Contents

Intaflam (Ibuprofen & Paracetamol Tablets)

ATC Code: M01AE51 – Musculoskeletal system, anti-inflammatory and antirheumatic products, non-steroids, propionic acid derivatives.

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 sensitize 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 sensitization 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.

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 dysmenorrhea, 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 requires stronger pain relief than ibuprofen 400 mg or paracetamol 1000 mg alone, and faster pain relief than ibuprofen.

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 requires stronger analgesia than ibuprofen or paracetamol alone.

Posology and method of administration

For short term-use only.

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The patient should consult a doctor if the symptoms persist or worsen or if the product is required for more than 3 days.

Adults: One tablet to be taken up to three times per day with water. Leave at least six hours between doses. 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 (3000mg Paracetamol, 1200mg Ibuprofen) in any 24 hours period. To minimize side effects, it is recommended that patients take Intaflam with food.

Elderly: No special dosage modifications are required. The elderly is at increased risk of the serious consequences of adverse reactions. If an NSAIDis 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.

Not for use by children under 18 years.

Method of Administration

For oral administration

Contraindications

This product is contraindicated:

In patients with a known hypersensitivity to ibuprofen, paracetamol or any other excipients in the product.
In concomitant use with other Paracetamol-containing products – increased risk of serious adverse effects.
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 Active, or a history of recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding).
In patients with a history of, or an existing gastrointestinal ulceration/perforation or bleeding, including that associated with NSAIDs.
Patients with defects in coagulation.
In patients with severe hepatic failure, severe renal failure or severe heart failure (NYHA Class IV).
In concomitant use with other NSAID containing products, including cyclo- oxygenase-2m(COX-2) specific inhibitors and doses of acetylsalicylic acid above 75 mg daily – increased risk of adverse reactions.
During the last trimester of pregnancy due to risk of premature closure of the foetal ductus arteriosus with possible pulmonary hypertension.

Special warning & precautions for use

Do not exceed the recommended dose. If symptoms persist consult your doctor.

Keep out of the sight and reach of children.

Paracetamol: The hazards of paracetamol overdose are greater in patients with non-cirrhotic alcoholic liver disease. 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.

Ibuprofen: Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms and by patients taking the dose with food.

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

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.

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

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

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

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischemic 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, and smoking) particularly if high doses of ibuprofen (2400 mg/day) are required.

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.

Gastrointestinal effects: 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.

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 hemorrhage or perforation 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.

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

Dermatological effects: 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. 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. Use of this product should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Impaired female fertility: There is limited evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may impair female fertility by an effect on ovulation and is not recommended in women attempting to conceive. This is reversible on withdrawal of treatment. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of the product should be considered.

Interactions with other medicinal products and other forms of interactions

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

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

Acetylsalicylic acid: Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects, unless low-dose acetylsalicylic acid (not above 75 mg daily) has been advised by a doctor

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

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.

Antihypertensive (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 coadministration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclooxygenase 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 thereafter. Diuretics may increase the risk of nephrotoxicity of NSAIDs.

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

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.

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 hematological toxicity with NSAIDS is given with Zidovudine. There is evidence of an increased risk of hemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with Zidovudine and ibuprofen.

Fertility, Pregnancy & lactation

Pregnancy: There is no experience of use of this product in humans during pregnancy. Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern.

In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of ductus arteriosus), use in the last trimester is contraindicated. The onset of labour may be delayed, and duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

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

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

Lactation: 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.

Effects on ability to drive & 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

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:

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

Regularly consumes alcohol in excess of recommended amounts.

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 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.

Intaflam (Ibuprofen & Paracetamol Tablets)

Intaflam (Ibuprofen & Paracetamol Tablets)