SOLPADEINE MIGRAINE IBUPROFEN & CODEINE TABLETS - summary of medicine characteristics

Solpadeine Migraine Ibuprofen & Codeine Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ibuprofen Ph Eur 200 mg

Codeine Phosphate Hemihydrate Ph Eur 12.8 mg

Excipients with known effect

Each Tablet contains:

200mg of Cellactose 80 (which is a one-body compound consisting of lactose monohydrate (73–77%) and cellulose (23–27%).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

White, film-coated capsule-shaped tablets with a white core. Embossed with Solpaflex, C+ or Migraine OR plain on both the sides.

4.

4.1. Therapeutic indications

Codeine is indicated in patients 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.

For such conditions as soft tissue injuries, including sprains, strains and musculo-tendonitis, backache, non-serious arthritic and rheumatic conditions, neuralgia, migraine, headache, dental pain and dysmenorrhoea.

4.2 Posology and method of administration

Adults:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section 4.4).

1–2 tablets, up to three times a day as required, preferably with or after food.

Leave at least four hours between doses and do not take more than 6 tablets in

any 24 hour period.

Paediatric population:

Children and adolescents aged 12 – 18 years:

1 – 2 tablets, up to three times a day as required, preferably with or after food.

Leave at least four hours between doses and do not take more than 6 tablets in any 24 hour period.

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).

Elderly:

Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in elderly patients who are prone to adverse events.

Route of Administration:

For oral administration and short-term use only.

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.

4.3. Contraindications

Solpaflex tablets / Cuprofen PLUS / Solpadeine Migraine Ibuprofen & Codeine Tablets are contraindicated in individuals with hypersensitivity to ibuprofen, codeine, opioid analgesics or any of the constituents in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal antiinflammato­ry drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe heart failure, renal failure or severe hepatic failure (see section 4.4).

Pregnancy (see section 4.6).

In all paediatric patients (0–18 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.

4.4 Special Warnings or Precautions for Use

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients taking other medications should consult a doctor prior to taking this product (see section 4.5).

Respiratory:

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Other NSAIDs:

The use of Solpaflex tablets / Cuprofen PLUS / Solpadeine Migraine Ibuprofen & Codeine Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease -increased risk of aseptic meningitis (see section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8)

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8).

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. □ 1200 mg daily) is associated with an increased risk of myocardial infarction.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/pros­taglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of

treatment (see section 4.6).

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see section 4.8).

Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Severe skin reactions:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at higher risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Acute generalized exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Ibuprofen should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

Masking of symptoms of underlying infections:

Solpadeine Migraine Tablets can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When this medicine is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

Solpadeine Migraine Ibuprofen & Codeine Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per 2 tablets, that is to say essentially ‘sodium- free’.

CYP2D6 metabolism

Codeine is metabolized by the liver enzyme CYP2D6 into morphine. 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 metabolizer 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:

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively 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 metabolize 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.

Codeine Dependence

Solpadeine Tablets contains codeine whose regular or prolonged use may produce psychological and physical dependence. This product should be used with caution in patients with current or past history of substance abuse or dependence (including drug or alcohol) or mental illness (e.g., major depression). Abuse or misuse may result in overdose and/or death (see

Section 4.9).

The leaflet will state:

Headlines section (to be prominently displayed)

This medicine is for the short-term treatment of acute moderate pain when other painkillers have not worked.

You should only take this product for a maximum of 3 days at a time. If you need to take it for longer than 3 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 3 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 3 days it can make them worse.

Section 1 What the medicine is for:

Solpadeine Migraine can be used in patients over the age of 12 years for the short- t e r m relief of moderate pain that is not relieved by other painkillers such as paracetamol or ibuprofen alone. It can be used for migraine, headaches, period and dental pain, muscle and joint pain, backache, fibrositis, tennis elbow, sports injuries (e.g. sprains, strains) and for pain due to non-serious arthritis.

Section 2 Before taking

This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it.

If you take a painkiller for headaches for more than 3 days, it can make them worse.

Section 3 Dosage

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.

Possible withdrawal effects

This medicine contains codeine and can cause addiction if you take it continuously for more than 3 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 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 as safe as possible by reporting any unwanted side-effects via the internet at http://yellowcard.mhra.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.

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 very unwell, but you feel better if you start taking the medicine again.

The label will

state:

Front of pack

Can cause addiction

Use for 3 days only

Back of pack

Solpadeine Migraine Ibuprofen & Codeine Tablets are for the shortterm treatment of acute moderate pain when other painkillers have not worked. Wait at least four hours after taking any other painkiller before you take this medicine. For: migraine, headache.

They can also be used for neuralgia, period pain, dental pain, muscle and joint pain, backache, fibrositis, tennis elbow, sports injuries (e.g. sprains, strains) and for pain due to non serious arthritis.

If you need to take this medicine continuously for more than 3 days you should see your doctor or pharmacist

This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worse.

Read the enclosed leaflet carefully before taking these tablets.

Do not take if you:

Have or have ever had a stomach ulcer, perforation or bleeding of the stomach

are allergic to ibuprofen, codeine, or any other ingredient of the product , aspirin or other related painkillers,

are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

suffer from severe liver or heart problems, or kidney problems

are pregnant

Speak to a pharmacist or your doctor before taking if you:

have or have had asthma, high cholesterol, high blood pressure, a

stroke or bowel problems

are a smoker

If symptoms persist or worsen, consult your

doctor.

Do not exceed the stated dose.

Keep out of the reach and sight of

children.

4.5 Interaction with other medicinal products and other forms of interactionThis medicine should be avoided in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDS including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Monoamine oxidase inhibitors (MAOIs): Opiate analgesics may interact with MAOIs and result in serotonin syndrome. Codeine is not considered a serotonin re-uptake inhibitor or to be associated with the risk of serotonin toxicity when used with MAOIs, however caution is advised (see section 4.4). Avoid concomitant use and for two weeks after stopping MAOIs – there is a possible CNS excitation or depression (hypertension or hypotension).

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Aminoglycosides: Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Antihypertensives and diuretics: NSAIDs may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Central nervous system depressants: Codeine may potentiate the depressive effects of central nervous system depressants including alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and psychotics such as phenothiazines.

Domperidone: Codeine may antagonize effect on gastrointestinal motility.

Hypoglycaemic agents: Inhibition of metabolism of sulfonylurea, prolonged half-life and increased risk of hypoglycaemia.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Metoclopramide: Codeine may antagonize effect on gastrointestinal motility.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8–12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6. Fertility, pregnancy and lactation

Pregnancy

Codeine:

This product should not be used during pregnancy. The safety of codeine during pregnancy has not been established relative to the possible adverse effect on foetal development. Maternal use of codeine during labour may cause respiratory depression in the child.

Ibuprofen:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of pregnancy, to:

possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, ibuprofen is contraindicated during the third trimester of pregnancy

Lactation

Ibuprofen:

In limited studies, ibuprofen appears in breast milk in very low concentration and is unlikely to adversely affect the breast fed infant.

Codeine:

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.

Female fertility

There is some evidence that drugs which inhibit cyclo-oxygenase/pros­taglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment (see section 4.4).

4.7. Effects on Ability to Drive and Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

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

4.8 Undesirable effects

Adverse reactions reported from extensive post-marketing experience are listed below by System Organ Class and frequency. The following convention has been utilised for the classification of undesirable effects: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated by available data).

Ibuprofen

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short term use. In treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Gastrointestinal disorders:

Uncommon: abdominal pain, nausea and dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis. Exacerbation of ulcerative colitis and Crohn’s disease (see section 4.4).

Nervous system disorders:

Common: Headache, drowsiness, dizziness, hearing disturbance (tinnitus). Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal and urinary disorders:

Very Rare: Acute renal failure, papillary necrosis, especially in long-term use,

associated with increased serum urea and oedema.

Hepatobiliary disorders:

Very rare: liver disorders.

Blood and lymphatic system disorders:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Skin and subcutaneous tissue disorders:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens- Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Not known: Acute generalised exanthematous pustulosis (AGEP) and photosensitivity reactions.

Immune system disorders:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Cardiac disorders:

Not known: Oedema, hypertension and cardiac failure.

Infections and infestations:

Not known: In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (See section 4.4)

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke), (see section 4.4).

Codeine

Undesirable effects depend on dose and individual patient metabolism.

Psychiatric disorders:

Not known: Drug dependency can occur after prolonged use of codeine at higher doses (see section 4.4).

Gastrointestinal disorders:

Not known: Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy (see section 4.4).

Nervous system disorders:

Not known: Dizziness, worsening of headache with prolonged use, drowsiness.

Skin and subcutaneous tissue disorder:

Not known: Pruritus, sweating.

4.9 Overdose

5.  PHARMACOLOGICAL PROPERTIES

5.1.   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Ibuprofen is rapidly absorbed following administration and is distributed throughout the whole body. The excretion is rapid and complete via kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1–2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

Codeine phosphate is absorbed from the gastrointestinal tract, with a relative bioavailability (versus parenteral administration) of about 75%. The half-life in plasma is about 2.5 – 3 hours, whilst its analgesic effect occurs from 15 minutes up to 4 – 6 hours after oral administration. Peak plasma concentrations occur about one hour post-dose. Codeine and its metabolites are excreted almost entirely via the kidneys.

5.3 Preclinical safety data

Both ibuprofen and codeine are well established analgesics with well-documented preclinical safety profiles.

6.1

6.2

Microcrystalline cellulose Hydrogenated vegetable oil Sodium starch glycollate Colloidal silicon dioxide Cellactose 80

Hydroxypropyl methyl cellulose Polyethylene glycol 400

Not applicable.

7   MARKETING AUTHORISATION HOLDER

8 MARKETING AUTHORISATION NUMBER(S)

PL 02855/0073

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

20/10/2006