Consultation outcome

Nuromol public consultation document

Published 13 May 2021

Product details:

Product name: Nuromol Dual Action Pain Relief 200mg/500mg tablets

Active substances: ibuprofen/paracetamol

Licence holder: Reckitt Benckiser Healthcare (UK) Ltd

Route of sale/supply: Current: Pharmacy Medicine (P) Proposed: subject to general sale

Indication: Temporary relief of mild to moderate pain, which has not been relieved by ibuprofen or paracetamol individually, such as migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, cold and flu symptoms, sore throat and fever in adults 18 years and over.

Marketing Authorisation Number: PL 00063/0649

Consultation is open from: 13 May 2021 – 3 June 2021

Reference: ARM 100

Contact: reclassification@mhra.gov.uk

1. Background on deciding where medicines are available

The role of the MHRA

The MHRA regulates medicines and medical devices in the UK, on behalf of the UK Licensing Authority. This means that the MHRA decides whether medicines are available:

• on prescription only - ‘prescription only medicine’ (POM)
• bought from pharmacies - ‘pharmacy medicine’ (P)
• bought from other shops - ‘general sales list medicine’ (GSL)

Reclassification of a medicine

Making a change on where a medicine is available is called ‘reclassification’. This is sometimes referred to as ‘switching’. To decide on this change, the MHRA may:

• take advice from its committees of external experts
• take advice from a group (‘stakeholder group’) of health professionals and representatives of people affected by the classification change
• run a public consultation

When a medicine is reclassified, it is usual for reclassification from POM to P to occur in the first instance, and once some experience is gained with the product in the pharmacy (P) setting, further reclassification from P to GSL may occur. In some cases, a medicine may be reclassified directly from POM to GSL, where it meets the necessary requirements and it is safe to do so. To be reclassified directly from POM to GSL, a medicine must meet both the requirements of POM to P and P to GSL reclassification.

To be reclassified from POM to P a medicine must:

• be unlikely to be a direct or indirect danger to human health when used without the supervision of a doctor, even if used correctly
• be generally used correctly (ie not frequently or to a wide extent used incorrectly)
• not contain substances or preparations of substances where the activity of the product or its side effects require further investigation
• not normally be prescribed by a doctor for injection (parenteral administration)

To be reclassified from P to GSL, it must be demonstrated that the medicine may be supplied with reasonable safety in outlets other than in pharmacies. ‘Reasonable safety’ is defined as ‘Where the hazard to health, risk of misuse and need for special precautions in handling of the medicine are small, and where the wider sale would be a convenience to the purchaser’.

Evidence required

A company or organisation can ask the MHRA for a medicine to be available as a pharmacy medicine or a general sale medicine. To do this, they need to get together evidence to show that the medicine:

a) is likely to be used appropriately, and b) with relatively little danger to the public

This evidence needs to focus on the risk to the public. This includes evidence on the possible abuse or misuse of the medicine. The evidence may include:

• clinical studies
• evidence showing acceptable level of side effects
• advice of experts
• views of relevant health professionals and their professional bodies
• views of relevant public associations and individuals with an interest in the medicine under consideration

How a final decision is made

The final decision on whether to approve a change is made by the MHRA, on behalf of the UK Licensing Authority.

2. About Nuromol

Nuromol was classified as a P medicine in 2010 when it was first licensed. This application concerns its reclassification from P to GSLf.

Nuromol contains two active ingredients: ibuprofen and paracetamol.

Ibuprofen belongs to a group of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs). NASIDs work by reducing pain, reducing swelling and lowering high temperatures. Paracetamol is a painkiller that works in a different way to ibuprofen to relieve pain and fever.

Nuromol is intended to be used only after a person has tried either ibuprofen or paracetamol alone for the first day of treatment.

The Commission on Human Medicines has advised that this product can be made available from non-pharmacy outlets, such as supermarkets and corner shops, as a medicine subject to general sale. This report outlines the background to this decision. Please tell us your views by using the response form at the end of this document (Annex 1).

The patient information leaflet, label and summary of product characteristics are provided in Annex 2, Annex 3 and Annex 4.

This is the first time an application has been made for a product containing a combination of ibuprofen and paracetamol to be available as a medicine subject to general sale.

2.1 Information about Nuromol

Nuromol contains 200mg ibuprofen and 500mg paracetamol in each tablet.

2.2 How Nuromol is used

Nuromol is used for the temporary relief of mild to moderate pain, which has not been relieved by ibuprofen or paracetamol individually, such as migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, cold and flu symptoms, sore throat and fever in adults 18 years.

3. Proposal to make Nuromol available as a General Sales medicine

3.1 Proposal applicant

The Licence Holder/Marketing Authorisation Holder for Nuromol (Reckitt Benckiser Healthcare (UK) Ltd) has applied to make this product available through general sales outlets.

3.2 The view of the Commission on Human Medicines

The Commission on Human Medicines has advised that Nuromol can be available as a medicine subject to general sale. Views on the use of this medicine without availability of advice from a doctor or pharmacist for the temporary relief of mild to moderate pain which has not been relieved by ibuprofen or paracetamol individually were also sought from the Pharmacovigilance Expert Advisory Group (PEAG) . The views of the PEAG were summarised and provided for CHM when they considered the reclassification application.

3.3 Proposed terms of reclassification

Details of this change

The application proposes to make Nuromol available on general sale as follows:

• For oral use
• Strength: 200mg ibuprofen/500mg paracetamol
• For the temporary relief of mild to moderate pain, which has not been relieved by ibuprofen or paracetamol individually, such as migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, cold and flu symptoms, sore throat and fever in adults 18 years and over
• Dose: one – two tablets to be taken up to three times per day
• Maximum dose: two tablets (400mg ibuprofen and 1000mg paracetamol)
• Maximum daily dose: 6 tablets (1200mg ibuprofen and 3000mg paracetamol).
• Maximum pack size: 16 tablets

4. How the proposal for Nuromol being available as a medicine on general sale has been assessed

A medicine may be sold in general sales outlets in the absence of healthcare professional advice if it does not meet the criteria for classification as a Prescription Only Medicine and if it fulfils the criterion for general sales.

The criteria for Prescription Only classification are:

1. A direct or indirect danger exists to human health, even when used correctly, if used without medical supervision

2. There is frequently incorrect use which could lead to direct or indirect danger to human health

3. Further investigation of activity and/or side-effects is required

4. The product is normally prescribed for parenteral administration (by injection)

   In the UK, these criteria are laid down in the Human Medicines Regulations 2012, regulation 62(3).

The criterion for General Sales is:

The product can, with reasonable safety, be sold or supplied otherwise than by or under the supervision of a pharmacist.

The term “with reasonable safety” has been defined as: “where the hazard to health, the risk of misuse, or the need to take special precautions in handling is small and where wider sale would be a convenience to the purchaser”

In the UK, these criteria are laid down in the Human Medicines Regulations 2012, regulation 62(5).

Since Nuromol is already classified as a Pharmacy Medicine, the MHRA considered the application against the General Sales criterion.

4.1 Hazard to health

Products containing paracetamol and ibuprofen as single ingredients have been available as GSL medicines for over 50 years and 30 years respectively and the safety of the two ingredients is well known.

Six years of use of Nuromol as a P medicine in the UK did not identify any unknown and significant safety risks and data from New Zealand, where Nuromol has been classified as medicine that can be sold without prescription in non-pharmacy outlets, revealed that the incidence of Adverse Drug Reactions (ADRs) is low.

In addition, consideration was given to the following issues:

The risk that a person may confuse the product with paracetamol alone and take the standard paracetamol dose of 2 tablets four times a day.

This would result in a person taking 400mg/day more of ibuprofen than currently authorised as P or GSL, resulting in a total ibuprofen daily intake of 1600mg. This is within prescribing limits of a maximum daily dose of 2400mg. Even at the conservative estimate of toxicity (100mg/kg) a 60kg adult would need to take 30 tablets at once to overdose.

The risk of low body-weight adults (up to 50kg) using this product

In relation to the paracetamol content of the product, the concerns about paracetamol toxicity apply to all solid dose oral paracetamol products including those already available as GSL. Considering the intake of paracetamol alone, when using Nuromol, the maximum daily dose is 1g less than that of single ingredient paracetamol products licensed for the treatment of pain and classified as GSL.

In relation to taking paracetamol and ibuprofen in combination, there is no evidence to suggest that this will potentiate the toxic effects of paracetamol and there is a lower rate of reported adverse events with the combination compared with the individual actives alone.

Nuromol has a reduced dosage of paracetamol compared to solid dose oral paracetamol products that are already authorised with GSL classification and there is a lower rate of reported adverse events with the combination compared with the individual actives alone. It was concluded that the risk of low body-weight adults (up to 50kg) using this product is not greater than and possibly less than the risk with existing GSL paracetamol products.

Justification for the dosing of paracetamol in Nuromol (in particular maximum daily dose) which is not consistent with dosages of currently available paracetamol products

The clinical studies that were provided to support the original marketing authorisation have confirmed that the reduced daily dose for paracetamol is effective.

A reduced daily dose of paracetamol (3g) in the combined product could have the benefit of reducing the risk of paracetamol exposure although it would increase the risk of ibuprofen exposure compared to taking 4g per day of paracetamol only. This supports the proposed indication that the product should be used as second line treatment.

Justification for the use of paracetamol and ibuprofen together for the treatment of pain in the GSL setting

The National Institute for Health and Care Excellence (NICE) clinical guidelines in the UK for the treatment of mild-moderate pain specify a stepwise approach to pain management, with medicines with paracetamol as a suitable first line choice for people who can take it. Step 2 is ibuprofen alone for those people who can take it; otherwise a weak opioid such as codeine. Step 3 is a combination of paracetamol (1g four times a day and ibuprofen (400mg three times a day) for those people who can take both products. Guidance from the Royal College of Emergency Medicine on the management of pain in Adults 2014 advocates paracetamol or ibuprofen for the treatment of mild pain and a combination of the two for moderate pain. It is therefore considered to be appropriate for a combination of paracetamol and ibuprofen to be used for the self-treatment of pain. Since the clinical guidance recommends the combination to be used when a single active ingredient has not relieved pain or if the pain is more than mild, it is appropriate for this product to be indicated for use as second line treatment.

4.2 Risk of misuse

Misdiagnosis

The proposed indications of ‘temporary relief of mild to moderate pain such as migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, cold and flu symptoms, sore throat and fever are well established in the GSL market so it is considered that the risk of misdiagnosis of the condition to be treated is no greater than for any other GSL painkiller.

Misuse and overdose

The maximum duration of treatment of three days is in line with other GSL painkillers. The proposed dose is up to two tablets, three times daily, with a maximum pack size of 16 tablets. The dose is within the currently authorised limits for GSL ibuprofen (maximum daily dose; 1200mg) and paracetamol (maximum daily does 4g). The pack sizes are also within maximum currently authorised limits (both ibuprofen and paracetamol have a maximum pack size of 16). As the pack size is limited to 16 tablets, treatment is limited to 3 days, and the label and leaflet clearly state the dose, it is considered that the risk of overdose is minimised acceptably.

Consideration needed to be given to the following issues:

The risk that a patient may confuse the product with paracetamol alone and take the standard paracetamol dose of 2 tablets four times a day.

This would result in the patient taking 400mg/day more of ibuprofen than currently authorised as P or GSL, resulting in a total ibuprofen daily intake of 1600mg. This would be within prescribing limits of a maximum daily dose of 2400mg and well within the conservative estimated harmful overdose for a 60kg adult of 30 tablets.

The risk that people will not appreciate that it contains both ibuprofen and paracetamol.

This was addressed in the content and design of the label which states that the product contains both ingredients and which also contains the appropriate warnings for both. Two user testing studies of the label confirmed that 100 percent of participants were able to identify that the product contained both paracetamol and ibuprofen.

4.3 Special precautions in handling

There are no special handling requirements for Nuromol that would prevent its availability as a General Sales medicine.

4.4 Role of the pharmacist

With respect to the ability of people to choose and use Nuromol without the supervision of the pharmacist, the key issues to address was how people will be able to choose the product as second line (over paracetamol or ibuprofen alone)

The applicant proposed to address this by adding a prominent statement on the front of the pack indicating that the product should only be used after trying ibuprofen and paracetamol first. This proposal was accepted by CHM on the condition that there were additional measures in the Risk Management Plan to manage the risk of people not using the product as second line treatment, including an appropriate study carried out before approval of the reclassification application to demonstrate that the product would be used as second-line treatment for pan relief.

Consequently, the applicant undertook a pilot and pivotal study to demonstrate that the product will be used as second-line treatment for pain relief and undertook two user testing studies of the label to demonstrate that participants could differentiate and self-select Nuromol from other products according to the criteria which would need to be taken into account when buying the product in the absence of a pharmacist. The pitot and pivotal study protocol were pre-approved by the Pharmacovigilance Expert Advisory Group.

4.5 Convenience to the purchaser

Wider availability and awareness of this product could potentially make this a better option than codeine or dihydrocodeine containing P products for stronger pain relief before advice is needed from a healthcare professional, for stronger pain relief. Codeine or dihydrocodeine products are more liable to be misused and lead to addiction.

5. Further details on the application

5.1 Label and leaflet

The patient information leaflet and label are provided in Annex 2 and Annex 3.

5.2 Summary of Product Characteristics

The Summary of Product Characteristics is provided in Annex 4. This document is a description of the properties of Nuromol and the conditions attached to its use. It is used as a reference by healthcare professionals.

6. What do you think?

• Nuromol Dual Action Pain Relief 200mg/500mg tablets are used for the temporary relief of mild to moderate pain, which has not been relieved by ibuprofen or paracetamol individually, such as migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, cold and flu symptoms, sore throat and fever in adults 18 years and over.
• We propose to make it available on general sale outside pharmacies.
• The Commission on Human Medicines has advised that this product can be available as a General Sales medicine.
• We want to know what you think about this change. Please tell us your views using the form in Annex 1.