Submission to support the proposed Appendix H entry for combinations of paracetamol and ibuprofen Overview Advertising for combinations of paracetamol and ibuprofen will bring important benefits in terms of better information for consumers on the availability of a combination product with rapid and effective pain relief and reduced doses of analgesic.

An alternative to separate packs of paracetamol and ibuprofen

Surveys of consumers and general practitioners in 2011 indicated that 41% of Australian GPs had recommended paracetamol and ibuprofen in combination and 22% of Australian consumers had taken the combination, mostly on the recommendation of a doctor or pharmacist. At that time combination products were not available in Australia, although they had been available in New Zealand and the UK for several years. Since then TGA has approved two new combination products:

MAXIGESIC tablets (AUST R 218785), paracetamol 500mg, ibuprofen 150mg (approved December 2013); and

NUROMOL tablets (AUST R 225322), paracetamol 500mg, ibuprofen 200mg (approved July 2014). Given that these products cannot currently be advertised, consumers following the advice of their GP may still purchase separate packs of paracetamol and ibuprofen from a supermarket or pharmacy and use them in combination. Responsible advertising will perform a valuable role in directing consumers to pharmacies as an alternative to continuing with separate packs of paracetamol and ibuprofen. Reduced dose of analgesic

A single paracetamol 500mg, ibuprofen 200mg tablet has been shown in clinical trials to provide more effective pain relief than paracetamol 1000 mg and equal pain relief to ibuprofen 400 mg with onset within 15 minutes and a duration of up to 9 hours1. Another study showed that one paracetamol 500mg / ibuprofen 200mg tablet was more efficacious than two Panadeine Extra tablets (1000 mg paracetamol plus 30 mg codeine) and with equivalent analgesic efficacy to two Nurofen Plus® tablets (ibuprofen 400mg plus codeine 26.6 mg)1. Responsible advertising will alert consumers to the availability from pharmacists of this effective and safe analgesic combination at half the regular dose of paracetamol and ibuprofen.

1 Product Information, Nuromol tablets

Body of submission

This submission is presented in terms of the 'Schedule 3 Advertising Guidelines 15 November 2000'2•

The potential public health benefit

commissioned a Nielson survey of Australian consumers and a Cegedim survey of Austra lian GPs

to determine the extent of use and prescribing of paracetamol and ibuprofen both in sequence and together.

The results of these surveys are presented in Attachment 1-. They indicate that the use of paracetamol and ibuprofen in combination is routine for many Australian GPs and consumers. Responsible advertising wi ll alert consumers that combination products are available from pharmacies with advice from the

pharmacist.

The public health benefits of this advertising are:

• Consumers wi ll be made aw are that an effective and safe combination product is available from pharmacists rather than buying separate packs of paracetamol and ibuprofen from a supermarket or pharmacy without the benefit of a pharmacist's advice;

• The combination products have additional precautions and contraindications on the label that do not appear separately on the labels of paracetamol and ibuprofen products;

• The combination products have doses of analgesic that are half the maximum dose of the ana lgesics used separately;

• The combination products have positive benefits for consumers, doctors and pharmacists in having clearly­defined, evidence-based directions for use together with appropriate precautions and contra indications specific to paracetamol and ibuprofen in combination;

• Advertising the avai lability of these products will bring consumers to pharmacies where they can receive appropriate advice.

There are also benefits in terms of analgesic efficacy:

• One single dose Nuromol tablet (paracetamol 500mg, ibuprofen 200mg) has been shown in randomised, double-blind placebo-controlled studies in post-operative denta l pain to provide more effective pain relief

than paracetamol 1000 mg and equal pain relief to ibuprofen 400 mg with confirmed perceptible pain relief in 15 minutes and a duration of action up to 9 hours3•

• A double-blind, placebo-controlled, randomised study compared Nuromol with a combination of paracetamol 1000 mg plus codeine 30 mg (Panadeine Extra) and ibuprofen 400 mg plus codeine 25.6 mg (Nurofen Plus®) in postoperative dental pain showed that one tablet of Nuromol was statistically significantly more efficacious than 2 tablets of Panadeine® Extra and equivalent in analgesic effect to 2 tablets of Nurofen Plus®3 •

Responsible advertising wi ll alert consumers to the availability from pharmacists of this effective and safe analgesic combination at half the regular dose of paracetamol and ibuprofen.

The likelihood of advertising of t he substance leading to inappropriate patterns of medicat ion use.

The advertising of paracetamol / ibuprofen combinations is extremely unlikely to lead to inappropriate patterns of use:

2 Available at: http://www.tga.gov .au/industry/advertising-schedule3.htm

3 Product Information, Nuromol tablets

Neither paracetamol nor ibuprofen has a history of inappropriate patterns of use in Australia despite their wide availability through supermarkets and other retail outlets;

Combination products will remain in Schedule 3 meaning a pharmacist must be involved in every sale;

The maximum pack size in Schedule 3 is 30 dosage units;

The adult dose of the combination product contains half or less of the amount of paracetamol and ibuprofen compared to the separate packs that are sold in supermarkets.

Statements on the pack recommend no more than 3 days treatment and warn that excessive use can be harmful.

The wider regulatory system through both the Advertising Code and the therapeutic goods registration process. TGA has approved two combination products to date:

MAXIGESIC tablets (AUST R 218785), paracetamol 500mg, ibuprofen 150mg (approved December 2013); and

NUROMOL tablets (AUST R 225322), paracetamol 500mg, ibuprofen 200mg (approved July 2014). As Schedule 3 medicines both products come with a Consumer Medicine Information (CMI) and Product Information (PI).

will ensure that all advertising complies fully with the Therapeutic Goods Advertising Code and relevant legislation.

The responsibility of pharmacists to be actively involved in the supply of substance(s) included in Schedule 3 of SUSDP. As Schedule 3 medicines pharmacists are required to be personally involved in every sale. A CMI is available to assist pharmacists in counselling consumers on safe use.

Available consumer medicine information. As Schedule 3 medicines, both products have a CMI available to consumers and to assist pharmacists in their counselling role. The approved CMI for Nuromol tablets is included as Attachment 2.

The level of patient education necessary to ensure correct use. Appropriate precautions and contraindications that apply to the combination appear on the product labels and CMI (see extract from label below and CMI as Attachment 2).

Pharmacists and consumers of separate paracetamol and ibuprofen products would be familiar with most of these label warnings. The level of patient education required is similar to these other single-ingredient analgesic products.

The desire of consumers to manage their own medication. Australian consumers are accustomed to self-management of pain from minor and transient conditions. The proposed product will be a valuable alternative to paracetamol and ibuprofen used separately (at higher doses) and to the existing paracetamol / codeine and ibuprofen / codeine combinations. The fixed combination paracetamol / ibuprofen products now available provide a safer alternative than the other available OTC analgesic combinations.4 The Schedule 3 classification requires a pharmacist’s advice at the point of sale. Substantial numbers of consumers are already using the combination to manage their pain (see page 2 above) without the benefit of specific products with evidence-based dosing, directions for use and label warnings. Responsible advertising will perform a valuable role in directing consumers to pharmacies as an alternative to continuing with separate packs of paracetamol and ibuprofen. We note that Clause 6.2(e) of the Advertising Code requires words to the effect of: "Your pharmacist's advice is required" in all advertisements for therapeutic goods containing Schedule 3 substances that are listed in Appendix H of the SUSDP.

4 Product Information, Nuromol tablets

Other information

From a safety perspective, the TGA eva luated safety data available to early 2011 during its approva l of Nuromol. The data submitted to the TGA included a double-blind, single dose, placebo-controlled, randomised study which compared 1 or 2 tablets of Nuromol ibuprofen 200 mg plus paracetamol 500 mg) w ith a combination of paracetamol lOOO mg plus codeine 30 mg (2 tablets Panadeine Extra®) and ibuprofen 400 mg plus codeine 25.6 mg (2 tablets Nurofen Plus®). Fewer treatment emergent, and treatment-related treatment emergent adverse events occurred with both 2 tablets of Nuromol (ibuprofen 400 mg plus paracetamol lOOO mg) and 1 tablet of Nuromol (ibuprofen 200 mg plus paracetamoi SOO mg) compared with Nurofen Plus®, Panadeine Extra® and placebo.5

Since that time two new Periodic Safety Update Reports (PSURs) have been prepared covering the period 1 March

2012 to 28 February 2014. These are provided at Attachments 3 and 4--. It is estimated that 9,413,201 patients have been treated since its International Birth Date, 15th September 2010.--. The PSURs consider the risks identified in the European Risk Management Plan and conclude that there has been no new information identified during the reporting interva l or cumulatively at the t ime of w riting the PSURs which

cou ld change the positive risk benefit profile of the product.--]. No safety concerns have been identified in the routine signal detection and no new important potential or identified risks associated with use of Nuromol products containing ibuprofen and paracetamol during the reporting period--.

Conclusions

The abi lity to advertise combinations of paracetamol and ibuprofen w ill have important benefits to Austra lian

consumers and pharmacists:

• Increased awareness of the availability of combination products through pharmacists will bring consumers to pharmacies where they can receive appropriate advice;

• Evidence-based precautions and contra indications appear on product labels and CMI that are not available to consumers who purchase paracetamol and ibuprofen products separately for use in combination;

• Pharmacists w ill control every sale and provide advice to consumers.

strongly supports the proposa l to include paracetamol and ibuprofen combinations in Appendix H.

5 Product Informat ion, Nuromol tablets

Attachment 2: CMI

Nuromol®

Ibuprofen and paracetamol

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common questions about Nuromol®. It does not contain all the available information. It does not take the place of talking to your pharmacist or doctor.

All medicines have risks and benefits. Your pharmacist or doctor has weighed the risks of you taking Nuromol® against the benefits they expect it will have for you.

If you have any concerns about

taking this medicine, ask your

pharmacist or doctor.

Keep this leaflet with the medicine.

You may need to read it again.

What Nuromol® is used for

Nuromol® is an analgesic (pain reliever). It works to relieve acute (short term) pain and / or inflammation associated with headache, migraine headache, tension headache, sinus pain, toothache, dental procedures, backache, muscular aches and pains, period pain, sore throat, tennis elbow, rheumatic pain and arthritis, and the aches and pains associated with colds and flu.

It contains ibuprofen and paracetamol.

Ibuprofen belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs).

Paracetamol works to stop the pain messages from getting through to the brain.

Ask your pharmacist or doctor if

you have any questions about this

medicine.

This medicine is not addictive.

It is only available from your pharmacist.

Before you take Nuromol®

When you must not take it

Do not take Nuromol® if you have an

allergy to:

• any medicine containing ibuprofen, aspirin or other NSAIDs

• any medicine containing paracetamol

• any of the ingredients listed at the end of this leaflet

• any other medicine for pain relief Some of the symptoms of an allergic reaction may include:

• shortness of breath • wheezing or difficulty breathing • swelling of the face, lips, tongue

or other parts of the body

• rash, itching or hives on the skin.

Do not take this medicine if you have

any of the following conditions:

• liver or kidney disease • heart problems • asthma • a stomach ulcer or duodenal ulcer

or if you have had either of these conditions or gastric bleeding or other gastrointestinal diseases in the past

• recently vomited blood or material that looks like coffee grounds

• recently bled from the back passage (rectum), had black sticky bowel motions or bloody diarrhoea

Do not take this medicine if you are

pregnant or plan to become pregnant.

Do not take this medicine/it after the

expiry date printed on the pack or if the

packaging is torn or shows signs of

tampering.

If it has expired or is damaged, return it to your pharmacist for disposal. Do not take this medicine if you are

aged 65 years or older.

Do not give this medicine to children

aged under 12 years.

Do not take this medicine if you are

taking any other product containing

paracetamol, ibuprofen or other

NSAIDs or if you are taking any other

medicine for pain relief.

If you are not sure whether you should

start taking this medicine, talk to your

pharmacist or doctor.

Before you start to take it

Tell your pharmacist or doctor if you

have allergies to any other medicines,

foods, preservatives or dyes.

Tell your pharmacist or doctor if you

currently have or have had in the past

:

• diabetes

Tell your pharmacist or doctor if you

have had any of the following medical

conditions in the past:

asthma

liver or kidney disease

heart problems

If you currently have these conditions,

do not take this medicine.

Ask your pharmacist or doctor about

taking this medicine if you are

breastfeeding.

Small amounts of ibuprofen and paracetamol pass into the breast milk.

If you have not told your pharmacist or

doctor about any of the above, tell

them before you start taking

Nuromol®.

Taking other medicines

Tell your pharmacist or doctor if you

are taking any other medicines,

including any that you get without a

prescription from your pharmacy,

supermarket or health food shop.

Some medicines and ibuprofen or paracetamol may interfere with each other. These include:

• warfarin, a medicine used to prevent blood clots

• lithium, a medicine used to treat mood swings and some types of depression

• medicines used to lower blood pressure

• methotrexate, a medicine used to treat arthritis and some types of cancer

• medicines used to treat heart failure • medicines such as prednisone,

prednisolone and cortisone, which reduce the activity of your immune system

• zidovudine, a medicine used to treat HIV infection

• aspirin, salicylates and other non- steroidal anti-inflammatory drugs (NSAIDs)

• medicines used to treat diabetes • metoclopramide, a medicine used

to control nausea and vomiting • medicines used to treat epilepsy or

fits • chloramphenicol, an antibiotic used

to treat ear and eye infections • alcohol Your doctor and pharmacist will have more information on these and other medicines to be careful with or avoid while taking this medicine.

How to take Nuromol®

Follow all directions for use written on

the medicine's label.

Do not take more than the recommended dose on the label or for a longer period of time.

If you do not understand the

instructions on the label, ask your

pharmacist or doctor for help.

How much to take

Adults under 65 and children from 12 years: Take one tablet every 8 hours with water when necessary.

Not recommended adults 65 years of age and over or children under 12 years of age.

Do not take more than 3 tablets in 24

hours.

How long to take it

Only take Nuromol® when required

for pain.

Adults: do not take Nuromol® for

more than 3 days at a time.

Adolescents (12 to 17 years): do not

take Nuromol® for more than 2 days

at a time.

If your symptoms persist, worsen or

new symptoms develop, talk to your

pharmacist or doctor.

If you take too much (overdose)

Immediately telephone your doctor or

the Poisons Information Centre

(telephone 13 11 26) for advice, or go to

Accident and Emergency at the

nearest hospital, if you think that you

or anyone else may have taken too

much Nuromol®. Do this even if there

are no signs of discomfort or

poisoning. You may need urgent

medical attention.

While you are using Nuromol®

Things you must do

Talk to your pharmacist or doctor if

your symptoms do not improve.

Your pharmacist or doctor will assess your condition and decide if you should continue to take the medicine.

Things you must not do

Do not take for more than 3 days at a

time (2 days for adolescents 12 to 17

years) unless your doctor tells you to.

Do not take more than the

recommended dose unless your

pharmacist or doctor tells you to.

Things to be careful of

Taking this medicine may increase the risk of you getting unwanted effects, such as stomach or heart problems.

Only drink small quantities of alcohol

(beer, wine or spirits) while taking

paracetamol.

Drinking large quantities of alcohol while taking paracetamol may increase the risk of liver side effects.

Do not take Nuromol® to treat any

other complaints unless your

pharmacist or doctor tells you to.

Do not give your medicine to anyone

else, even if they have the same

condition as you.

Side effects

Tell your pharmacist or doctor as soon as

possible if you do not feel well while you

are taking Nuromol®.

This medicine helps most people with relief of pain, but it may have unwanted side effects in a few people. All medicines can have side effects.

Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists

of side effects. You may not experience

any of them.

Ask your pharmacist or doctor to

answer any questions you may have.

It is rare to get side effects from ibuprofen and paracetamol if taken for a short period of time and in the doses in OTC medicines.

Tell your pharmacist or doctor if you

notice any of the following and they

worry you:

nausea., heartburn, or

stomach pain

loss of appetite

dian"l10ea

dizziness

drowsiness

headache

netv ousness

The above list includes the more collllnon side effects of your medicine. They are usually mild.

Tell your doctor as soon as possible if you notice any of the following:

get slUlbumt more quickly than usual.

The above list includes serious side effects that may require medical attention. Serious side effects are rare for low doses of this medicine and when used for a sh01t period of time.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

fluid retention

vomiting blood or bleeding from the back passage

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue or other prut s of the body

rash, itching or hives on the skin

The above list includes vety serious side effects. You may need urgent medical attention or hospitalisation. These side effects ru·e very rare for low doses of this medicine and when used for a short period of time.

Tell your pharmacist or doctor if you notice anything that is m aking you feel unwell.

Other side effects not listed above may also occtu· in some people.

After using Nuromol®

Storage

Keep your medicine in the original pack until it is time to take.

Keep your medicine in a cool dry place where the temper ature stays below 30°C.

Do not stor e Nuromol® or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one­and-a-half metres above the groWld is a good place to store medicines.

Disposal

Ask your pharmacist what to do with any medicine that is left over after the expiry date has passed.

Product description

What it looks like

Nuromol® is a white to off white, pearlescent, oval shaped, film coated tablet, de-bossed with a identifying helix

Each Nuromol® tablet contains 200mg of ibuprofen and 500mg of paracetamol.

It also contains:

Cellulose - microctystalline

Croscannellose sodimn

Opadry II complete fihn coating system85F18422

Opadty fx special effects fihn coating system 63F97546 silver

Magnesimn stearate

Steruic acid

Silica - colloidal anhydrous

Nuromol® does not contain gluten, wheat, lactose or sucrose.

-® = Registered Trademark

This leaflet was prepru·ed in Mru·ch 2014

AUST R munber 225322

91h September 2014

The Secretary Communications and Secretariat Therapeutic Goods Administration PO Box 100 WODEN ACT 2606

Dear Sir or Madam,

Re: Invitation for public comment- ACMS meeting, November 2014 Notice inviting public submissions under Reg 42ZCZK of the Therapeutic Goods Regulations 1990 Paracetamol in combination with Phenylephrine • Proposal to reclassify to Schedule 3 or Schedule 2 when combined with doses of phenylephrine above 2.5 mg

like to provide comments on the scheduling proposals that are to be considered by the ACMS at the November 2014 meeting. We wish to address relevant matters under section 52E of the

Therapeutic Goods Act 1989, as applicable to the proposal to amend the entry for paracetamol in combination with phenylephrine. The comments are contained in the attached document and literature references.

• does not support the proposal to amend the scheduling of paracetamol plus phenylephrine combination products and believes that the current scheduling remains appropriate. There is no documented safety issue with the existing products and the way that they are scheduled. We believe that "up-scheduling" should take place

when a public health risk is demonstrated, and the scheduling proposal does not appear to meet this criterion.

Yours sincerely,

 

   

Proposed amendment for consideration by the ACMS, November 2014 

Paracetamol in combination with phenylephrine  

1) Proposal to include in Schedule 3:  

500 mg paracetamol when combined with more than 2.5 mg phenylephrine per tablet / 

capsule / caplet 

Individually wrapped powders or sachets of granules containing paracetamol 1000mg 

and more than 5 mg phenylephrine per dose 

 

2) Proposal to include in Schedule 2: 

500 mg paracetamol when combined with 2.5 mg phenylephrine or less per tablet / 

capsule / caplet 

Individually wrapped powders or sachets of granules  containing paracetamol 1000mg 

and 5 mg phenylephrine or less per dose in packs containing more than 10 such powders 

or sachets 

 

3) Proposal to exempt from scheduling: 

500 mg paracetamol when combined with 2.5 mg phenylephrine or less per tablet / 

capsule / caplet in packs containing 20 or less tablets / capsules / caplets per pack 

Individually wrapped powders or sachets of granules  containing paracetamol 1000mg 

and 5 mg phenylephrine or less per dose in packs containing 10 or less such powders or 

sachets 

  does not support the proposal to include in Schedule 3: 

500 mg paracetamol when combined with more than 2.5 mg phenylephrine per tablet / 

capsule / caplet 

Individually wrapped powders or sachets of granules containing paracetamol 1000mg 

and more than 5 mg phenylephrine per dose 

 

1. INTRODUCTION  The proposed scheduling change requests an upwards scheduling for existing, currently marketed paracetamol and phenylephrine combination products, which would result in products that are currently either in Schedule 2 or exempt from scheduling being up‐scheduled to Schedule 3.  A similar change will be evaluated by the New Zealand Medicines Classification Committee at their forthcoming meeting.  According to the Scheduling Policy Framework, Schedule 3 medicines are substances for which mandatory professional advice is required in order to ensure safe use.     

• does not agree that the existing Schedu le 2 and exempt paracetamol plus phenylephrine combination products meet the criteria for a Schedu le 3 medicine and strongly opposes the above re-scheduling proposal.

2. BACKGROUND

The. products impacted by the abovementioned proposals contain fixed dose combination of paracetamol +phenylephrine hydroch loride as well as paracetamol + phenylephrine hydrochloride+ guaiphenesin.

In general, paracetamol and phenylephrine hydrochloride products are indicated for the relief of symptoms of colds and influenza, including the relief of aches and pains, sore throat, headaches, nasal congestion, and lowering of temperature.  2.1 Current Scheduling Status of Paracetamol and Phenylephrine Combination Products  The NDPSC at its June 2007 meeting approved availability of paracetamol and phenylephrine combination medicines in small pack sizes as unscheduled products. In Record of Reasons Decision 2007/50‐14 it is stated: “The Committee agreed that the safety profile of these substances was such that allowing their fixed combination to be exempt from scheduling was reasonable. Furthermore, there was sufficient Australian market experience to support this down scheduling. Thus the Committee agreed to exempt from scheduling paracetamol 500 mg solid dose forms / 1000 mg powders or granules when combined with phenylephrine.”  Combination paracetamol plus phenylephrine products have been available in Australia as Schedule 2 medicines many years and small packs have been available for self‐selection in grocery since 2007. Lemsip Max Cold & Flu Lemon has been marketed in the UK continuously since 1992 and the related product Lemsip Cold and Flu Lemon (paracetamol 650 mg, phenylephrine hydrochloride 10 mg) has been marketed in the UK since 1971. These products have been marketed globally in a similar way in New Zealand, the UK and other European countries, Asia and the USA. There has therefore been extensive global market experience within the OTC environment.  During this extensive period in which these products have been marketed directly to the public in UK and world‐wide very few adverse events considered probably or possibly related to treatment have been reported suggesting that the labelling is sufficient to promote safe use of the product.  Despite extensive use within the community, there is no evidence of any documented safety issues that could justify the up‐scheduling of these medicines to Schedule 3. These products have had many years of use and have a favourable safety profile.  This submission will address the scheduling factors outlined in the National Coordinating Committee on Therapeutic Goods  “Scheduling Policy Framework for Medicines and Chemicals” , effective date 1 July 2010.    3. RISK/BENEFIT ANALYSIS   The published literature on review of cold and influenza symptoms is extensive and, the incidence of cold and influenza varies between studies as most have been country specific. However it can be inferred that on an average adult have about two to four colds a year and children have three to eight as their immune system is more vulnerable to infection (Madeline Simasek et al, 2007). The cold and flu symptoms result in discomfort and time lost away from work and thus relief of symptoms is of some economic importance (Hellgren J, 2010).  The medical need and benefits of treating cold and influenza symptoms, and thus reducing the economic burden associated with it, can be achieved by having access to an effective symptomatic treatment such as Lemsip Max (paracetamol and phenylephrine) which is indicated for the relief of symptoms associated with cold and influenza, including the relief of aches and pains, sore throat, headaches, nasal congestion, and lowering of temperature. 

 Lemsip Multi Relief is indicated for the relief of the symptoms of colds and flu: headaches, sore throat, fever, body aches and pains, blocked or runny noses, and to loosen and help clear chest congestion.   3.1 What is the Hazard?  3.1.1 Paracetamol 

Paracetamol is a widely used analgesic for the treatment of mild to moderate pain and its safety at 

recommended doses  is well accepted.    In a  community based  trial  (Noyelle RM, 1987) where  the 

relative safety and efficacy of single doses of aspirin 650 mg and 1000 mg,  ibuprofen 400 mg and 

paracetamol  1000 mg  in  capsule  format were  studied  in  a  total  of  339  patients,  the  side‐effects 

reported are presented in Table 1 to Table3 below. 

Table 1. Side effects recorded spontaneously by patients.

Table 2. Side effects elicited by direct questioning.

Table 3. Total number of side effects reported for each treatment group.

The tables shows that paracetamol at a single dose of 1000 mg is very well tolerated. 

Paracetamol  overdose  is  often  associated  with  hepatotoxic  sequelae;  however,  the  use  of 

paracetamol in single doses of 1000 mg and daily doses of up to 4000 mg is very unlikely to give rise 

to hepatotoxicity.   A wide ranging review  (Prescott LF, 1996) shows quite clearly that  in numerous 

studies  involving  such  doses  for  prolonged  periods  changes  in  liver  function  are  rare,  even  in 

patients with pre‐existing liver disease.   

 

The  incidence  of  adverse  effects  related  to  paracetamol  is  low;  the  most  commonly  reported 

adverse  events  being  allergic  in  nature,  such  as  erythematous  rash,  pruritis  and  urticaria.  

Anaphylaxis  is rare (Prescott LF, 1996).   There are reports of adverse haematological effects, but a 

critical  appraisal of  these  indicates  that  if  effects  such  as  thrombocytopenia,  agranulocytosis  and 

leucopaenia do occur they are very uncommon(Prescott LF, 1996). 

 

3.1.2 Phenylephrine hydrochloride 

A detailed  side‐effect profile  following  three different doses of orally administered phenylephrine 

hydrochloride has been reported (Cohen BM, 1972).  Clinical cardiovascular effects following a 10 mg 

dose of phenylephrine hydrochloride were indistinguishable from placebo; 15 and 25 mg doses lead 

to a decline in mean diastolic blood pressure as shown in Figure 1 below. 

Figure 1. Responses of mean systolic (S) and diastolic (D) arterial blood pressure during the administration of phenylephrine (10.0, 15.0 and 25.0 mg doses) and placebo in a double-blind crossover protocol for 48 patients with common colds, arranged according to the individual paired comparisons.

There was a modest increase in heart rate compared with placebo for the 10 mg dose at three time 

points, for the 15 mg dose at one time point and for the 25 mg dose at four time points, Table4.

Table 4. Mean heart rates and statistically significant differences observed in a comparison of oral doses of phenylephrine with placebo.

 

Side‐effects  were  described  as  of  a  transient  ‘nuisance’  variety which  increased with  increasing 

doses.   For  the 10 mg dose,  two adverse drug  reactions  (ADRs)  involving dry mouth and dry nose 

were noted.  A total of 13 ADRs were reported for the 15 mg dose, five of which were ‘nervousness’.  

The placebo leg resulted in six ADRs, including dry mouth, dry nose and nervousness. 

A review (Chua SS, 1988) described a series of studies which investigated the cardiovascular effects 

of varying doses of phenylephrine in normotensive individuals.  It suggested that the minimum single 

dose  required  to  elicit  an  increase  in  blood  pressure  was  50 mg,  approximately  five  times  the 

therapeutic dose.   Doses  in excess of 120 mg were  required  to elicit a  significant effect on blood 

pressure.  A 10 mg dose produced no appreciable effect. 

A  comprehensive  search  of  60  medical  and  scientific  databases  has  revealed  few  examples  of 

published  cases of  central nervous  system  (CNS) excitation by orally administered phenylephrine. 

The  literature  suggests  that phenylephrine has very  little effect on  the CNS unless  taken  in doses 

higher than that present in the Lemsip Max formulation. 

CNS excitation, such as respiratory stimulation, increase in wakefulness and reduction of appetite, is 

a feature of many sympathomimetic drugs.  However, not all drugs in this class show these types of 

effects  to  the same degree.   Epinephrine  for example  is not a powerful CNS stimulant  (Goodman, 

1975), whereas the structurally related compound methamphetamine has pronounced effects.   An 

authoritative  reference  on  sympathomimetic  drugs  suggests  that  for  phenylephrine  “central 

stimulant action  is minimal”  (Goodman, 1975).   This  is also  stated  in a  second monograph  source 

(Dollery CT, 1999)  which states that for phenylephrine “there are no significant CNS effects”. 

  3.2 How widespread is the hazard? 

Lemsip Max (paracetamol and phenylephrine) has a well‐established safety and efficacy profile as an 

over‐the‐counter treatment over many years of use. No safety concerns have been identified in 

routine signal detection activities. Section 4 of this submission will present data that show there 

have been no important, potential or identified risks associated with use of Lemsip Max 

(paracetamol and phenylephrine) during the period the products have been on the market. The 

benefit risk balance with treatment of Lemsip Max (paracetamol and phenylephrine) remains 

positive. 

  3.3 In what circumstances will the hazard arise? 

There is no documented safety issue with the existing products and the way that they are scheduled. 

 believes that “up‐scheduling” should only take place when a public health risk is demonstrated, 

and the scheduling proposal does not appear to meet this criterion.  

 

The marketed paracetamol plus phenylephrine products carry labelling warnings as per the TGA 

MASS 2014 as follows: 

See your doctor or pharmacist before taking this product if you are pregnant, have high blood 

pressure or heart problems or are taking antidepressant medication. 

This product may cause sleeplessness. 

Do not take with other products containing paracetamol, unless advised to do so by a doctor. 

  3.4 What is the likelihood of the hazard arising? 

Each  dosage  unit  contains  1000  mg  paracetamol  and  12.2  mg  phenylephrine  hydrochloride 

(equivalent to 10 mg phenylephrine base) or paracetamol 500 mg and phenylephrine hydrochloride 

6.1 mg  as  the  active  ingredients.  These  well‐established  active  ingredients  exert  their  different 

effects  by  completely  unrelated  pharmacological  mechanisms;  paracetamol  is  an 

analgesic/antipyretic  for  aches  and  pains  and  lowering  of  temperature  that  acts  via  inhibition  of 

prostaglandin  synthesis  and  phenylephrine  is  a  sympathomimetic  agent  (α1‐adrenergic  agonist) 

which  acts  by  vasoconstriction  as  a  nasal  decongestant  for  a  blocked  or  runny  nose.    Therefore, 

there is little potential for any pharmacodynamic interaction between the two active ingredients. 

Also, the metabolic pathways  for paracetamol and phenylephrine appear to be distinct so there  is 

little indication of potential for any pharmacokinetic interaction. 

 

A letter published in NEJM in 2014 showing an observed increase in plasma levels of phenylephrine 

when co‐administered with paracetamol is interesting. The authors of the study raised hypothetical 

concerns  that  the  observed  interaction  may  have  an  impact  on  safety  for  individuals  with 

undiagnosed cardiac conditions and hypertension; however there is no evidence that in reality this is 

the case.   safety data confirm that the likelihood of a hazard arising is very low (see section 4.4).  

  3. 5 Who or what is at risk? 

There are some groups of patients in whom Lemsip Max Cold & Flu Lemon should be used with care 

and these are mentioned on pack as the groups to which the MASS 2014 statements apply. The 

vasoconstrictive action of phenylephrine may cause adverse events in patients with severe coronary 

heart disease, cardiovascular disorders, hypertension, hyperthyroidism, Raynaud’s Syndrome and 

also during pregnancy.  However, the dose of phenylephrine provided by the recommended dose of 

Lemsip Cold & Flu Lemon is well below that needed to produce consistent and meaningful increases 

in diastolic pressure and reflex bradycardia.  Sympathomimetics may also raise glucose levels posing 

a risk for patients with type I diabetes, although this is considered less likely to occur with 

phenylephrine. Paracetamol should be used with care by patients with severe renal or hepatic 

impairment to guard against the possibility of renal damage or hepatotoxicity.  The information on 

the pack advises patients in these groups to seek medical advice before using the product.  

 

3.6 What are the consequences of the hazard in terms of severity (morbidity and mortality) and duration? Combination paracetamol plus phenylephrine products have been available in Australia as unscheduled medicines for many years. Despite extensive use within the community, there is no evidence of any documented safety issues that could justify the up‐scheduling of these medicines to Schedule 3.  These products are intended for symptomatic relief of cold and flu, for short treatment duration. Products are labelled with appropriate safety warning statements, as per TGA requirements.    4. FACTORS FOR PHARMACY MEDICINES (SCHEDULE 2)   4. 1 The quality use of the medicine can be achieved by labelling, packaging, and/or provision of other information; however access to advice from a pharmacist is available to maximise the safe use of the medicine.  These products are used for symptomatic relief of cold and flu symptoms, for short treatment duration. Products are labelled with the following safety warning statements, as per the Medicines Advisory Statements Specification 2014 (MASS) Schedule 2: 

See your doctor or pharmacist before taking this medicine if you have high blood pressure or 

heart problems or are taking antidepressant medication. 

This product may cause sleeplessness 

 

Consumers who are aware that they have heart conditions or hypertension are clearly advised to 

consult their doctor or pharmacist. 

4. 2 The use of the medicine is substantially safe for short term treatment and the potential for harm from inappropriate use is low.  

 is of the view that the risk of hypertension is a potential risk; however it is not based on firm evidence.  Although a relationship between sympathomimetic drugs such as phenylephrine and vasopressor effects has been documented and has a pharmacological basis, the literature generally does not provide evidence of any specific dose‐response relationship between phenylephrine / phenylephrine combined with paracetamol and blood pressure.  Importantly, the product is intended for short term, symptomatic relief, and therefore any effect on blood pressure will be short lived and of limited clinical significance for the vast majority of people who use this product. 4.3 The use of the medicine at established therapeutic dosage levels is unlikely to produce dependency and the medicine is unlikely to be misused, abused or illicitly used.  The product is intended for short term, symptomatic relief of cold and flu. If used according to the directions on the pack there is an extremely low likelihood of dependency, misuse, abuse or illicit use.    

4.4 The risk profile of the medicine is well defined and the risk factors can be identified and managed by a consumer through appropriate packaging and labelling and consultation with a medical practitioner if required . • believes that this criterion for Schedule 2 status for paracetamol/phenylephrine combination products is met. The adverse event profile of the products is well defined, and the products have a long record of being used safely by the majority of consumers.

4.4.1 Summary of Internal. Safety Data In order to demonstrate an excellent record of rovide the fo llowing summary of safety

relating to the active Fixed Dose rochloride during the period 1 June 2009

all contain racetamol and phenylephrine

olds the marketing authorisation for paracetamol and ne ucts in 17 countries. The products are authorised for the-in

Austra lia, Brunei Darussalam, Hong Kong, Ireland, Jordan, Korea, Kuwait, Ma laysia, Malta, Mexico, New Zea land, Russian Federation, Singapore, South Africa, Ukraine, United Arab Emirates and United Kingdom.

4.4.2 Safety data for paracetamol and phenylephrine hydrochloride during the reporting period 1 June 2009 to 30 June 2014

  

  

  

  

  4.4.3 Safety data for paracetamol and phenylephrine hydrochloride from the   to 30 June 2014  

  

4. 5 The use of the medicine at established therapeutic dosage levels is not likely to mask the symptoms or delay diagnosis of a serious condition.  The combination products are intended for short term treatment of self‐limiting conditions and the appropriate warnings are on the label.    5. POSSIBLE IMPACT OF RESCHEDULING   

 is concerned that there would be consumer confusion for many consumers who are familiar with the products’ existing availability in pharmacy as a Schedule 2 medicine and within grocery with packs of 20 or less tablets   The volume of queries and requests to pharmacists from consumers for these commonly used products will have an unwanted effect on the day to day practice of busy pharmacists.  Pharmacists are not in a position to diagnose individuals who have cardiovascular conditions or hypertension since they are not adequately trained; it is not something intended to be done by pharmacists prior to recommending particular products.    6.   CONCLUSIONS AND RECOMMENDATIONS  

 does not support the proposal to amend the scheduling of paracetamol plus phenylephrine combination products and believes that the current scheduling remains appropriate.  There is no documented safety issue with the existing products and the way that they are scheduled. We believe that “up‐scheduling” should take place when a public health risk is demonstrated, and the scheduling proposal does not appear to meet this criterion.   

The marketed paracetamol plus phenylephrine products carry labelling warnings as per the TGA MASS 2014, advising people with cardiac conditions and hypertension to consult their doctor or pharmacist before use.   

 contends that there is no evidence that the existing scheduling arrangements for currently available products are placing people with undiagnosed cardiac conditions or hypertension at risk. Pharmacists cannot diagnose these conditions so a move to Schedule 3 would not offer any advantage for this defined group of people in any case.  

   

 

Appendix I Manual summary tabulation (as per RSI)