1.4 Esomeprazole

On this page: Referred scheduling proposal | Scheduling application | Current scheduling status and relevant scheduling history | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegate | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted to down-schedule esomeprazole from Schedule 3 to Schedule 2 of the Poisons Standard in oral preparations containing 20 mg or less per dosage unit in packs containing not more than 14 days' supply and to delete the current Schedule 3 entry for esomeprazole.

Scheduling application

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

The applicant's reasons for the proposal are:

• Increasing the pack size limit of Schedule 2 esomeprazole from 7 to 14 days' supply will result in improved access to a safe and effective 14-day proton pump inhibitor (PPI) treatment course which is recommended as the initial therapy for frequent heartburn sufferers.
• For over 2 years, consumers in other comparable overseas countries such as the UK and US have been able to self-select 14 days' supply of PPIs. It would be appropriate for consumers in Australia to be afforded similar access to an effective treatment course within the pharmacy setting where support and advice from a pharmacist can be still be accessed as needed.
• Ranitidine, a histamine 2 receptor antagonist (H2RA) is currently available from the pharmacy for self-selection in packs containing 14 days' supply. Tolerance can develop with H2RAs resulting in a diminished therapeutic effect with continued administration, and resistance to increased doses of this class of medications.
• H2RAs are inferior in the inhibition of food stimulated acid secretion. In fact, only 15% of gastro-oesophageal reflux disease (GORD) patients treated with H2RAs achieve complete symptom relief. Of note, an Australian-based population study shows that a significant number of frequent heartburn sufferers are not satisfied with their treatment outcomes on H2RAs.
• The limitations of H2RAs underscore the need to improve access to a more effective PPI treatment course aligned with that already available for ranitidine.
• A clinical study evaluating the efficacy and quality of life (QOL) impact of a daily dose esomeprazole 20 mg clearly demonstrated that at this strength and dosing frequency, there are significant benefits regarding relief/reduction of both the frequency and severity of heartburn and acid regurgitation.
• Importantly, an improved QOL outcome (improved sleep quality, work productivity and functionality) resulting from the effective relief of the symptoms of heartburn and acid reflux was also clearly demonstrated.
• An Australian survey recently undertaken revealed that a significant proportion of consumers (61%) who purchased a 7-day pack of esomeprazole needed to be treated for longer than 7 days and had to go back to the pharmacy to obtain another pack. As a result, consumers are not currently afforded appropriate access to the recommended 14-day treatment regimen as initial therapy. The inconvenience of having to return to the pharmacy to purchase another pack may potentially result in less than optimal therapy for those who require 14-day treatment as initial therapy.
• Access to the 14-tablet pack of esomeprazole will be more cost-effective and convenient than access to two of the 7-tablet pack on separate occasions, for consumers requiring 14-day treatment as initial therapy.

Current scheduling status and relevant scheduling history

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

In November 2000, the National Drugs and Poisons Committee (NDPSC) considered a proposal to schedule esomeprazole in Schedule 4 of the Poison Standard. The committee supported this proposal based on esomeprazole being a new substance, and the indicated condition being one that requires medical management. The decision was further based on the grounds of harmonisation with New Zealand.

In November 2013, the Advisory Committee on Medicines Scheduling (ACMS) considered an application to down-schedule esomeprazole from Schedule 4 to Schedule 3 in oral preparations containing 20 mg or less per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply. The ACMS recommended the delegate to down-schedule esomeprazole to Schedule 3, as requested.

In March 2015, the ACMS delegate accepted a proposal to include esomeprazole in Appendix H.

In August 2015, the ACMS considered a proposal to down-schedule esomeprazole in oral preparations containing 20 mg or less per dosage unit in packs containing not more than 7 days' supply from Schedule 3 to Schedule 2. The delegate supported the proposal, and down-scheduled as requested.

Australian regulatory information

According to the TGA Ingredient Database - external site, esomeprazole is available for use as an:

• Active ingredient in biologicals and prescription medicines;
• Excipient ingredient in biologicals, devices and prescription medicines; and
• Equivalent ingredient in prescription medicines.

Esomeprazole (and its salts) is listed in 142 products on the Australian Register of Therapeutic Goods (ARTG). The dose forms approved include tablets, enteric coated tablets, enteric capsules, sachets of enteric coated granules for oral suspension and powder for injection. The ARTG also includes a listing for a composite pack, containing clarithromycin tablets, amoxicillin capsules and esomeprazole tablets.

n the last 20 years there have been 731 adverse event reports listed on the Database of Adverse Event Notifications - Medicines - external site: 523 cases with a single suspected medicine and 13 cases of death as a reported outcome. In the cases where the single medicine suspected was esomeprazole, reactions included: affect lability, arthralgia, dyspnoea, malaise, paraesthesia, abdominal pain, diarrhoea, nausea, hypoglycaemia, insomnia, aggression, agitation, confusion, depression, suicide attempt.

International regulations

USA

The USA down-scheduled esomeprazole from a prescription medicine to an over-the-counter medicine in 20 mg delayed release capsules/tablets in 2014.

Canada

Health Canada regulated esomeprazole as a prescription medicine until August 2016 when the first over-the-counter product was registered, and indicated for the treatment of frequent heartburn (heartburn occurring on 2 or more days of the week). The 20 mg capsules are provided in bottles of 14, contained in a carton with 1, 2 (total 28 capsules) or 3 bottles (total of 42 capsules).

New Zealand

In New Zealand, Medsafe lists esomeprazole as a prescription and pharmacy only medicine. The conditions for pharmacy only use are "n divided solid dosage forms for oral use containing 20 milligrams or less with a maximum daily dose of 20 milligrams for the short-term symptomatic relief of gastro-oesophageal reflux-like symptoms in sufferers aged 18 years and over when sold in the manufacturers original pack containing not more than seven dosage units".

United Kingdom

In 2014, the UK's government body The Medicines and Healthcare products Regulatory Agency (MHRA) reclassified esomeprazole from a pharmacy (P) medicine to a general sales list medicine (GSL) in the UK for the short-term treatment of reflux symptoms (e.g. heartburn and acid regurgitation) in adults.

Substance summary

Esomeprazole is a proton pump inhibitor (PPI) and is the S-isomer of the PPI omeprazole. It is optically stable in vivo, with negligible conversion to the R-isomer. Esomeprazole reversibly reduces gastric acid secretion by specifically inhibiting the gastric enzyme H+, K+-ATPase proton pump in the parietal cell.

Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretary canaliculi of the parietal cell, where it inhibits both basal and stimulated acid secretion.

Esomeprazole is acid labile and is therefore formulated as gastro-resistant enteric-coated pellets of esomeprazole magnesium trihydrate in tablets, capsules or granules for oral suspension. The enteric coating film, protecting the esomeprazole magnesium trihydrate, dissolves at a pH above 5.5. Hence, esomeprazole magnesium trihydrate is not released until the pellets are emptied into the duodenum.

Table 1.4.1: Chemical properties of esomeprazole

Property	Esomeprazole
CAS number	217087-09-7 (as magnesium trihydrate)
Chemical structure	(as magnesium trihydrate)
Molecular formula	C34H36N6O6S2Mg.3H2O (as magnesium trihydrate)
Molecular weight	767.2 g/mol (as magnesium trihydrate)
IUPAC and/or common and/or other names	di-(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium salt trihydrate

Pre-meeting public submissions

Five (5) submissions were received, two (2) in support and three (3) opposed.

Main points in support:

• The down-scheduling of a larger pack size will allow for better availability for non-prescription use via pharmacist advice.
• The side-effect profile of the medicine is well-known, and potential risk factors could be identified by the consumer through appropriate packaging and labelling. The quality use of the medicine can be facilitated through this same manner.
• The use of the medicine at established therapeutic dose levels is not likely to mask the symptoms of a serious condition or delay diagnosis.
• The inclusion of 14 days' supply of esomeprazole in Schedule 2 is consistent with current scheduling factors and comparable overseas regulations.

Main points opposed:

• The current arrangement as a Pharmacist Only Medicine allows the pharmacist to consider the therapeutic appropriateness of a 14 day treatment in the context of individual patient factors, and can recommend immediate referral if atypical or alarm symptoms are reported.
• It was flagged that the long term use of proton pump inhibitors (PPIs) is one of the top 5 tests, treatments or procedures which should be questioned by GPs and their patients. That statement is based on the evidence that a high proportion of patients are kept on maximal doses long term, and adverse effects of long term use include increased risk of gastrointestinal infection (incl. Clostridium difficile), community acquired pneumonia, osteoporotic fractures, interstitial nephritis, and nutritional deficiencies, particularly in the elderly or immunocompromised.
• Pharmacists are best-placed to identify risk factors and consider any lifestyle modifications that may enhance the outcomes of esomeprazole use.

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

Summary of ACMS advice to the delegate

The committee recommended that the Schedule 3 entry for esomeprazole in the Poisons Standard be deleted, and the Schedule 2 and Schedule 4 entries for esomeprazole be amended as follows:

The committee also recommended an implementation date of 1 February 2018.

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 were:

• Esomeprazole is a safe and effective first line treatment for the common symptoms of GORD and heartburn.
• A 14 day supply of esomeprazole in Schedule 2 better reflects the appropriate initial treatment duration for GORD.
• The majority of adverse effects of esomeprazole are mild and transient in nature and the safety and tolerability is well-established. The toxicity is low when used for 14 days at 20 mg. The risks are primarily associated with longer term use.
• A decrease in pharmacist advice may result in underlying conditions being undiagnosed or an overuse of the medicine. However, there is still access to a pharmacist as the proposed product is in Schedule 2 and therefore available in a pharmacy.
• The proposed pack size, labelling (including RASML warning statements) and provision of CMI will help ensure appropriate use of the 14 day pack size as a Schedule 2 medicine. Available information does not suggest that over-the-counter proton pump inhibitors use that is consistent with label instructions is associated with substantial health risks.
• Esomeprazole is a more effective treatment of GORD than ranitidine, which is currently available as an unscheduled medicine (seven days' supply) and as a Schedule 2 medicine (fourteen days' supply).

Delegate's considerations

The delegate considered the following regarding 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 down-schedule esomeprazole from Schedule 3 to Schedule 2 in oral preparations containing 20 mg or less per dosage unit in packs containing not more than 14 days' supply and to delete the current Schedule 3 entry. The proposed Schedule entry is:

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

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

The reasons for the interim decision are:

1. the risks and benefits of the use of a substance:
   • Esomeprazole is a safe and effective first line treatment for the common symptoms of GORD and heartburn.
   • Risks are primarily with longer term use.
   • Risk with lack of pharmacist discussion and advice may result in underlying conditions being undiagnosed and overuse.
   • Available information does not suggest that over-the-counter proton pump inhibitors use that is consistent with label instructions is associated with substantial health risks.
   • Benefit is that a 14 day supply of esomeprazole in Schedule 2 better reflects the appropriate initial treatment duration for GORD.
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • Heartburn and other symptoms of GORD are common.
3. the toxicity of a substance:
   • The safety and tolerability of esomeprazole are well‑established. The majority of adverse events are mild and transient in nature. Esomeprazole has low toxicity when used for 14 days' treatment at a dose of 20 mg per day. The risks are primarily associated with longer term use.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • The proposed pack size, labelling (including RASML warning statements) and provision of CMI will help ensure appropriate use of the 14 day pack size as a Schedule 2 medicine.
5. any other matters that the Secretary considers necessary to protect public health.
   • Esomeprazole is more effective in the treatment of GORD than ranitidine which is currently available as an unscheduled medicine (seven days' supply) and as a Schedule 2 medicine (in a pack containing 14 days' supply).
   • The available information does not suggest that over-the-counter proton pump inhibitor use that is consistent with label instructions is associated with substantial health risks.
   • Although a decrease in pharmacist advice may result in underlying conditions being undiagnosed or an overuse of the medicine. There is still access to advice from a pharmacist if the product is purchased from a pharmacy.