that loratadine be exempt from scheduling in preparations containing loratadine 10 mg or less in divided preparations for oral use in packs containing not more than 10 dosage units when used in children 6 years of age for the treatment of seasonal allergic rhinitis.

Schedule 4 - Amend Entry

LORATADINE 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 6 12 years of age and over when:
    1. in a primary pack containing 10 dosage units or less; and
    2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.

Schedule 2 - Amend Entry

LORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis when:

  1. in a primary pack containing 10 dosage units or less when labelled for children 612 years and over; and
  2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.

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; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice comprised the following:

  • Loratadine for children has been available at the general sales level in both UK and USA since 2002, without increased adverse events.
  • Adults should be able to identify seasonal allergic rhinitis based on symptoms. Symptoms in children are no different to symptoms in adolescents or adults, for whom loratadine is already exempt from scheduling.
  • There are risks of delay in correct diagnosis in the younger age group, however risk of adverse outcomes as a result are relatively low, and there is a public health benefit in wider availability of a first line treatment for allergic rhinitis in children.
  • The risks can be limited by placing restrictions on the number of days of supply or number of units to an appropriate pack size and appropriate labelling.
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)
  • Other relevant information
Delegate's interim decision

The delegate's interim decision is to exempt loratadine from scheduling in preparations containing loratadine 10 mg or less in divided preparations for oral use in packs containing not more than 10 dosage units when used in children 6 years of age and over for the treatment of seasonal allergic rhinitis.

The proposed Schedule entry is as follows:

Schedule 4 - Amend Entry

LORATADINE 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 6 years of age and over when:
    1. in a primary pack containing 10 dosage units or less; and
    2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.

Schedule 2 - Amend Entry

LORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis when:

  1. in a primary pack containing 10 dosage units or less when labelled for children 6 years and over; and
  2. labelled with a recommended daily dose not exceeding 10 mg of loratadine.

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; 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.
  • Loratadine for children has been available at the general sales level in both UK and USA since 2002, without increased adverse events.
  • Adults should be able to identify seasonal allergic rhinitis based on symptoms. Symptoms in children are no different to symptoms in adolescents or adults, for whom loratadine is already exempt from scheduling.
  • There are risks of delay in correct diagnosis in the younger age group, however risk of adverse outcomes as a result are relatively low, and there is a public health benefit in wider availability of a first line treatment for allergic rhinitis in children.
  • The risks can be limited by placing restrictions on the number of days of supply or number of units to an appropriate pack size and appropriate labelling.

Footnotes

  1. Therapeutic Goods Administration Search results
  2. Database of Adverse Event Notifications - medicines
  3. Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2016
  4. Details for: ACTIVELLE LD
  5. Database of Medicine Classifications

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