AGIPAROFEN®

Composition: Each bi-layer tablet contains:
Paracetamol . . . . . . . . . . . . . . . . . . . . .325 mg
Ibuprofen. . . . . . . . . . . . . . . . . . . . . . . .200 mg
Presentation:
Box of 5 blisters x 10 bi-layer tablets.
Indications:
Agiparofen® tablets are used for the temporary relief of mild to moderate pain associated with headache, backache, dysmenorrhea, dental pain, pain in bones and joints, cold and flu symptoms, sore throat and fever.
This product is especially suitable for pain not responding to paracetamol or ibuprofen therapy alone.

LIÊN HỆ MUA HÀNG HOẶC CẦN TƯ VẤN

Dosage and administration

Dosage: Agiparofen® is used for adults with the usual dose is as follows:
For the relief of pain, anti-inflammation
Acute treatment: 1-2 tablets, 3 – 4 times daily.
The maintenance dose: 1 tablet, three times daily.
The recommended maximum dose is 12 tablets per day.
Treatment of flu and fever: 1 – 2 tablets, three times daily.
The recommended maximum dose is 6 tablets per day.
Dysmenorrhea: 1 tablet, 3-4 times daily, it should be used as soon as the pain occurs. The dose may be increased to 2 tablets if necessary, however, should not exceed 6 tablets per day.
Intervals between doses are at least 4 hours.
Without advice from physician, Agiparofen should not be used for self-medication of pain for longer than 10 days or fever for longer than 3 days.
Administration: Oral administration after a meal.
Contraindications

You have a known history of hypersensitivity to paracetamol, ibuprofen, or any excipient of this medicine, other NSAIDs (e.g. bronchospasm, urticaria, rash, bronchial asthma, etc.).
You have a history of gastrointestinal bleeding associated with NSAIDs.
Concomitant use with drugs containing NSAIDs (including selective COX2 inhibitors) or paracetamol.
You have progressive gastric and duodenal ulcers.
You are being treated with coumarin anticoagulants.
You have asthma or bronchospasm, bleeding disorders.
You have hepatic failure, congestive heart failure, intravascular volume depletion due to diuretics or renal impairment (increased risk of renal dysfunction).
You are at the first and the third trimester of pregnancy.
Children under 12 years of age.
Warnings and precautions for use

Glucose – 6 – phosphate dehydrogenase deficiency (G6PD).
Patients should be alerted to the signs of serious skin reactions such as Stevens- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or Lyell's syndrome, and acute generalized exanthematous pustulosis (AGEP).
When starting the treatment, urinary excretion and renal function should be monitored closely in patients with heart failure, cirrhosis and impaired renal function, chronic renal failure, patients receiving diuretics, and particularly in the elderly.
Ibuprofen can cause ulcers, bleeding or perforation of the stomach and intestines, patients with a history of gastro-duodenal ulcers, diaphragmatic hernia or gastrointestinal bleeding should be monitored. Ibuprofen should be used with caution at the lowest effective dose for the shortest duration in these patients.
Ibuprofen should be used with caution in patients with pre-existing anemia, heart disease and hypertension, peripheral arterial disease, and/or cerebrovascular disease. Ibuprofen may lead to increase in blood pressure or worsening of pre-existing hypertension, increases the risk of cardiovascular events, and the risk of serious cardiovascular events due to thrombosis.
Risk of cardiovascular thrombotic events:
Non-steroidal anti-inflammatory drugs (NSAIDs), different from aspirin, with systemic effects may cause an increased risk of cardiovascular thrombotic events, including heart attack and stroke which can be fatal. This risk may occur early in the first few weeks of treatment and increase with time. The risk of cardiovascular thrombotic events has been mainly observed at high doses.
Doctors should periodically evaluate the occurrence of cardiovascular events, even in the absence of previous CV symptoms. Patients should be warned about the symptoms of a serious cardiac events and should meet the doctor as soon as these symptoms occur.
Agiparofen should be used at the lowest effective dose for the shortest possible duration to minimize the risk for adverse cardiovascular events.
Caution should be taken in patients over the age of 65 years because of an increased risk of adverse effects such as heart failure, gastrointestinal ulceration and renal impairment. Those who require therapy for longer than 10 days should consult their physician.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Recommendation for pregnancy and breastfeeding

Pregnancy
Agiparofen should be used with caution in the first trimester of pregnancy.
This product is contraindicated during the third trimester of pregnancy (risk of poisoning to fetal kidneys, heart and lung, risk of premature closure of the ductus arteriosus) and absolutely contraindicated in the last few days before expected birth (due to the risk of hemorrhage both in the mother and fetus caused by prolonged bleeding time).
Breastfeeding
Agiparofen should be used with caution in breastfeeding mothers.
Both ibuprofen and paracetamol are excreted in breast milk but not in a clinically significant amount. It is not necessary to interrupt breastfeeding for short-term treatment.
Effects on ability to drive and use machines

Agiparofen may cause dizziness. If affected, caution should be considered when driving and operating machines.
Interactions, incompatibilities of medicine

Agiparofen is contraindicated in combination with other paracetamol, ibuprofen containing products or NSAIDs.
Paracetamol:
Paracetamol may mildly enhance the anticoagulant effect of coumarin and indandione derivatives in long-term use of high doses
Alcohol, anticonvulsants (including phenytoin, barbiturate, carbamazepine) and isoniazid may increase paracetamol-induced hepatotoxicity.
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone.
Coadministration of paracetamol and cholestyramine decreases the absorption of paracetamol, therefore cholestyramine should not be used within 1 hour after taking paracetamol to have optimal analgesic effect.
Paracetamol increases plasma concentrations of chloramphenicol.
Ibuprofen:
Quinolone antibiotics: Ibuprofen increases the adverse effects of quinolone antibiotics on the central nervous system and may lead to convulsions.
Methotrexate: Ibuprofen enhances the toxicity of methotrexate.
Cardiac glycosides: Ibuprofen may increase the plasma concentrations of cardiac glycosides such as digoxin.
Furosemide: Ibuprofen can reduce the natriuretic effect of furosemide and thiazides.
Corticosteroid and other nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use ibuprofen with corticosteroids and other NSAIDs including aspirin increases risk of gastrointestinal ulceration or bleeding.
Anticoagulants, including warfarin: Concomitant use with ibuprofen may increase risk of severe bleeding and haemorrhage.
Antihypertensive drugs: Ibuprofen may reduce the anti-hypertensive effect of ACE inhibitors, beta-blockers and diuretics and may cause natriuresis and hyperkalemia in patients under these treatments.
Lithium: Ibuprofen may increase plasma concentration of lithium and decrease elimination of lithium via kidney.
Zidovudine: Ibuprofen may prolong bleeding time in patients treated with zidovudine.
Mifepristone: Ibuprofen should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Tacrolimus, ciclosporin: Increased risk of nephrotoxicity when Ibuprofen is given concomitantly.
Ibuprofen may also interact with probenecid, antidiabetic medicines and phenytoin.
Undesirable effects (ADRs)

When used in the recommended doses and treatment duration Agiparofen has few side effects. However, attention should be paid to risk of cardiovascular thrombosis (see “Conditions where caution should be taken”), following side effects may occur:
Common, ADR > 1/100
Gastrointestinal disorders: Abdominal pain, vomiting, diarrhea, nausea, indigestion and abdominal discomfort.
Skin and subcutaneous tissue disorders: Rash, pruritus.
Uncommon, 1/100 > ADR > 1/1000
Immune system disorders: Hypersensitivity with urticaria and pruritus.
Nervous system disorders: Headache and dizziness.
Gastrointestinal disorders: Peptic ulcer, gastrointestinal perforation or gastrointestinal haemorrhage, vomiting blood, mouth ulceration, exacerbation of colitis and Crohn's disease, pancreatitis, flatulence and constipation.
Blood disorders: Prolonged bleeding time.
Very rare, ADR < 1/10000
General disorders: Fatigue, malaise.
Blood and lymphatic system disorders: Hematopoietic disorders (neutropenia, pancytopenia, leucopenia), anemia.
Immune system disorders: Serious hypersensitivity reactions. Symptoms can include facial, tongue and throat swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).
Psychiatric disorders: Confusion, depression and hallucinations.
Nervous system disorders: Depression, aseptic meningitis, optic neuritis and somnolence.
Eye disorders: Visual disturbances.
Ear disorders: Reduced hearing, tinnitus and dizziness.
Cardiac disorders: Heart failure and edema.
Vascular disorders: Hypertension.
Respiratory disorders: Respiratory reactions include: Asthma, exacerbation of asthma, bronchospasm, and dyspnea.
Hepatobiliary disorders: Abnormal liver function, hepatitis and jaundice.
Skin and subcutaneous tissue disorders: Bullous reactions including Stevens Johnson Syndrome, erythema multiforme, and toxic epidermal necrolysis. Exfoliative dermatoses, purpura and photosensitivity.
Renal and urinary disorders: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and acute and chronic renal failure.
Overdose and management

Overdose:
Paracetamol:
Liver damage and even liver failure can occur after paracetamol overdose (in adults who have taken ≥ 10g). 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. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may proceed to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis, may develop even if severe liver damage is not present. Cardiac arrhythmias have been reported.
Ibuprofen:
Symptoms of ibuprofen overdose include abdominal pain, nausea, vomiting, lethargy and drowsiness, rebound headaches, cramps, CNS inhibition, convulsions, hypotension, tachycardia, rapid breathing and atrial fibrillation.
Rare cases of metabolic acidosis, coma, acute renal failure, hyperkalemia, apnea (mainly in children), respiratory depression and respiratory failure have been reported.
Management:
If any symptom of overdose occurs (as in section Undesirable effects), discontinue the medication and contact a physician immediately and patients should be moved to healthcare facilities as soon as possible.
The treatment is usually symptomatic and supportive. If large dose was ingested, the following measures should be applied to enhance drug elimination and inactivation: Gastric lavage, induction of emesis and diuretics, oral administration of activated charcoal or saline cathartics.
As Agiparofen contains Paracetamol, N-Acetylcysteine should be taken orally or intravenously as a specific antidote and should be given immediately if it is less than 36 hours after a significant paracetamol overdose.
Pharmacodynamic properties

Agiparofen is the combination of ibuprofen and paracetamol to form analgesic and anti-inflammatory therapies. In addition, because of lower therapeutic dose of active substances in the formula side effects caused by Agiparofen are less than those caused by the single actives alone.
Paracetamol:
Paracetamol (Acetaminophen or N-acetyl-p-aminophenol) is an active metabolite of phenacetin, an effective analgesic – antipyretic agent. Paracetamol is used for temporary pain relief in the treatment of mild to moderate pain. Paracetamol is most effective in relieving low intensity pain of nonvisceral origin.
Paracetamol reduces body temperature in people with fever, but rarely lowers normal body temperature. It acts on the hypothalamus to produce antipyresis, heat dissipation increases due to vasodilation and increased peripheral blood flow.
At therapeutic doses, the drug has little effect on the cardiovascular and respiratory system, does not cause irritation ulcers, has no effect on platelet aggregation or bleeding time.
When paracetamol is overdosed, N-Acetyl-p-benzoquinone imine metabolite causes serious hepatotoxicity.
Ibuprofen:
Ibuprofen is a nonsteroidal anti-inflammatory drug derived from propionic acid.
As with other nonsteroidal anti-inflammatory drugs, ibuprofen has analgesic, antipyretic and anti-inflammatory properties. It acts by inhibiting prostaglandin synthetase and thus prevents prostaglandin production, thromboxane and other products of cyclooxygenase. Ibuprofen also inhibits prostacyclin synthesis in the kidneys and may cause the risk of fluid retention by reducing renal blood flow. This activity should be noticed in patients with renal impairment, heart failure, liver failure and patients with disorders of the plasma volume.
Anti-inflammatory effect of ibuprofen appears after two days of treatment. Antipyretic effect of Ibuprofen is stronger than that of aspirin, but less than indomethacin.
Pharmacokinetic properties

Agiparofen is absorbed rapidly and almost completely from the gastrointestinal tract.
Paracetamol:
After oral administration, paracetamol is absorbed rapidly, peak plasma levels occur within 30 to 60 minutes, paracetamol is distributed quickly and evenly in most tissues of the body. About 25% of paracetamol in the blood is bound to plasma proteins.
The plasma half-life of paracetamol is 1.25 – 3 hours, prolonged at toxic dose or in patietns with liver damage. It is metabolized in the liver and mostly excreted in the urine (90% – 100% of the therapeutic dose on the first day of therapy), mainly by conjugation with glucuronic acid.
Ibuprofen:
Peak plasma concentrations are reached in 1 to 2 hours after oral administration. Ibuprofen is highly bound to plasma proteins.
Half-life is about 2 hours. Ibuprofen is rapidly excreted in the urine (1% as unchanged, 14% as conjugated).
Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.

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