ARM 41

CONSULTATION PERIOD 12 APRIL TO 23 MAY

RECLASSIFICATION SUMMARY FOR POM TO P APPLICATION FOR

NAPROXEN 250mg TABLETS

1. APPLICANT DETAILS

Galpharm International Ltd

2.  PRODUCT DETAILS

Name: Naproxen 250mg tablets

Indication:  Primary dysmenorrhoea (period pain) in women aged between 15 and 50 years. 

Dosage: 

• Day 1:  The initial dose is 2 tablets (500mg) followed 6 to 8 hours later by a second tablet (250 mg) if needed. 

• On subsequent days (i.e. days 2 and 3), the dose is 1 tablet (250mg) every 6 to 8 hours if needed. 

• This represents a maximum daily dose of 750mg.

The maximum pack size is equivalent to 3 days treatment, i.e. 9 tablets.

Names of existing POM product:  TimpronTM 250 EC, Naproxen 250mg Enteric Coated Tablets

MA number of existing POM product:  PL 00289/0129

3.  RATIONALE FOR THE RECLASSIFICATION

Dysmenorrhoea or period pain is a common, chronic, recurring condition which affects 40-70% of women of reproductive age.  A significant number (10%) of dysmenorrhoea sufferers will experience interference with everyday life, in some cases leading to absence from work, school, sport, social and family life.   Primary dysmenorrhoea typically starts six to twelve months after the menarche.  The average age of menarche in the UK is slightly over 12 years of age. 

For many years women have managed their period pain using over the counter (OTC) medicines.  These include aspirin, paracetamol and ibuprofen as well as combination analgesics which may contain low levels of codeine.  There are many such OTC analgesics which are licensed for a range of short term self limiting painful conditions such as headache, toothache, backache, flu , and dysmenorrhoea.   

Dysmenorrhoea responds well to treatment with non-steroidal anti-inflammatory drugs (NSAIDs).  NSAIDs inhibit the production of the hormone-like substances, prostaglandins. Prostaglandins play a role in mediating the smooth muscle contractility of the womb and women with dysmenorrhoea have been shown to have high levels of prostaglandins. 

Ibuprofen is currently the only available non-prescription NSAID licensed for the relief of dysmenorrhoea.  Naproxen would be a valuable alternative.  Naproxen has a well-established history as an effective prescription only medicine (POM) for dysmenorrhoea. 

Pharmacists have demonstrated their ability to recommend OTC treatments for period pain over the years. 

The criteria for prescription control are detailed in legislation.  The applicability of the relevant criteria is considered below.

3.1 Likely to present a direct or indirect danger

Adverse reactions

Naproxen has been licensed in the UK for over 30 years as a prescription medicine.  Naproxen has also been available worldwide for a number of years. 

The commonest adverse reactions for NSAIDs including naproxen are gastrointestinal reactions such as nausea, vomiting, diarrhoea, dyspepsia, abdominal pain and less frequently gastrointestinal ulceration and perforation.  In addition, hypersensitivity reactions (including anaphylaxis, serious skin reactions and exacerbation of asthma), neurological reactions, bone marrow depression, nephrotoxocity, fluid retention and hepatic impairment may occur.  The use of some NSAIDs may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). These serious adverse effects are usually associated with longer term, higher dose prescription use of naproxen in older patients.

The nature of this application means that the use of naproxen will be limited to short periods of time at the lowest effective dose in otherwise healthy young females.  This is  emphasized in the product’s labelling.

Since the 1990’s, naproxen has also been available as a non-prescription medicine in Europe, the United States and Australia.  A review of the Netherlands, German, Australian and American pharmacovigilance data did not detect any specific safety concern associated with non-prescription use.

Safety related to misdiagnosis

Primary dysmenorrhoea has been accepted as a suitable condition for self-diagnosis. There are currently P and GSL medicines available for its treatment.

3.2 Frequent and widespread incorrect use

Naproxen is unlikely to be used incorrectly.  Naproxen is not a drug of abuse and has a wide safety margin in accidental or intentional overdose.  The product labelling and limited pack size (not more than 9 tablets) will help to reduce the possibility of incorrect use.

3.3 Activity and/or side effects require further investigation

The safety of NSAIDs including naproxen is regularly reviewed.  Concerns tend to be primarily related to long-term prescription use often by “at risk” groups of patients, rather than short term intermittent use by otherwise healthy women. 

4.  SUPPORT FOR THE RECLASSIFICATION

This is a company application.

5. SPECIFIC OTC REQUIREMENTS

Since period pain rarely lasts for longer than 3 days it is proposed that the pack size be restricted to 3 days treatment (i.e. 9 tablets).  The number of tablets that women need to take to relieve their period pain varies considerably from a single dose to a couple of doses over one to three days.  Very few women have to take the full daily dose over three days to manage their symptoms.  The “prn” (as needed) dosing enables women to titrate to the lowest effective dose.  The product labelling will emphasize the fact that only the individual’s lowest effective dose needs to be taken up to a maximum of 3 tablets each day for 3 days.

Warnings consistent with those required for the existing oral OTC NSAID, ibuprofen, will be included in the product information for naproxen 250mg tablets.

6. CONSIDERATION BY COMMISSION ON HUMAN MEDICINES

The Commission on Human Medicines (CHM) considered this reclassification application and advised that naproxen 250mg tablets could safely be supplied without a prescription as a Pharmacy medicine, under the following conditions: 

• Tablets for the treatment of primary dysmenorrhoea in women aged between 15 and 50 years

• Maximum strength:  250mg

• Maximum dose:  500mg

• Maximum daily dose:  750mg

• Maximum duration of treatment:  3 days

• Maximum pack size:  9 tablets

The CHM has also made the following remark to the applicant:

The applicant should put forward proposals to monitor the usage and the safety profile of naproxen in the pharmacy setting. 6 monthly Periodic Safety Update Reports (PSURs) should be provided including any cases with serious gastrointestinal adverse drug reactions reported in the proposed target population.

7. SAFETY PROFILE

The safety of NSAIDs and the risk factors for NSAID-induced adverse events, particularly on the gastrointestinal tract and cardiovascular system have been the subject of many studies and reviews. 

Gastrointestinal safety

NSAID use is associated with gastrointestinal toxicity. The risk of gastrointestinal ulcer with bleeding and perforation during NSAID use depends on the underlying patient characteristics.  The risk is both dose and patient-age related.  Data demonstrate that the risk rises with dose, age, and it is greater in men than in women.

Ulcer disease is infrequent in women less than 50 years old. The risk of adverse upper gastrointestinal events in the proposed treatment population should be low because of limited drug exposure and because evidence suggests that women are at lower risk than men, as are younger than older people.  Therefore, the risk of gastrointestinal adverse events with naproxen treatment is likely to be low in women receiving treatment for dysmenorrhoea. 

Cardiovascular Safety

Following a review of cardiovascular safety of NSAIDs including naproxen, the Committee for Medicinal Products for Human Use (CHMP) published an assessment report, which concluded that the use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of naproxen (1000mg daily) may be associated with a lower risk, some risk cannot be excluded. 

The overall risk-benefit of naproxen is favourable when it is used in accordance with the product information. 

 

This leaflet has important information about your medicine. Please read it carefully before you take these tablets. 

If you have any questions, please ask your doctor or pharmacist.

What is your medicine for?

These tablets contain 250mg of naproxen.  This medicine is used to treat period pain (also called menstrual pain or dysmenorrhoea)

  Naproxen belongs to a group of painkillers called Non-Steroidal Anti-inflammatory Drugs (also called NSAIDs). 

  Other medicines in this group include ibuprofen and aspirin.

Who should take this medicine?

Only take this medicine if you are between 15 and 50 years old.

Ask your doctor, pharmacist or nurse if you need more information.

Things to know before taking your medicine

Do not take this medicine if you have, or have ever had a stomach ulcer, or other serious stomach problems, or you have severe heart failure    

 This includes any stomach pain that did not go away and any bleeding in the stomach.  

 If you have ever had anything like this then you should not take these tablets.

Do not take this medicine if you are already taking aspirin, low dose aspirin or any other non-steroidal anti-inflammatory drug (NSAID) like ibuprofen.  This includes cyclo-oxygenase-2 selective inhibitors (COX2) like celecoxib.  If you are taking these medicines, talk to your doctor before taking this medicine.

Do not take this medicine if you have ever had an allergic reaction to:

 Naproxen, aspirin, ibuprofen, or another non-steroidal anti-inflammatory drug (NSAID)

 Anything else in these tablets (look at the list in the ‘What’s in these tablets’ section, at the end of the leaflet).

Allergic reactions can include wheezing, itchy runny nose, rashes or swelling of the skin.

Do not take this medicine unless your doctor said you can, if:

 You are breast feeding, or there is a chance you may be pregnant.

Do not take this medicine unless your doctor said you can, if you have these illnesses:

 Heart problems, previous stroke or think you might be at risk of these conditions (for example if you have high blood pressure, diabetes or high cholesterol or are a smoker).

 Kidney or liver problems.

 A blood clotting problem, or you take an anticoagulant (blood thinner) like heparin or warfarin.

 Asthma or any allergic illness which makes it hard to breath.

Important information about some of the ingredients of this medicine

 This medicine contains lactose.  If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 

Talk to your doctor or pharmacist first, if you are taking any of these other medicines:

 Ciclosporin - a medicine used after organ transplants

 Steroids  (also called corticosteroids) - like prednisolone

 Quinolone antibiotics (ciprofloxacin, norfloxacin or levofloxacin) or sulphonamides (like co-trimoxazole)

 Lithium – a medicine for depression

 Methotrexate – a medicine for cancer and other illnesses

 Probenecid – a medicine for gout

 Water tablets (diuretics)

 Medicines for high blood pressure (anti-hypertensives)

 Medicines for your heart (digoxin or glycosides)

 Phenytoin - a medicine for epilepsy

 Mifepristone to terminate a pregnancy in the last 8 - 12 days.

 Low dose aspirin – a medicine for “thinning the blood”

 Antidepressants of the serotonin re-uptake inhibitor (SSRI) type like fluoxetine

How to take this medicine

First day:

 When the pain starts, take two tablets

 Then after 6 to 8 hours, take one more tablet that day, if you need it

Second day:

 Take one tablet every 6 to 8 hours if needed

Third day:

 Take one tablet every 6 to 8 hours if needed

Do not take more than 3 tablets each day

Always take the lowest effective dose for you.  Do not take more than the recommended dose of up to three tablets in a day, or the duration of up to three days treatment in any one month (menstrual cycle).

Taking the tablets:

 Swallow the tablets whole with a drink of water. Do not chew or crush them

 Take the tablets with or after food 

 Only take the tablets for as long as you need them for the period pain. You may not need to take the tablets all the time for all 3 days. If you still have pain after 3 days of treatment, talk to your doctor. Do not take the tablets for more than 3 days in any one period (cycle)

 If you see a doctor, pharmacist or nurse or go into hospital, tell them you are taking this medicine

 Overdose: If you (or someone else) takes too many tablets, go to the nearest hospital casualty department or your doctor straight away

 

Side effects that might happen while taking your medicine

Like all medicines, these tablets can cause side effects

If any of the following happen to you, stop the tablets and tell a doctor, pharmacist or nurse immediately:

  Sickness or being sick (possibly with blood), diarrhoea (sometimes with blood and mucus), dark “tarry” stools

  Stomach pain, indigestion, stomach ulcers and bleeding in the stomach

 Worsening of stomach problems (ulcerative colitis or Crohn’s disease)

  Sore mouth or unusual painful mouth ulcers

  Allergic reactions like asthma, wheezing or difficulty breathing

  Blood in the urine, more or less urine than normal or cloudy urine.  Pain around the kidneys (upper back)

  Severe blisters and bleeding of the skin, nose and mouth (Stevens-Johnson syndrome)

  Skin problems including rashes, itching, nettle rash or a bruise-like rash.  There may also be blistering and flaking of the skin

  Swelling of the face, lips, tongue and throat (causing difficulty swallowing or breathing)

  Jaundice (yellowing of the skin or whites of the eyes and or pale coloured stools and dark urine)

  Fits (convulsions)

  NSAIDs such as this medicine may be associated with a small increased risk of heart attack (“myocardial infarction”) or stroke

If you have any of the following while taking this medicine, stop taking it and tell your doctor:

 Swelling of the blood vessels and a build up of fluid which may cause swollen ankles

 Kidney or liver problems: these will show up in blood or water tests

 Nervous system: altered vision, headaches, pins-and-needles or numbness, depression, confusion, hallucinations, dizziness and vertigo, insomnia, ringing in the ears, hearing problems, tiredness, drowsiness, inability to concentrate, mental slowing, a general feeling of being unwell or fever with a dislike of light

 Blood problems – these may cause unusual tiredness or weakness, unusual bleeding or unexplained bruising, fever or chills, sore throat, ulcers in your mouth or throat

 Sensitivity to light

 Hair loss (alopecia).

Other side effects that may occur include those listed below.  If you experience any of these symptoms or have a any other unusual symptoms or concerns with your medicine, stop taking the tablets and see your doctor.

 Other stomach and intestine effects include flatulence or constipation

 High blood pressure and heart failure have been reported with NSAID use

 NSAIDs have been associated with aseptic meningitis which can include symptoms of headache, stiff neck, disorientation, fever and sensitivity to light in people with auto-immune disorders.

Medicines which contain NSAIDs such as naproxen may be associated with a small increased risk of heart attack (“myocardial infarction”) or stroke.  Any risk is more likely with high doses and prolonged treatment. 

Adrenal function tests: The tablets may interfere with these tests – check with your Doctor before the test.

Driving and using machines: These tablets may make you dizzy, sleepy or cause vertigo, loss of concentration, difficulty sleeping, depression or visual problems.  Do not drive or use machines if this happens to you.

 

How to store your tablets

 Do not use this medicine after the use-by date

 Keep these tablets in their original packaging and do not store above 25oC

 Store your medicine in a safe place, out of the reach and sight of children

 This medicine is for you ONLY, do not give it to anyone else

 Return all unused medicines to your pharmacist for safe disposal

What is in these tablets?

Each white round coated tablet contains 250mg of naproxen, which is the active medicine. The tablets come in boxes of 3, 6, 8 or 9 tablets. The tablet is gastro-resistant (covered with a coating which stops the tablet dissolving in the stomach). This means that the naproxen is released further down in your gut.

The tablets also have inactive contents: lactose, maize starch, polyvidone, sodium starch glycollate and magnesium stearate. Also, the coating contains colloidal silicon dioxide, polyvinyl acetate phthalate, polyethylene glycol, stearic acid, hydroxypropyl methylcellulose, sodium alginate, sodium bicarbonate, purified talc, triethyl citrate, the colour titanium dioxide (E171) and black printing ink.

The marketing authorisation holder and company responsible for manufacture is Approved Prescription Services Limited, Eastbourne, BN22 9AG, England.

Remember

This leaflet does not contain all the information about these tablets. Please ask your doctor, nurse or pharmacist if you have any questions.

Revised: March 2007

 

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