Active ingredients
Paracetamol .... 325 mg
Ibuprofen ........ 200 mg
Excipients: q.s ……….. 1 tablet
Tablet.
Product description: A capsule-shaped, orange tablet, scored on one side, a rhombus on the other side, undamaged edges.
Box of 10 blisters x 5 tablets. Box of 25 blisters x 10 tablets.
Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products. Propionic acid derivatives: Ibuprofen, combinations, ATC code: M01AE51
The medicinal product combines two active substances: ibuprofen with peripheral analgesic, antipyretic and additional anti-inflammatory effects, and paracetamol with central analgesic and antipyretic properties.
Ibuprofen is a derivative of propionic acid. It has anti-inflammatory, analgesic and antipyretic properties. The mechanism of action is based on the inhibition of the activity of cyclooxygenase isoenzymes: COX-1 and COX-2, which leads to inhibition of the synthesis of prostanoids: prostaglandins and thromboxane.
Ibuprofen, by inhibiting cyclooxygenase, especially its COX-2 isoenzyme, reduces the synthesis of cyclic peroxides, which are direct precursors of prostaglandins that exhibit pro-inflammatory effects and are involved in the generation and transmission of pain sensation. In addition, ibuprofen inhibits reversibly aggregation of platelets.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose aspirin on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400 mg was taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. 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. The occasional intake of ibuprofen is not considered to be of significant clinical importance.
It has been shown that, among the first-generation non-steroidal anti-inflammatory drugs, ibuprofen has the highest COX-2 blocking capacity and the most favorable COX-1/COX-2 inhibitory concentration ratio. Hence its relatively low toxicity, lower incidence of side effects and better tolerance compared to other first-generation non-steroidal anti-inflammatory drugs.
Paracetamol has an analgesic and antipyretic effect. This effect is mainly due to its ability to inhibit prostaglandin synthesis in the central nervous system, thus reducing the sensitivity of pain receptors to mediators such as kinins and serotonin, which increases the pain threshold.
The combination in one medicinal product of centrally acting paracetamol and ibuprofen with a peripheral mechanism of action is a combination of two substances with different analgesic action mechanisms.
Absorption
The active substances of this medicinal product are easily absorbed from the gastrointestinal tract, ibuprofen in more than 80%, paracetamol in about 90%. After oral administration of ibuprofen, maximum blood concentration is reached after 1 - 2 hours, and paracetamol after 0.5 - 1.5 hours.
Distribution
Ibuprofen is more than 90% bound to plasma proteins. The main binding proteins are albumin. The volume of distribution is on average 0.16 L/kg. Ibuprofen slowly penetrates into the joint cavities, the maximum concentration in the synovial fluid occurs 5 - 6 hours after oral administration, then slowly decreases.
Paracetamol is 15 - 20% bound to plasma proteins. The volume of distribution is estimated in the range of 0.9 L/kg to 1.8 L/kg and does not change with age.
Metabolism and elimination
Ibuprofen and paracetamol are mainly metabolised in the liver. 50% to 60% of an orally administered dose of ibuprofen is excreted in the urine in the form of metabolites and glucuronic acid conjugation products. The half-life of ibuprofen is 1.5 - 2 hours. It is completely excreted within 24 hours after the last dose, and does not accumulate in the body.
Paracetamol is conjugated with glucuronic acid (approximately 60% of the dose) and sulfate ions (approximately 30% of the dose). Only 3 - 4% of the dose is oxidized by cytochrome P-450 to the toxic intermediate metabolite N-acetyl-benzoquinone imine. This metabolite is rapidly conjugated with glutathione and excreted in the urine as non-toxic mercapturan. This mechanism is easily saturated with high doses of paracetamol. This means that, following an overdose of paracetamol, hepatic glutathione reserves may be depleted, causing a significant build-up of toxins in the body, which can lead to liver cell damage, necrosis and acute liver failure.
Paracetamol is 100% excreted in the urine, of which about 5% is unchanged. The half-life of paracetamol is 1 - 2.5 hours.
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected patients should not drive or operate machinery.
Pregnancy: The medicinal product is contraindicated during pregnancy.
Breast-feeding: The medicinal product is contraindicated during lactation.
Fertility: There is evidence that drugs that inhibit cyclooxygenase (prostaglandin synthesis) can impair female fertility by influencing ovulation. This effect is transient and disappears after the end of therapy. Administration of ibuprofen should be considered in women who have difficulty conceiving or undergoing testing for infertility.
As with any paracetamol containing product, the combination of this medicinal product with other paracetamol-containing products should be avoided due to increased risk of serious adverse reactions.
Concomitant use with other NSAIDs, including COX-2 inhibitors and doses of acetylsalicylic acid above 75 mg daily - increased risk of adverse reactions.
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
Experimental data indicate that ibuprofen can competitively inhibit the effect of low dose aspirin in inhibiting platelet aggregation when these drugs are administered concomitantly. Although it is uncertain whether these data can be extrapolated to clinical situations, it cannot be excluded that regular, long-term use of ibuprofen may limit the cardioprotective effects of low doses of acetylsalicylic acid. The occasional intake of ibuprofen is not considered to be of significant clinical importance.
This product, like any other paracetamol-containing product, 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 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.
- Medicinal products that increase hepatic metabolism, such as rifampicin, antiepileptics, barbiturates: risk of liver damage, even at recommended doses.
- MAO inhibitors: possibility of agitation and high fever.
- Propantheline and other drugs that inhibit peristalsis: delayed absorption of paracetamol.
This product, like any other NSAID and ibuprofen-containing drug, should be used with caution in combination with:
- Anticoagulants: NSAIDs may enhance the effects of anticoagulants, i.e. warfarin.
- Antihypertensives: NSAIDs may reduce the effect of these drugs.
- 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.
- 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.
Alcohol consumption during treatment may lead to toxic liver damage and liver failure.
Clinical trials with the combination of ibuprofen and paracetamol 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.
The side effects are ranked by frequency using the following terms: very common: ≥1/10, common: ≥1/100 to <1/10, uncommon: ≥1/1,000 to <1/100, rare: ≥1/10,000 to 1 <1,000, very rare: <1/10,000, not known (cannot be estimated from the available data)
Blood and lymphatic system disorders
Very rare: Haematological disorders (agranulocytosis, anemia, aplastic anemia, haemolytic anemia, leukopenia, neutropenia, and thrombocytopenia). First signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising and nose bleeding.
Immune system disorders
Very rare: Cases of hypersensitivity have been reported. They can take the form of non-specific allergic reactions and anaphylaxis. Severe hypersensitivity reactions. Symptoms include: swelling of the face, tongue and larynx, dyspnoea, tachycardia, arrhythmias, hypotension (anaphylaxis, angioedema or severe shock).
Mental disorders
Very rare: Confusion, depression and hallucinations.
Nervous system disorders
Uncommon: Headache and dizziness.
Rare: Insomnia.
Very rare: Paraesthesia, optic neuritis and somnolence, agitation, irritability. In patients with pre-existing autoimmune diseases (systemic lupus erythematosus, mixed connective tissue disease), isolated cases of aseptic meningitis with symptoms of neck stiffness, headache, nausea, vomiting, fever, confusion have been reported during ibuprofen treatment. In isolated cases, psychotic reactions and tinnitus have been reported.
Eye disorders
Very rare: Visual disturbance.
Ear and labyrinth disorders
Very rare: Tinnitus and vertigo.
Cardiac disorders
Very rare: Edema, hypertension and cardiac failure have been reported in association with the use of NSAIDs in high doses.
Risk of cardiovascular thrombosis (see section Special warnings and precautions for use).
Respiratory, thoracic and mediastinal disorders
Very rare: Respiratory system responsiveness including: asthma, asthma exacerbation, bronchospasm and shortness of breath.
Gastrointestinal disorders
Common: Abdominal pain, diarrhea, indigestion, nausea, stomach discomfort and vomiting.
Uncommon: Peptic ulcer, perforation or bleeding in the gastrointestinal tract, with symptoms such as melaena and bloody vomiting, sometimes fatal, especially in the elderly. Ulcerative stomatitis and exacerbation of ulcerative colitis and Crohn's disease. Pancreatitis has been reported less frequently.
Rare: Gastritis.
Hepatobiliary disorders
Very rare: Abnormal liver function, hepatitis and jaundice, enlarged liver. After overdose, paracetamol may cause acute liver failure, liver failure, liver necrosis and liver damage.
Skin and subcutaneous tissue disorders
Uncommon: Rashes of various types, including itching and hives. Angioedema and facial edema.
Very rare: Excessive sweating, purpura and photosensitivity. Exfoliative dermatitis. Bullous reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Very rare cases of severe skin reactions have been reported.
Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Renal and urinary disorders
Rare: Edema.
Very rare: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and acute and chronic renal failure, dysuria, decreased urine, papillary necrosis, elevated serum urea, elevated plasma sodium levels (sodium retention).
General disorders and administration site conditions
Very rare: Fatigue and malaise.
Investigations
Common: Alanine aminotransferase increased, gamma-glutamyltransferase increased as well as altered hepatic parameters after the use of paracetamol. Blood creatinine increased, blood urea increased.
Uncommon: Aspartate aminotransferase increased, blood alkaline phosphatase increased, blood creatine phosphokinease increased, haemoglobin decreased and platelet count increased.
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).
Please inform your doctor of all undesirable effects upon drug administration.
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. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with a liver unit.
Ibuprofen
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 vertigo, 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.
Store in dry places, not exceeding 30oC, protect from light.
Concomitant use with other NSAIDs, including COX-2 inhibitors and doses of acetylsalicylic acid above 75 mg daily - increased risk of adverse reactions.
This medicinal product contains paracetamol. Check that other medicines you are taking do not contain paracetamol. Concomitant use of other paracetamol-containing medications may lead to overdose and increase the risk of serious side effects.
Concomitant, long-term use of various analgesic drugs may lead to kidney damage with the risk of renal failure.
There is a risk of renal dysfunction in dehydrated children and adolescents.
Caution should be exercised when administering the medicinal product to patients with appear:
- impairment of the liver and/or kidneys and the circulatory system; in patients with these disorders, the lowest effective dose should be used, with simultaneous monitoring of the liver and/or kidneys and the cardiovascular system,
- bronchial asthma or allergy - taking the medicinal product may cause bronchospasm,
- systemic lupus erythematosus and mixed connective tissue disease - it is increased risk of developing aseptic meningitis,
- history of gastrointestinal disease (ulcerative colitis, Crohn's disease) - symptoms may get worse,
- heart rhythm disturbances, high blood pressure, a heart attack or a history of heart failure - fluid retention may occur due to worsening of kidney function,
- simultaneous use of anticoagulants or blood clotting disorders - ibuprofen may extend the bleeding time.
In patients over 65 years of age, there is a greater risk of side effects than in younger patients.
The risk of side effects may be reduced by using the lowest effective dose for the shortest possible time necessary to control symptoms.
Cardiovascular and cerebrovascular effects
Clinical trials indicate that the use of ibuprofen, especially in high doses (2400 mg/day), may be associated with a slightly increased risk of arterial thromboembolic events (e.g. myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤1200mg/day) 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 effects
There is a risk of gastrointestinal haemorrhage, ulceration or perforation which may be life-threatening and which may not necessarily be preceded by warning signs or may occur in patients who have had these warning signs. In the event of gastrointestinal haemorrhage or ulceration, treatment should be discontinued immediately.
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.
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 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
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.
Do not drink alcohol while using paracetamol because of the risk of liver damage.
The risk of liver damage is particularly high in people who are fasted and drink alcohol regularly.
The use of the product may lead to false results of some laboratory tests performed with the use of redox methods (e.g. determination of blood glucose concentration).
Skin reactions
Serious skin reactions, some of them life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported 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 signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.
The medicinal product may mask the symptoms of an existing infection.
Patients should be advised to contact a physician or pharmacist in the event of new or worsening symptoms.
For paracetamol-containing medicines: Physicians should warn patients of signs of severe skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or Lyell’s syndrome, acute generalized exanthematous pustulosis (AGEP).
Cardiovascular thrombotic events
Nonsteroidal anti-inflammatory drugs (NSAIDs), non-aspirin, by systemic route, have shown an increased risk of cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the first weeks of treatment and may increase with duration of use. The increase in cardiovascular thrombotic risk has been observed most consistently at higher doses.
Physicians should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. To minimize the potential risk for an adverse cardiovascular event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.
Excipients
Lactose monohydrate: Patients with problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Wheat starch: This medicine contains only very low levels of gluten and is very unlikely to cause problems if you have coeliac disease. If you have wheat allergy, you should not take this medicine.
Orange E110: may cause allergic reactions.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.
This medicinal product is analgesic, antipyretic and anti-inflammatory.
Therapeutic indications:
- Pains of various origins, including headaches, migraine, menstrual cramps, toothache, muscle aches, pain in bones and joints, lumbosacral pain, post-traumatic pain, nerve pain.
- Fever.
Hypersensitivity to the active substances or to any of the excipients in the medicinal product.
Hypersensitivity to NSAIDs, including acetylsalicylic acid; history of aspirin-induced asthma, angioedema, bronchospasm, rhinitis or urticaria associated with acetylsalicylic acid or other NSAIDs.
Severe renal and/or hepatic insufficiency.
A history of, or an existing gastrointestinal ulceration/perforation or bleeding, including that associated with NSAIDs.
Severe high blood pressure.
Severe diseases of the cardiovascular system, tachycardia, angina.
Severe heart failure (New York Heart Association (NYHA) class IV)
Pregnancy and breastfeeding.
Bleeding diathesis and taking anticoagulant drugs.
Urinary retention.
Congenital deficiency of glucose-6-phosphate dehydrogenase.
Children under 12 years of age.
Alcoholism.
METHOD OF ADMINISTRATION
For oral administration. The medicinal product should be taken after a meal.
DOSAGE: The recommended dosage is as follows:
- Adults: 1 or 2 tablets at a time. If necessary, the dose can be repeated up to three times a day. Do not use more than 6 tablets a day.
- Adolescents over 12 years of age: 1 tablet at a time. If necessary, the dose can be repeated up to three times a day. Do not use more than 3 tablets a day.
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.
- Elderly patients: no dosage adjustment is required.
The elderly are at increased risk of the serious consequences of adverse reactions. The patient should be monitored regularly for gastrointestinal bleeding during NSAID therapy.
Or as directed by the physician.
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