CUPROFEN PLUS

1.

NAME OF THE MEDICINAL PRODUCT Solpaflex tablets Cuprofen PLUS Solpadeine Migraine Ibuprofen & Codeine Tablets

2.

Qualitative and Quantitative Composition Ibuprofen Ph Eur 200 mg Codeine Phosphate Hemihydrate Ph Eur 12.8 mg

3.

Pharmaceutical Form White film-coated capsule-shaped tablets.

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 in 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 Dosage: Do not take for more than 3 days continuously without medical review. Adults: The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. 200 mg 400 mg, 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 1200 mg in any 24 hour period. Children under 12 years: Not recommended 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.

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 anti-inflammatory 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 hepatic failure (see section 4.4). Pregnancy (see section 4.6).

4.4.

Special Warnings or Precautions for Use Undesirable effects may be minimised 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 cyclo-oxygenase-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, Crohns 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 anytime 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. Dermatological: 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. Solpaflex tablets/ Cuprofen PLUS / Solpadeine Migraine Ibuprofen & Codeine Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Solpadeine Migraine Ibuprofen & Codeine Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucosegalactose malabsorption should not take this medicine. Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers 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 is for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin 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. Usually it is safe to take this medicine while breast feeding as the levels of the active ingredients of this medicine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels in their breast milk. If any of the following side effects develop in you or your baby, stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing. Section 3 Dosage



Do not take for more than 3 days. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist. 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 short term 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.

Interactions with other Medicaments and other forms of Interaction This 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).

This medicine should be used with caution in combination with: 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 embryofoetal 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 oligohydroamniosis; 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: At normal therapeutic doses codeine and its active metabolites 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 metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant. If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects. 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.

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 Crohns 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. Skin and subcutaneous tissue disorders: Uncommon: Various skin rashes Very rare: Severe forms of skin reactions such as bullous reactions, including StevensJohnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur. 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 Overuse of this product, defined as consumption of quantities in excess of the recommended dose, or consumption for a prolonged period of time may lead to physical or psychological dependency. Symptoms of restlessness and irritability may result when treatment is stopped. Codeine The effects in over dosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms

An overdose of codeine is characterised, in the first phase, by nausea and vomiting. An acute depression of the respiratory centre can cause cyanosis, slower breathing, drowsiness, ataxia and, more rarely, pulmonary oedema. Respiratory pauses, miosis, convulsion, collapse and urine retention as well as signs of histamine release have been observed as well. Hypotension and tachycardia are possible but unlikely. Management This should include 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. Ibuprofen In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours. Symptoms: Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics. Management: Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5.
5.1.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic Properties
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation. Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. 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. Codeine is a centrally-acting opioid analgesic.

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.

Pharmaceutical Particulars 6.1. List of Excipients Microcrystalline cellulose Hydrogenated vegetable oil Sodium starch glycollate Colloidal silicon dioxide Cellactose 80 Hydroxypropyl methyl cellulose Polyethylene glycol 400 6.2. Incompatibilities Not applicable.

6.3.

Shelf Life Three years

6.4.

Special Precautions for Storage None.

6.5

Nature and contents of container
White opaque polyvinyl chloride (250m)/aluminium foil (20m) blister packs containing 4, 6, 12 or 24 tablets.

6.6.

Instruction for Use/Handling Not applicable.

Administrative Data 7. Marketing Authorisation Holder SmithKline Beecham (SWG) Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom Trading as: GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K. 8. Marketing Authorisation Number PL 00071/0431

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/10/2006

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DATE OF REVISION OF THE TEXT
09/01/2012