1. Name Of The Medicinal Product
Cuprofen PLUS
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.
4. Clinical Particulars
4.1 Therapeutic Indications
Symptomatic relief of mild to moderate pain in such conditions as soft tissue injuries, including sprains, strains and musculo-tendonitis, backache, non-serious arthritic and rheumatic conditions. Also for the relief of mild to moderate pain in 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 minimum effective dose should be used for the shortest time necessary to relieve symptoms.
One or two tablets every four to six hours.
Not more than 6 tablets should be taken in 24 hours.
Children under 12 years:
Not recommended
Elderly:
No specific dosage recommendations are required unless renal or hepatic function is impaired, in which case dosage should be assessed individually.
Route of Administration:
For oral administration and short-term use only.
4.3 Contraindications
Cuprofen PLUS are contraindicated in individuals with hypersensitivity to the active ingredients 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 previous peptic ulcer.
History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see section 4.5 Interactions).
Severe hepatic failure, renal failure or severe heart failure (see section 4.4, Special warnings and precautions for use).
Last trimester of pregnancy (See section 4.6 Pregnancy and lactation).
4.4 Special Warnings And Precautions For Use
Cuprofen PLUS should be used with caution in patients with gastro-intestinal disease. In patients receiving anti-coagulant therapy, prothrombin time should be monitored daily for the first few days of combined treatment.
Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease. The possibility of cross-sensitivity with aspirin and other non-steroidal anti-inflammatory agents should be considered.
The elderly are at increased risk of the serious consequences of adverse reactions.
Patients should be advised to consult their doctor if their headaches become persistent.
Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8 Undesirable effects)
Chronic inflammatory intestinal disease (ulcerative colitis, Crohn's disease) – as these conditions may be exacerbated (See section 4.8 Undesirable effects)
Caution (discussion with a 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.
Renal impairment as renal function may further deteriorate (See section 4.3 Contraindications and Section 4.8 Undesirable effects)
Hepatic dysfunction (See section 4.3 Contraindications and section 4.8 Undesirable effects)
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 the treatment.
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.
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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5 Interactions).
When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Cardiovascular and cerebrovascular effects
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.
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 leaflet will state in a prominent position in the 'before taking' section:
• If you need to use this medicine for more than three days at a time, see your doctor, pharmacist or health care professional.
• Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.
• Taking a painkiller for headaches too often or for too long can make them worse.
The label will state (To be displayed prominently on outer pack -not boxed):
• If you need to use this medicine for more than three days at a time, see your doctor or pharmacist. Taking codeine regularly for a long time can lead to addiction.
• Taking a painkiller for headaches too often or for too long can make them worse.
Read the enclosed leaflet before taking this product.
Do not take if you
• have or have ever had a stomach ulcer, perforation or bleeding
• are allergic to ibuprofen 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
• are in the last 3 months of pregnancy
Speak to a pharmacist or your doctor before you take this product if you
• have asthma, liver, heart, kidney or bowel problems
• are in the first 6 months of pregnancy
If symptoms persist or worsen, consult your doctor
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Caution should be exercised in patients taking mono-amine oxidase inhibitors.
Ibuprofen should not be used 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 4.3 Contraindications).
Other NSAIDS: As these may increase the risk of adverse effects (See section 4.3 Contraindications).
Ibuprofen should be used with caution in combination with:
Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).
Antihypertensives and diuretics: NSAIDS may diminish the effects of these drugs.
Corticosteroids: May increase the risk of adverse reactions in the gastrointestinal tract (See section 4.4 Special warnings).
Lithium: There is evidence for potential increases in plasma levels of lithium.
Methotrexate: There is a potential for an increase in plasma methotrexate.
Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
4.6 Pregnancy And Lactation
Based on animal studies and clinical experience there is no evidence to suggest that foetal abnormalities are associated with the use of ibuprofen or codeine. As with all drugs, use should be avoided in pregnancy and lactation unless essential.
During the 3rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and its duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications).
See section 4.4 regarding female fertility.
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
Codeine may cause constipation, nausea, dizziness and drowsiness 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 then stopped.
Prolonged use of a painkiller for headaches can make them worse.
Hypersensitivity reactions have been reported and these may consist of:
a) Non-specific allergic reactions and anaphylaxis
b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnoea
c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)
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.
Hypersensitivity reactions:
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.
Gastrointestinal:
Uncommon: abdominal pain, nausea and dyspepsia.
Rare: diarrhoea, flatulence, constipation and vomiting.
Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in the elderly. Exacerbation of ulcerative colitis and Crohn's disease (See section 4.4).
Nervous system:
Uncommon: Headache
Renal:
Very Rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.
Hepatic:
Very rare: liver disorders.
Haematological:
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:
Uncommon: Various skin rashes
Very rare: Severe forms of skin reactions such as erythema multiforme and epidermal necrolysis can occur.
Immune system:
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)
Others:
Hearing disturbance.
Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.
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).
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 overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.
Symptoms
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
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. Pharmacological Properties
5.1 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.
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.
6. 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 (250μm)/aluminium foil (20μm) blister packs containing 4, 6, 12, 24, 48 or 96 tablets.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
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(S)
PL 00071/0431
9. Date Of First Authorisation/Renewal Of The Authorisation
8 February 1996
10. Date Of Revision Of The Text
10 April 2007
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