Migraleve
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Migraleve
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Migraleve Pink tablet contains:
Paracetamol DC 96% 520 mg
(equivalent to Paracetamol 500 mg)
Codeine Phosphate 8 mg
Buclizine Hydrochloride 6.25 mg
Each Migraleve Yellow tablet contains:
Paracetamol DC 96% 520 mg
(equivalent to Paracetamol 500 mg)
Codeine Phosphate 8 mg
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated Tablets.
Migraleve Pink Tablets
Pink, capsule-shaped, film-coated tablets marked MGE on one face.
Migraleve Yellow Tablets
Yellow, capsule-shaped, film-coated tablets marked MGE on one face.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the short term treatment of acute moderate pain which is not relieved by Paracetamol, ibuprofen or aspirin alone such as migraine attacks including the symptoms of migraine headache, nausea and vomiting.
Codeine is indicated in children older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen (alone).
4.2 Posology and method of administration
Route of administration - oral.
The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.
Adults and Children 15 years and over: Two Migraleve Pink tablets to be swallowed immediately it is known that a migraine attack has started or is imminent. If further treatment is required, two Migraleve Yellow tablets every 4 hours.
Maximum dose: 8 tablets (two Migraleve Pink and six Migraleve Yellow) in 24 hours.
Children 12 - 14 years:
One Migraleve Pink tablet to be swallowed immediately it is known that a migraine attack has started or is imminent. If further treatment is required, one Migraleve Yellow tablet every 4 hours.
Maximum dose: 4 tablets (one Migraleve Pink and three Migraleve Yellow) in 24 hours.
Children aged less than 12 years:
Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).
4.3 Contraindications
In all paediatric patients (0 to 18 years of age) who undergo tonsillectomy and/or adenoidectomy for Obstructive Sleep Apnoea Syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4).
In women during breastfeeding (see section 4.6).
In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers
Hypersensitivity to any of the ingredients.
4.4 Special Warnings and Precautions for Use
Migraine should be medically diagnosed.
CYP2D6 metabolism
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression which may be life-threatening and very rarely fatal.
Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:
|
Population |
Prevalence % |
|
African/Ethiopian |
29% |
|
African American |
3.4% to 6.5% |
|
Asian |
1.2% to 2% |
|
Caucasian |
3.6% to 6.5% |
|
Greek |
6.0% |
|
Hungarian |
1.9% |
|
Northern European |
1%-2% |
When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose (see section 4.6 Use during pregnancy and lactation).
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.
Migraleve tablets contain potent medicaments and should not be taken continuously for extended periods without the advice of a doctor. Do not exceed the stated dose.
Buclizine has an antimuscarinic action and therefore should be used with caution in prostatic hypertrophy, urinary retention. Also where susceptibility to angle-closure glaucoma.
Post-operative use in children
There have been reports in the published literature that codeine given postoperatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.
Children with compromised respiratory function
Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.
For products in packs of 32 tablets or fewer:
Front of pack
• Can cause addiction.
• For three days use only.
Back of Pack
• This medicine can make you feel sleepy. Do not drive while taking this medicine until you know how it makes you feel. See the leaflet inside for more information.
• Migraleve is for use in acute moderate pain associated with migraine which has been previously diagnosed by a doctor and where other painkillers have not worked. Do not take less than four hours after taking other painkillers.
• List of indications as agreed in 4.1 of the SmPC.
• If you need to take this medicine for more than three days you must see your doctor or pharmacist.
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse.
For both POM and P products:
Patient Information Leaflet Headlines (at the start of the PIL)
• For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone such as migraine attacks including the symptoms of migraine headache, nausea and vomiting.
• You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice.
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it.
• If you take this medicine for headaches for more than three days it can make them worse.
Section 1: What this medicine is for
For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone such as migraine attacks including the symptoms of migraine headache, nausea and vomiting.
Codeine can be used in children over 12 years of age for the short-term relief of moderate pain that is not relieved by other painkillers such as paracetamol or ibuprofen alone.
This product contains codeine. Codeine belongs to a group of medicines called opioid analgesics which act to relieve pain. It can be used on its own or in combination with other pain killers such as paracetamol.
Section 2: Before taking this medicine
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it.
• If you take this painkiller for headaches for more than three days it can make them worse.
• Ask your doctor or pharmacist for advice before taking this medicine if you are pregnant.
Do not use this medicine:
• For pain relief in children and adolescents (0-18 years of age) after removal of their tonsils or adenoids due to obstructive sleep apnoea syndrome
• If you know that you metabolise very rapidly codeine into morphine
• If you are breastfeeding
Warnings and precautions
Codeine is transformed to morphine in the liver by an enzyme. Morphine is the substance that produces pain relief. Some people have a variation of this enzyme and this can affect people in different ways. In some people, morphine is not produced or produced in very small quantities, and it will not provide enough pain relief. Other people are more likely to get serious side effects because a very high amount of morphine is produced. If you notice any of the following side effects, you must stop taking this medicine and seek immediate medical advice: slow or shallow breathing, confusion, sleepiness, small pupils, feeling or being sick, constipation, lack of appetite.
Children and adolescents
Use in children and adolescents after surgery
Codeine should not be used for pain relief in children and adolescents after removal of their tonsils or adenoids due to Obstructive Sleep Apnoea Syndrome.
Use in children with breathing problems
Codeine is not recommended in children with breathing problems, since the symptoms of morphine toxicity may be worse in these children.
Pregnancy and breastfeeding
Do not take codeine while you are breastfeeding. Codeine and morphine passes into breast milk.
Special warnings about drowsiness
These tablets may cause drowsiness. If affected do not operate machinery. This medicine can affect your ability to drive.
Do not drive whilst taking this medicine until you know how this medicine affects you.
It may be an offence to drive when taking this medicine if your ability to drive safely is affected.
Talk to your doctor or pharmacist if you are not sure whether it is safe for you to drive while taking this medicine.
There is further information for patients who are intending to drive in the UK - go to https://www.gov.uk/drug-driving-law.
Avoid alcoholic drink.
Section 3: How to take this medicine
Under the sub-heading ‘Check the tables below to see how much medicine to take’
• Do not take less than four hours after taking other painkillers.
• Children aged 12 years or above should take one Migraleve Pink tablet to be swallowed immediately if it is known that a migraine attack has started or is imminent. If further treatment is required, one Migraleve Yellow tablet every 4 hours. Do not take more than 4 tablets (one Migraleve Pink and three Migraleve Yellow) in 24 hours.This medicine should not be taken for more than 3 days. If the pain does not improve after 3 days, talk to your doctor for advice.
• This medicine should not be taken by children below the age of 12 years, due to the risk of severe breathing problems.
Under the sub-heading ‘Special warnings about addiction’
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.
Section 4: Possible Side-effects
Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk ; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday - Friday) or fill in a paper form available from your local pharmacy.
Under the sub-heading ‘How do I know if I am addicted?’
If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the
following apply to you it is important that you talk to your doctor:
• You need to take the medicine for longer periods of time.
• You need to take more than the recommended dose.
• When you stop taking the medicine you feel unwell but you feel better when you start taking the medicine again.
The following statements should also be included:
• Do not take with any other product paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well. (carton)
• Contains Paracetamol. (carton)
• If you drink large amounts of alcohol, you may be more open to the side-effects of paracetamol. (leaflet)
• Do not exceed the stated dose.
• Migraleve Pink Tablets only: May cause drowsiness. If affected, do not drive or operate machinery. Avoid alcoholic drink.
• If symptoms persist, consult your doctor.
• Keep out of the reach and sight of children.
4.5 Interaction with other medicinal products and other forms of interaction
Codeine
Codeine may antagonise the effects of metoclopramide and domperidone on gastrointestinal motility.
Codeine may enhance the effects of other CNS depressants such as alcohol, hypnotics, sedatives, tranquilisers and other opioid analgesics. Codeine should be given with care to patients receiving monoamine oxidase inhibitors (MAOIs) or who have used MAOIs in the previous two weeks.
Paracetamol
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
Buclizine
Sedating antihistamines, such as buclizine, have an additive sedative effect with alcohol and other CNS depressants. Sedating antihistamines have an additive antimuscarinic action with other antimuscarinic drugs such as atropine and some antidepressants (both tricyclics and MAOIs).
4.6 Fertility, pregnancy and lactation
There is inadequate evidence for the safety of codeine in human pregnancy.
Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.
Although experiments in some animal species gave rise to adverse effects following the administration of buclizine to pregnant animals e.g. foetal abnormalities and maternal deaths, these occurred at doses in excess of 120 times the human daily dose. Whilst Migraleve is not absolutely contraindicated during pregnancy, it should only be used when the physician has considered the potential benefit outweighs the potential risk.
Codeine should not be used during breastfeeding (see section 4.3).
At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.
Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.
There is no data available relating to the safety of buclizine in breast-feeding mothers.
4.7 Effects on Ability to Drive and Use Machines
May cause drowsiness. If affected do not operate machinery.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However you would not be committing an offence (called ‘statutory defence’) if:
o The medicine has been taken to treat a medical or dental problem and o You have taken it according to the information provided with the medicine and
o It was not affecting your ability to drive safely.
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law.
Avoid alcoholic drink.
4.8 Undesirable effects
Codeine may cause constipation, drowsiness, dizziness, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy, difficulty with micturition, pruritus and sweating according to dosage and individual susceptibility.
Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is stopped.
Prolonged use of a painkiller for headaches can make them worse.
Adverse effects of paracetamol are rare. Very rarely hypersensitivity and anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocystosis but these were not necessarily causality related to paracetamol.
Buclizine hydrochloride may cause drowsiness. In addition, sedating antihistamines such as buclizine may cause headache, psychomotor impairment, dizziness, gastrointestinal disturbance, dry mouth, thickened respiratory tract secretions, difficulty in micturition or blurred vision. Hypersensitivity reactions have also been reported, in particular, skin rashes, erythema, urticaria and angioedema.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Codeine
The effects in codeine overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.
Codeine overdose associated with central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.
Management of codeine overdose includes general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.
Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.
Paracetamol
Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).
Risk Factors:
If the patient
■ Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.
Or
■ Regularly consumes ethanol in excess of recommended amounts.
Or
■ Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.
Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.
Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.
Buclizine
Overdose with sedating antihistamines is associated with antimuscarinic, extrapyramidal, and CNS effects. When CNS stimulation predominates over CNS depression, which is more likely in children or the elderly, it causes ataxia, excitement, tremors, psychoses, hallucinations and convulsions; hyperpyrexia may also occur. Deepening coma and cardiorespiratory collapse may follow. In adults, CNS depression is more common with drowsiness, coma, and convulsions, progressing to respiratory failure and cardiovascular collapse.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Codeine is a centrally acting weak analgesic. Codeine exerts its effect through p opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.
Paracetamol has analgesic, antipyretic and mild, acute anti-inflammatory properties. Paracetamol inhibits prostaglandin synthesis, especially in the CNS. Paracetamol does not inhibit chronic inflammatory reactions.
The combination of paracetamol and codeine has been shown to have hyperadditive analgesic effects in animals.
Buclizine is a piperazine derivative with the actions and uses of H1-receptor antagonists. It has anti-muscarinic and central sedative properties. It is used mainly for its anti-emetic properties.
5.2. Pharmacokinetic Properties
Paracetamol is rapidly absorbed from the upper GI tract after oral administration, with the small intestine being an important site of absorption. Peak blood levels of 15-20mcg/ml after normal 1g oral doses of paracetamol occur within 30 - 90 minutes. Depending upon dosage form, it is rapidly distributed throughout the body and is primarily metabolised in the liver with excretion via the kidney. Elimination half-life is about 2 hours after reaching a peak following a 1g oral dose. Paracetamol crosses the placental barrier and is present in breast milk.
Codeine is absorbed from the gastro-intestinal tract and peak plasma concentrations occur after one hour. Codeine is metabolised by O- and N-demethylation in the liver to morphine, norcodeine and other metabolites. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. Codeine is not extensively bound to
plasma proteins. The plasma half-life has been reported to be between 3 and 4 hours.
Buclizine hydrochloride is more slowly absorbed from the GI tract (Tmax 3 hours). The elimination half-life is approximately 15 hours.
5.3. Preclinical Safety Data
No data presented.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Migraleve Pink Tablets Gelatin
Magnesium Stearate Colloidal Anhydrous Silica Stearic Acid
Pregelatinised Maize Starch Erythrosine (E127) Hypromellose Titanium Dioxide (E171) Macrogol 400 Aluminium Oxide
Migraleve Yellow Tablets Gelatin
Magnesium Stearate Colloidal Anhydrous Silica Stearic Acid
Pregelatinised Maize Starch Hypromellose Titanium Dioxide (E171) Macrogol 400 Iron Oxide Yellow (E172) Quinoline Yellow (E104) Aluminium Oxide
6.2. Incompatibilities
None known.
Shelf life
6.3.
36 months
6.4. Special precautions for storage
None
6.5 Nature and contents of container
Packs of: 12 tablets (8 Migraleve Pink and 4 Migraleve Yellow)
Packs of: 24 tablets (16 Migraleve Pink and 8 Migraleve Yellow)
Packs of: 48 tablets (32 Migraleve Pink and 16 Migraleve Yellow)
Blister strips consist of clear amber PVC blister film and paper/aluminium foil child-resistant blister lidding.
6.6. Instruction for use and handling, (and disposal)
None.
7. MARKETING AUTHORISATION HOLDER
McNeil Products Limited
Foundation Park
Roxborough Way
Maidenhead
Berkshire
SL6 3UG
UK
8. MARKETING AUTHORISATION NUMBER
PL 15513/0105
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 28/01/2009
10
DATE OF REVISION OF THE TEXT
22/05/2014