NUROMOL DUAL ACTION 200 MG 500 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Nuromol Pain Relief 200mg/500mg Film Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains ibuprofen 200 mg and paracetamol 500 mg.

For a full list of excipients see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet (Tablet)

White to off-white, oval shaped, pearlescent tablets de-bossed with an identifying helix.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the temporary relief of mild to moderate pain associated with migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, pain of non-serious arthritis, cold and flu symptoms, sore throat and fever. This product is especially suitable for pain which has not been relieved by ibuprofen or paracetamol alone.

Nuromol Pain Relief 200mg/500mg Film Coated Tablets is indicated in adults aged 18 years.

4.2 Posology and method of administration

For oral administration and short term-use only (not more than 3 days).

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section 4.4). The patient should consult a doctor if the symptoms persist or worsen or if the product is required for more than 3 days.

This medicine is for short-term use and it is not recommended for use beyond 3 days.

Adults: One tablet to be taken up to three times per day with water. The interval between single doses should be at least six hours.

If the one tablet dose does not control symptoms, a maximum of two tablets may be taken up to three times a day. Leave at least six hours between doses.

Do not take more than six tablets (1200mg Ibuprofen, 3000mg Paracetamol) in any 24 hours period.

To minimise side effects, it is recommended that patients take this medicine with food.

Elderly: No special dosage modifications are required (see section 4.4).

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used for the shortest possible duration. The patient should be monitored regularly for gastrointestinal bleeding during NSAID therapy.

Paediatric population

Not for use by children and adolescents under 18 years.

Method of administration

Oral use.

4.3 Contraindications

This product is contraindicated:

In patients with a known hypersensitivity to active substances – ibuprofen, paracetamol or to any of the excipients listed in section 6.1.

In patients with a history of hypersensitivity reactions (e.g. bronchospasm, angioedema, asthma, rhinitis, or urticaria) associated with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs).

In patients with a history of, or an existing gastrointestinal ulceration/per­foration or bleeding, including that associated with NSAIDs (see Section 4.4).

Patients with defects in coagulation.

In patients with severe hepatic failure, severe renal failure or severe heart failure (NYHA Class IV) (see Section 4.4).

In concomitant use with other NSAID containing products, including cyclo-oxygenase-2 (COX-2) specific inhibitors and doses of acetylsalicylic acid above 75 mg daily -increased risk of adverse reactions (see Section 4.5).

In concomitant use with other paracetamol-containing products – increased risk of serious adverse effects (see Section 4.5).

During the last trimester of pregnancy due to risk of premature closure of the foetal ductus arteriosus with possible pulmonary hypertension (see Section 4.6)

4.4 Special warnings and precautions for use

This medicine is for short-term use and is not recommended for use beyond 3 days.

Paracetamol:

Care is advised in the administration of Paracetamol to patients with severe renal or severe hepatic impairment. The hazard of paracetamol overdose is greater in patients with noncirrhotic alcoholic liver disease. Do not take with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed, serious liver damage (see section 4.9).

Ibuprofen:

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Section 4.2, and gastrointestinal and cardiovascular risks below) and by patients taking the dose with food (see Section 4.2).

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see Section 4.2).

Caution is required in patients with certain conditions:

Respiratory disorders:

In patients suffering from, or with a history of, bronchial asthma or allergic disease NSAIDs have been reported to precipitate bronchospasm.

Cardiovascular, renal and hepatic impairment:

The administration of NSAIDs may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients. Treatment should be stopped in those patients who develop severe renal failure (see Section 4.3).

Dose reduction is recommended in patients showing signs of worsening hepatic function. Treatment should be stopped in those patients who develop severe liver failure (see section 4.3).

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical studies suggest that use of ibuprofen, particularly at high doses (2400 mg daily) with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. <1200mg daily) is associated with an increased risk of arterial thrombotic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided.

Careful consideration should be exercised before initiating long-term treatment for patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) particularly if high doses of ibuprofen (2400 mg/day) are required.

Gastrointestinal bleeding, ulceration and perforation:

Gastrointestinal (GI) bleeding, ulceration and 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. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and 4.5).

Patients with a history of GI toxicity, particularly the 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 antiplatelet agents such as acetylsalicylic acid (see Section 4.5).

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

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

SLE and mixed connective tissue disease:

In patient with systemic lupus erythematosus (SLE) and mixed connective tissue disease disorders there may be an increased risk of aseptic meningitis (see Section 4.8).

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 highest 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 generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Use of this product 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.

Impaired female fertility:

The use of the product may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of the product should be considered.

Masking of symptoms of underlying infections

This medicinal product 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.

4.5 Interaction with other medicinal products and other forms of interaction

This product (like any other paracetamol containing products) is contraindicated in combination with other paracetamol containing products – increased risk of serious adverse effects (see Section 4.3).

This product (like any other ibuprofen containing products and NSAIDs) is contraindicated in combination with:

Acetylsalicylic acid, unless low-dose acetylsalicylic acid (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 competitively inhibit the effect of low dose acetylsalicylic acid on platelets aggregation when they are dosed concomitantly. Although, there are uncertainties regarding the extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional use (see section 5.1).

Other NSAIDs including cyclo-oxygenase-2 selective inhibitors as these may increase the risk of adverse effects (see Section 4.3).

This product (like any other paracetamol containing products) should be used with caution in combination with:

Chloramphenicol: Increased plasma concentration of chloramphenicol.

Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, cholestyramine should not be taken within one hour if maximal analgesia is required.

Metoclopramide and Domperidone: The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

Warfarin: 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.

This product (like any other ibuprofen containing products and NSAIDs) should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, i.e. warfarin.

Antihypertensives: (ACE inhibitors and Angiotensin II Antagonists) and diuretics: NSAIDs may reduce the effects of these drugs. In some patients with compromised renal function (e.g dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking a coxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically therafter. Diuretics may increase the risk of nephrotoxicity of NSAIDS.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see Section 4.4).

Acetylsalicylic acid: Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

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

Ciclosporin: Increased risk of nephrotoxicity.

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

Diuretics: Reduced diuretic effect. Diuretics may increase the risk of nephrotoxicity of NSAIDs.

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate.

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

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.

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

Zidovudine: Increased risk of haematological toxicity with 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.

4.6 Pregnancy and lactation

Pregnancy:

There is no experience of use of this product in humans during pregnancy.

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol use at the recommended dosage.

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

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 a 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 the 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 3rd trimester of pregnancy (see section 4.3).

Therefore if possible, the use of this product should be avoided in the first six months of pregnancy and contraindicated in the last three months of pregnancy (see Section 4.3).

Breastfeeding

Ibuprofen and its metabolites can pass in very small amounts (0.0008% of the maternal dose) into the breast milk. No harmful effects to infants are known.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breastfeeding.

Therefore it is not necessary to interrupt breastfeeding for short-term treatment with the recommended dose of this product.

Fertility:

See Section 4.4 regarding female fertility.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected patients should not drive or operate machinery.

4.8 Undesirable effects

Clinical trials with this product have not indicated any other undesirable effects other than those for ibuprofen or paracetamol alone.

The following table lists adverse effects from pharmacovigilance data experienced by patients taking ibuprofen alone or paracetamol alone in short-term and long-term use.

1Examples include agranulocytosis, anaemia, aplastic anaemia, haemolytic anaemia leucopenia, neutropenia, pancytopenia and thrombocytopenia.

First signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising and nose bleeding.

2Hypersensitivity reactions have been reported. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity, e.g. asthma, aggravated asthma, bronchospasm or dyspnoea, or © various skin reactions e.g, pruritus, urticaria, angioedema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis, and erythema multiforme).

3The pathogenic mechanism of drug-Induced aseptic meningitis is not fully understood.

However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, Single cases of aseptic meningitis in patients with existing autoimmune disorders (such as systemic lupus erythematosus and mixed connective tissue disease) during treatment with Ibuprofen, with symptoms such as: stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see Section 4.4).

4Clinical studies suggest that use of ibuprofen, particularly at high doses (2400mg/day) may be associated with a small increased of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4)

5The adverse events observed most often are gastrointestinal in nature.

6Sometimes fatal, particularly in the elderly.

7 See section 4.4.

8In overdose Paracetamol can cause acute hepatic failure, hepatic failure, hepatic necrosis and

liver injury (see Section 4.9).

9 Especially in long-term use, associated with increased serum urea and oedema. Also, includes papillary necrosis.

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10 g (equivalent to 20 tablets) or more of paracetamol. Ingestion of 5 g (equivalent to 10 tablets) or more of paracetamol may lead to liver damage if the patient has one or more of the risk factors below:

a) Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

b) Regularly consumes alcohol in excess of recommended amounts.

c) Is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia

Symptoms

Symptoms of paracetamol overdose in the first 24 hours include pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion as liver function tests become abnormal. 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.

Management

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.

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.

Patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should seek medical advice from a poisoning specialist and be managed in accordance with established guidelines.

Ibuprofen

In children ingestion of more than 400 mg/kg of Ibuprofen 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 if there is a co-incident of dehydration. 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:- Musculoskeletal system, anti-inflammatory and antirheumatic products, non-steroids, propionic acid derivatives. Ibuprofen combinations.

ATC Code: M01AE51

The pharmacological actions of ibuprofen and paracetamol differ in their site and mode of action. These complementary modes of action are synergistic which results in greater antinociception and antipyresis than the single actives alone.

Ibuprofen is an NSAID that has demonstrated its efficacy in the common animal experimental inflammation models by inhibition of prostaglandin synthesis. Prostaglandins sensitise nociceptive afferent nerve terminals to mediators such as bradykinin. Ibuprofen therefore elicits an analgesic effect through peripheral inhibition of the cycloxygenase-2 (COX-2) isoenzyme with a subsequent reduction in sensitisation of nociceptive nerve terminals. Ibuprofen has also been shown to inhibit induced-leucocyte migration into inflamed areas. Ibuprofen has a pronounced action within the spinal cord due, in part, to the inhibition of COX. Ibuprofen's an­tipyretic effects are produced by the central inhibition of prostaglandins in the hypothalamus. Ibuprofen reversibly inhibits platelet aggregation. In humans, ibuprofen reduces inflammatory pain, swellings and fever.

Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelets aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release acetylsalicylic acid (81mg), a decreased effect of acetylsalicylic acid 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 (see section 4.5).

Paracetamol's exact mechanism of action is still not completely defined; however there is considerable evidence to support the hypothesis of a central antinociceptive effect. Various biochemical studies point to inhibition of central COX 2 activity. Paracetamol may also stimulate the activity of descending 5-hydroxytryptamine (serotonin) pathways that inhibit nociceptive signal transmission in the spinal cord. Evidence has shown that paracetamol is a very weak inhibitor of peripheral COX-1 and 2 isoenzymes.

The clinical efficacy of ibuprofen and paracetamol has been demonstrated in pain associated with headache, toothache and dysmenorrhoea, and fever, furthermore efficacy has been shown in patients with pain and fever associated with cold and influenza and in pain models such as sore throat, muscular pain or soft tissue injury and backache.

This product is especially suitable for pain which has not been relieved by ibuprofen 400 mg or paracetamol 1000 mg alone, and faster pain relief than ibuprofen.

Randomised, double-blind placebo-controlled studies were conducted with the combination using the acute pain model of post-operative dental pain. The studies show that:

This product provides more effective pain relief than paracetamol 1000 mg (p<0.0001) and ibuprofen 400mg (p<0.5) which are clinically and statistically significant

Duration of analgesia was significantly longer for this product (8.4 hours) compared to paracetamol 500 mg (4 hours, p<0.0001) or 1000 mg (5.2 hours, p<0.0001).

The global evaluation of the study medication by the subjects showed high levels of satisfaction with 88.0% rating the product as ‚good‘, ‚very good‘ or ‚excellent‘ in achieving pain relief. The fixed combination product performed significantly better than ibuprofen 200mg, paracetamol 500mg and 1000 mg (p<0.001 in all cases).

A one tablet dose of this product provides more effective pain relief than a combination of paracetamol 1000 mg / codeine phosphate 30 mg (p=0.0001) and was shown to be noninferior to a combination of ibuprofen 400 mg / codeine phosphate 25.6 mg.

This product has a fast onset of action with ‚confirmed perceptible pain relief‘ achieved in a median of 15.6 minutes (1tablet dose) or 18.3 minutes (2 tablets dose), which is faster than for ibuprofen 200 mg (30.1 minutes, p<0.001), ibuprofen 400 mg (23.8 minutes, p=0.0001) and paracetamol 500 mg (23.7 minutes, p=0.0001). ‚Meaningful pain relief‘ for this product was achieved in a median of 39.3 minutes (1 tablet dose) or 44.6 minutes ( 2 tablets dose), which was significantly faster than for ibuprofen 200 mg (80.0 minutes, p<0.0001), ibuprofen 400 mg (70.5 minutes, p=0.0001), paracetamol 500 mg (50.4 minutes, p=0.001) and paracetamol 1000 mg (45.6 minutes, p<0.05)

Other randomised, double-blind placebo-controlled studies were conducted with the combination using the acute pain model of post-operative dental pain. The studies show that:

This product provides more effective pain relief than paracetamol 1000 mg (p<0.0001) and ibuprofen 400 mg (p< 0.05).

Duration of analgesia was significantly longer for this product (9.1 hours) compared to paracetamol 500 mg (4 hours) or 1000 mg (5.2 hours).

The global evaluation of the study medication by the subjects showed high levels of satisfaction with 93.2% rating the product as ‚good‘, ‚very good‘ or ‚excellent‘ in achieving pain relief. The fixed combination product performed significantly better than paracetamol 1000 mg (p<0.0001).

Another randomised, double-blind controlled clinical study was conducted with the product in the treatment of chronic knee pain. The study showed that:

The product provides more effective pain relief than paracetamol 1000 mg in short term treatment (p<0.01) and long term treatment (p<0.01).

The global evaluation of the product by the subjects showed high levels of satisfaction with 60.2% rating the product as ‚good‘ or ‚excellent‘ as a long term treatment for a painful knee. The product performed significantly better than paracetamol 1000 mg (p<0.001).

This product provides more effective pain relief than a combination of paracetamol 1000 mg / codeine phosphate 30 mg (p<0.0001), and a combination of ibuprofen 400 mg / codeine phosphate 25.6 mg (p=0.0001).

5.2 Pharmacokinetic properties

Absorption

Ibuprofen is well absorbed from the gastrointestinal tract and is extensively bound to plasma proteins. Ibuprofen diffuses into the synovial fluid. Plasma levels of ibuprofen from this product are detected from 5 minutes with peak plasma concentrations achieved within 1–2 hours after ingestion on an empty stomach. When this product was taken with food peak ibuprofen plasma levels were lower and delayed by a median of 25 minutes, but overall extent of absorption was equivalent.

Biotransformation

Ibuprofen is metabolised in the liver to two major metabolites with primary excretion via the kidneys, either as such or as major conjugates, together with a negligible amount of unchanged ibuprofen. Excretion by the kidney is both rapid and complete. The elimination half-life is approximately 2 hours.

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

No significant differences in ibuprofen pharmacokinetic profile are observed in the elderly.

Paracetamol is readily absorbed from the gastrointestinal tract. Plasma protein binding is negligible at usual therapeutic concentrations, although this is dose-dependent. Plasma levels of paracetamol from this product are detected from 5 minutes with peak plasma concentrations occurring at 0.5–0.67 hours after ingestion on an empty stomach. When this product was taken with food peak paracetamol plasma levels were lower and delayed by a median of 55 minutes, but overall extent of absorption was equivalent.

Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates, with about 10% as glutathione conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life is approximately 3 hours.

A minor hydroxylated metabolite, which is usually produced in very small amounts by mixed function oxidases in the liver and detoxified by conjugation with liver glutathione, may accumulate following paracetamol overdose and cause liver damage.

No significant differences in the paracetamol pharmacokinetic profile are observed in the elderly.

The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol taken as this product are not altered when taken in combination as a single or repeat dose.

This product is formulated using a technology which releases both Ibuprofen and Paracetamol simultaneously, so that the active ingredients deliver a combination effect.

5.3 Preclinical safety data

The toxicological safety profile of ibuprofen and paracetamol has been established in animal experiments and in humans from extensive clinical experience. There are no new preclinical data of relevance to the prescriber which are additional to the data already presented in this Summary of Product Characteristics.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Croscarmellose sodium Microcrystalline cellulose Colloidal anhydrous silica Magnesium stearate Stearic acid

Polyvinyl alcohol

Titanium Dioxide

Talc

Macrogol

Potassium aluminium silicate (E555) Polysorbate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Opaque, white PVC with PVdC (polyvinylidene chloride), heat-sealed to aluminium foil, blister pack containing:

4, 6, 8, 10, 12, 16, 20, 24, 32 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Reckitt Benckiser Healthcare (UK) Ltd

Slough, Berkshire

SL1 3UH

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00063/0579

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

31/10/2013