Consultation outcome

Nuromol public assessment report

Published 13 May 2021

Public Assessment Report

Pharmacy to General Sales Reclassification

Nuromol Dual Action Pain Relief 200mg/500mg tablets (ibuprofen/paracetamol)

PL 00063/0649 - 0028

Reckitt Benckiser Healthcare (UK) Ltd

1. About Nuromol

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

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.

1.1 What is in Nuromol

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

1.2 What Nuromol is used for

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.

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

2.1 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 under the name of: Nuromol Dual Action Pain Relief 200mg/500mg Tablets (ibuprofen/paracetamol). For the rest of this document the product will be referred to as Nuromol.

2.2 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.

2.3 Proposed terms of reclassification

2.3.1 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

3. How was the proposal for Nuromol being available as a medicine on general sale was 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.

3.1 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:

3.1.1 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.

3.1.2 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.

Considering the reduced dosage of paracetamol in Nuromol compared to solid dose oral paracetamol products that are already authorised with GSL classification and the 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.

3.1.3 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.

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

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.

3.2 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:

3.2.1 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.

3.2.2 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.

3.3 Special precautions in handling

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

3.4 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 pain 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 pilot and pivotal study protocol were pre-approved by the Pharmacovigilance Expert Advisory Group.

3.5 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.

4. Consultation on General Sales Availability of Nuromol

Consultation ARM 100, which summarises the proposals on the pharmacy only to general sales reclassification of Nuromol, was posted on the GOV.UK website on 13 May 2021. The deadline for comments was given as 3 June 2021.

ARM 100 can be accessed via the following link: https://www.gov.uk/government/consultations/nuromol-dual-action-pain-relief-200mg500mg-tablets-ibuprofenparacetamol-public-consultation/nuromol-public-consultation-document

13 responses were received. The responses provided have not raised any new safety concerns with respect to reclassification of Nuromol Dual Action Pain Relief 200mg/500mg Tablets as a General Sales (GSL) medicine.

Of the 7 positive respondents;

1 industry body, 1 individual/patient, 2 individual pharmacists, and 3 respondents who wished their responses to remain confidential, they considered that there were no safety issues associated with availability of the product without pharmacy supervision. Two of the individual/patient respondents stated that they already use a combination of paracetamol and ibuprofen to treat their pain, one having been recommended to do so by her doctor. The other individual/patient respondent considered that taking one medicine combining both active substances was easier and safer, reducing the number of tablets they needed to take in a day and reducing the need to remember which tablets had been taken.

Of the 5 negative respondents:

1 professional body (pharmacy), 1 NHS trust, 1 individual pharmacist and two respondents who wished their responses to remain confidential, the main concerns raised where about the increased risk of overdose resulting from people taking Nuromol in addition to products containing single ingredient paracetamol and ibuprofen products. This issue has been thoroughly considered in assessment of the application and by CHM. Repeated user testing and subsequent amendment of the label and leaflet have provided reassurance that the user will understand that Nuromol contains both paracetamol and ibuprofen and that it should not be taken with any other products containing these active ingredients.

Concerns were also raised about and the risk of people familiar with the 4-daily dosing for paracetamol taking Nuromol 4 times a day, resulting in an individual taking more than the maximum daily dose of ibuprofen. This risk was considered during assessment and by CHM. Again, thorough and repeated user testing and subsequent amendment of the label and leaflet have provided reassurance that the user will understand the maximum daily dose of this product. Moreover, if a user did take the product incorrectly 4 times a day, this is within the prescribing limits for ibuprofen and would not result in ibuprofen toxicity. As the pack size is limited to 16 tablets, treatment is limited to 3 days, and the label and leaflet clearly state the dose, CHM considered that the risk of overdose is minimised acceptably.

Concerns were also raised about the different dosing intervals for individual products containing paracetamol and ibuprofen and that using Nuromol instead of two separate products would result in a sub-optimal dose of paracetamol. This issue was considered during assessment and by CHM. The clinical trial data provided at the time of licensing of Nuromol have demonstrated a superiority in efficacy of the combined product compared to taking the single actives on their own, so for those individuals for whom it is appropriate to take a combination of paracetamol and ibuprofen to treat pain, rather than provide a sub optimal dose of paracetamol, the combined product with a lower daily dose of paracetamol is more effective. This indicates that taking Nuromol instead of two separate single ingredient products will proved better pain relief and less exposure to paracetamol.

A concern was raised about the use of the product as second line treatment when the National Institute for Health and Care Excellence (NICE) clinical guidelines in the UK for the treatment of mild-moderate pain recommend a combination of paracetamol and ibuprofen as third line treatment. This was considered at assessment and by CHM. NICE guidelines are not specifically written for the treatment of pain using OTC medicines. Since the management of pain in the OTC setting should be short term it would be inappropriate for any P to GSL painkiller to be indicated as third line treatment. By the time a third line treatment becomes an option, an individual should be seeking medical advice. The British Pain Society advice for the management of pain, published in 2010, makes no distinctions between paracetamol, ibuprofen and aspirin as first line treatment but recommends OTC medicines containing codeine or dihydrocodeine for the treatment of pain not relieved by the single active alone. It should be acceptable therefore for Nuromol to be indicated as a second line treatment for pain, as an alternative to codeine or dihydrocodeine-containing analgesics, in the OTC setting.

A concern was raised about the possibility that people who only have Nuromol available to hand may take this as first line treatment. This was considered at assessment and by CHM. The label has a prominent warning on the front of the pack advising that it should only be used after trying ibuprofen or paracetamol first. User testing of the label and a pilot and pivotal study have demonstrated that this warning can be found on the label at the point of selection when the product is on display shelves and that it is understood. It is accepted that users can ignore the warning if they choose but they can also ignore advice given by the pharmacist at point of sale and when the product is available in their homes if they choose. Therefore, this risk is not considered to be any higher than if the product was classified as P.

A general point was raised by some respondents (pharmacists and pharmacy body) about statements on the labelling and leaflet of GSL medicines advising people to seek advice from their doctor or pharmacist. For all medicines, the MHRA considers it appropriate to signpost individuals to where they can get more information about medicines or about the treatment of their condition if they need it. In the case of GSL medicines these are prominent on the pack to help people decide whether they should purchase the product or seek professional help rather than purchase. In the case of P medicines, users are informed through the label and leaflet under which circumstances they should seek advice from a pharmacist and when to seek advice directly from a doctor. These are measures to manage the risk of P and GSL classification rather than indicate if a medicine should be classified as P or GSL.

Regarding the respondent expressing no definitive view:

An individual pharmaceutical consultant considered there was insufficient information provided in the ARM document on safety as a P medicine in the UK and safety as a “GSL equivalent” medicine in New Zealand. The details of safety data provided in a reclassification application and their assessment and consideration by CHM are not provided in an ARM consultation.

Label, leaflet and SPC:

Some specific points were raised about the label and leaflet. However, these had already been considered during assessment and addressed during the user testing of both documents.

One respondent pointed out an inconsistency in wording in sections 4.1 and 4.4 regarding when a doctor should be consulted. This was addressed so the SPC in both sections reads: “If symptoms persist for more than 3 days, or worsen consult your doctor”

5. Data exclusivity

The applicant has been granted one years’ data exclusivity in relation to studies that CHM required the applicant to undertake before it could advise on the GSL classification of this product.

6. Conclusion

The MHRA has taken the decision to approve GSL classification of Nuromol Dual Action Pain Relief 200mg/500mg Tablets (ibuprofen/paracetamol). under the following conditions:

• 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

10. Further information

The summary of product characteristics and the patient information leaflet are available on the MHRA website: http://www.mhra.gov.uk/spc-pil/

Medicines and Healthcare products Regulatory Agency, July 2021