Propain Syrup

Naproxen.

White or almost white homogeneous suspension.
Each 1 mL suspension contains: Naproxen 25 mg.
Excipients/Inactive Ingredients: Sorbitol liquid (non-crystallizing), Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Anhydrous citric acid, Sodium citrate, Glycerol 85%, Xanthan gum, avicel RC 591, polysorbate 80; sucralose (E955); chocolate flavour 40.136; Purified water.

Pharmacotherapeutic groups: Propionic acid derivatives. ATC code: M01AE02.
Pharmacology: Pharmacodynamics: Naproxen is a racemic non-steroidal anti-inflammatory analgesic that belongs to propionic acid derivatives. The pharmacological activity of naproxen is considered to lie with the S enantiomer, which is the sole enantiomer in the clinically used naproxen, and it is based on the inhibition of cyclooxygenase enzymes and prostaglandin synthesis. Naproxen reduces fever through inhibition of central prostaglandin synthesis and alleviates inflammation and pain by inhibiting peripheral prostaglandin synthesis, which in turn reduces the release of mediators that intensify pain and inflammation. The effects of naproxen on protective mechanisms in the gastric mucosa, renal perfusion, and platelets are also due to prostaglandin synthesis inhibition.
Pharmacokinetics: Following oral administration, naproxen is absorbed completely (95-100%). In connection with food intake, absorption slows down but bioavailability remains unaffected. Following administration of a single dose of 250 mg (25 mg/mL, 10 mL) to healthy adults, the peak plasma concentration is achieved in 1 to 1.5 hours, and the peak concentration is about 50 microg/mL. The therapeutic plasma concentration is considered to be 30-90 mcg/mL. Plasma protein binding of naproxen is extensive (>99%); it binds mainly to albumin but also to globulins, and its distribution volume is about 0.15 L/kg. The total naproxen concentration in synovial fluid is 65-7% from that in plasma, whereas the concentrations of unbound naproxen are the same. Naproxen has linear pharmacokinetics with single doses of up to 500 mg. At doses higher than this, plasma protein binding is saturated, the concentration of unbound naproxen increases, and elimination is accelerated.
The elimination half-life in plasma is 12-15 hours and in synovial fluid up to 30 hours.
Naproxen is eliminated in the liver (CYP450 isoenzymes 1A2, 2C8, and 2C9) into pharmacologically inactive 6-O-demethylnaproxen. Naproxen and 6-O-demethylnaproxen are excreted mainly in the urine as sulfate and glucuronide conjugates. Enterohepatic circulation apparently exists but its degree is not known. Only 1-2% of the total dose is excreted in the feces. Pharmacokinetics of naproxen in children and adults are the same whereas in the elderly the plasma concentrations of unbound naproxen are higher and elimination slower. Naproxen is not accumulated to a significant degree in connection with renal failure. Naproxen is not dialysable. If creatinine clearance is less than 10 mL/min, 6-odemethylnaproxen is accumulated but it can be eliminated in hemodialysis. In connection with hepatic failure, the elimination of naproxen slows down, and if plasma albumin concentrations decrease, plasma concentrations of unbound naproxen increase.

Adults: Rheumatoid arthritis, spondyloarthropathies (including ankylosing spondylitis); Osteoarthrosis; Acute gout; Acute musculoskeletal disorders with pain; Dysmenorrhoea.
Children: Juvenile rheumatoid arthritis.

Method of administration: For oral administration: To be taken preferably with or after food.
Adverse drug reactions can be reduced by taking the lowest effective dose for the shortest duration possible to manage the symptoms.
Posology: Adults: Usually, 250-500 mg (10-20 mL) twice a day based on the individual need.
If the predominant symptom in rheumatoid arthritis is morning stiffness, a single dose of 500-750 mg (20-30 mL) in the evenings may be adequate.
In the treatment of acute gout, the recommended dose is 750 mg at once then 250 mg every 8 hours until the attack has passed.
In the treatment of acute musculoskeletal disorders and dysmenorrhoea, the recommended dose is 500 mg initially followed by 250 mg at 6-8 hour intervals as needed, with a maximum daily dose after the first day of 1250 mg.
Pediatric population (over 5 years): For juvenile rheumatoid arthritis: in children aged over 5 years, the recommended daily dose is 10 mg/kg divided into two doses. Dosing as per the table as follows. Patients weighing over 50 kg may be administered the adult dosage. (See Table 1.)


Click on icon to see table/diagram/image


Elderly patients: Compared with younger patients, the plasma concentration of unbound naproxen is higher, and the elimination of naproxen is slower in those aged over 70 years. Elderly patients are more susceptible to adverse effects of antiinflammatory analgesics than other patients. Due to these reasons, lower single doses, i.e. 250 mg (10 mL) twice a day, are recommended for elderly patients. The patient should be monitored regularly for GI bleeding during NSAID therapy.
Renal failure: For patients with mild renal failure, the lowest effective dose should be used, and renal function must be monitored. If possible, the use of naproxen should be avoided in patients with moderate renal failure (creatinine clearance 50-10 mL/min or S-CR 160-565 micromol/L). Naproxen is contraindicated in patients with severe renal impairment.
Hepatic failure: Naproxen should be used with caution in patients with mild to moderate hepatic failure or cirrhotic hepatic diseases. The lowest effective dose should be administered. Naproxen is contraindicated in patients with severe hepatic impairment.

Symptoms: Symptoms of overdosage include headache, heartburn, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhea, disorientation, excitation, drowsiness, dizziness, tinnitus, fainting. In cases of significant poisoning acute renal failure and liver damage are possible. In adults, overdoses from 5 to 25 g have been described without any specific adverse effects, yet in some individuals overdoses as low as 6-12 g have caused a serious intoxication (metabolic acidosis, renal failure, convulsions, apnoea, central nervous system suppression).
Respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.
In one case of naproxen overdose, transient prolongation of the prothrombin time due to hypothrombinaemia may have been due to selective inhibition of the synthesis of vitamin-K dependent clotting factors.
A few patients have experienced seizures, but it is not known whether these were naproxen-related or not. It is not known what dose of the drug would be life-threatening.
Management: Patients should be treated symptomatically as required. Activated charcoal should be administered to the patient within one hour to inhibit absorption and to interrupt the enterohepatic circulation. Alternatively in adults gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.
Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. However, hemodialysis may still be appropriate in a patient with renal failure who has taken naproxen. Hemodialysis can accelerate the elimination of the main metabolite of naproxen, 6-O-demethylnaproxen.
Administration of an H2 blocker or proton pump inhibitor should be considered to prevent gastrointestinal complications. Good urine output should be ensured. Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam.
Other measures may be indicated by the patient's clinical condition.

Contraindicated for use in the following cases: Third trimester of pregnancy; A history of asthma, rhinitis, nasal polyps or urticarial in association with acetylsalicylic acid or NSAIDs; Hypersensitivity to the active substance or to any of the excipients of this medicine; Severe cardiac failure; Severe renal and hepatic impairment; History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy; Active gastric or duodenal ulcer, or history of recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding); Other conditions predisposing to gastrointestinal hemorrhages.

The use of naproxen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Undesirable effects may be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms. Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.
Effects on the heart, blood circulation, and cerebral circulation: Appropriate monitoring and advice are required for patients with hypertension and/or mild or moderate cardiac failure as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that the use of coxibs and some other anti-inflammatory analgesics may be associated with a small increased risk of arterial thrombotic events (such as myocardial infarction or stroke, which can lead to death). Although current data suggests that the risk may be lower in connection with naproxen use (1,000 mg/day), it cannot be excluded entirely. This risk may appear as early as the first few weeks of taking the drug and may increase over time. The risk of cardiovascular thrombosis is observed mainly at high doses.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with naproxen only after careful consideration. Similar considerations should be made before initiating long-term therapy in patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Periodic examination for the appearance of cardiovascular events is necessary, even if the patient has no prior cardiovascular symptoms. Patients should be warned of symptoms of serious cardiovascular complications and advised to seek medical attention as soon as symptoms appear.
To minimize the risk of cardiovascular adverse effects, naproxen should be used at the lowest effective daily dose for the shortest possible duration.
Serum potassium concentrations should be monitored especially in patients receiving angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or potassium-sparing diuretics. Anti-inflammatory analgesics may decrease the efficacy of some antihypertensive drugs.
Renal effects: Patients with renal or hepatic failure, hypertension, or cardiac failure, and elderly patients should be monitored for renal function and hemodynamics during naproxen treatment. Naproxen should be avoided, if possible, in patients with moderate renal failure. Naproxen is contraindicated in patients with severe renal impairment (baseline creatinine clearance less than 30 mL/min) or severe hepatic impairment.
Dehydration during the use of an anti-inflammatory analgesic (i.e. NSAID) increases the risk of acute renal failure, so the patient's possible dehydration should be corrected before naproxen treatment is initiated. The naproxen treatment should be started with caution in patients with a history of considerable dehydration. Like other anti-inflammatory analgesics, long-term treatment with naproxen has caused renal papillary necrosis and other pathological renal alterations.
Renal toxicity has also been detected in patients in whom renal prostaglandins maintain renal perfusion. In these patients, the use of anti-inflammatory analgesics may cause a dose-dependent reduction in the formation of prostaglandins, leading to reduced renal perfusion. This may progress into renal failure. The risk is highest in elderly patients, those using diuretics, ACE inhibitors, or angiotensin-II receptor antagonists, and in patients with renal or hepatic impairment or cardiac failure. Discontinuation of treatment usually corrects the patient's status to the pre-treatment level.
Gastrointestinal hemorrhages, ulcers, and perforations: Gastrointestinal bleeding, ulceration, or 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.
Naproxen reduces thrombocyte activation and aggregation but this effect is transient and lasts less than 48 hours after a single dose. This should be taken into account when treating postoperative patients with an increased risk of hemorrhage, patients on anticoagulant medication, patients with hemophilia, or other patients with diseases impairing the functioning of the coagulation system or with thrombocytopenia. The risk of gastrointestinal haemorrhage increases even by this mechanism.
The risk of GI bleeding, ulceration, or perforation is higher with increasing NSAID doses, in patients with a history of ulcers, particularly if complicated with hemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest possible 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 adverse reactions, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid.
When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.
Cutaneous adverse 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 the highest risk for these reactions early in the course of therapy: the onset of the reaction occurs in the majority of cases within the first month of treatment. Naproxen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Anaphylactic (anaphylactoid) reactions: Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory drugs, or naproxen-containing products. They may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma), rhinitis, and nasal polyps.
Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
SLE and mixed connective tissue disease: In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.
Ocular effects: Studies have not shown changes in the eye attributable to naproxen administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis, and papilloedema, have been reported in users of NSAIDs including naproxen, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with naproxen-containing products should have an ophthalmological examination.
The use of naproxen 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 naproxen should be considered.
Anti-inflammatory analgesics may aggravate bronchospasm in patients with allergic disease.
As with other non-steroidal anti-inflammatory drugs, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal), have been reported with this drug as with other non-steroidal anti-inflammatory drugs. Cross-reactivity has been reported.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for naproxen dosing is unknown but it is prudent to use the lowest effective dose. Naproxen is contraindicated in patients with severe hepatic impairment.
Pseudoporphyria (blistering cutaneous photosensitivity) has been reported in up to 10% of pediatric rheumatic patients in connection with naproxen treatment exceeding four weeks. Patients should be monitored for this reversible phenomenon and the use of the preparation should be discontinued if symptoms occur.
The antipyretic and anti-inflammatory activities of naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Excipients: Naproxen oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).
Naproxen oral suspension contains 400 mg/mL sorbitol. Daily doses as per instructions yield 1.6 g-20 g sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Sorbitol may have a mild laxative effect.
This medicinal product contains 0.8 mg/mL sodium, 24 mg sodium per 30 mL dose, which is equivalent to 1.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on Ability to Drive and Use Machines: Usually, naproxen has no influence on the ability to drive and use machines. Occasional adverse effects include tiredness, difficulty in ability to concentrate, dizziness, or visual disturbances. If these symptoms occur, driving a car or using machines should be avoided.
Use in the Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs; especially gastrointestinal bleeding and perforation which may be fatal. Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.

Pregnancy: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development. Data from epidemiological studies suggest an increased risk of miscarriage of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation and gastroschisis 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 prostaglandin synthesis inhibitor has been shown to result in increased pre- and postimplantation loss and embryo/fetal 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, naproxen should not be given unless clearly necessary. If naproxen 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 the duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to: Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligo-hydroamniosis.
At the end of pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate to: Prolongation of bleeding time because of an anti-aggregation effect of the platelets, which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labor.
Consequently, naproxen is contraindicated during the third trimester of pregnancy.
Lactation: Naproxen is excreted in very small amounts in breast milk. The use of naproxen is not recommended during breastfeeding.

Adverse effects caused by naproxen mostly occur in the gastrointestinal tract and central nervous system, and they are usually dose-dependent. Terms and frequencies of adverse effects are determined as follows: Very common: R ≥1/10; Common: 1/10 >R ≥1/100; Uncommon: 1/100 >R ≥1/1,000; Rare: 1/1,000 >R ≥1/10,000; Very rare: R <1/10,000; Not known: Cannot be estimated from the available data. (See Table 2.)


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Immediately notify a doctor or pharmacist of any adverse reactions that may be encountered when using the drug.

Probenecid slows down the elimination of naproxen by competing for glucuronidation and biliary and tubular secretion. If these active substances are used concomitantly in the treatment of e.g. gout, a reduction in naproxen dosage and careful monitoring of the patient for possible adverse reactions are recommended.
Concomitant administration of antacid or cholestyramine can delay the absorption of naproxen but does not affect its extent.
Concomitant administration of food can delay the absorption of naproxen but does not affect its extent.
NSAIDs should not be used for 8–12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.
Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anticoagulants, other NSAIDs, aspirin or a highly protein-bound sulphonamide should be observed for signs of overdosage of these drugs. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulfonylurea should be observed for adjustment of dose if required. No interactions have been observed in clinical studies with naproxen and anticoagulants or sulfonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class. Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking quinolones may have an increased risk of developing convulsions.
Concomitant use of bisphosphonates and NSAIDs may increase the risk of gastric mucosal damage.
Combination use with diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the antihypertensive effect of diuretics and other antihypertensive 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 cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. 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 renal toxicity of anti-inflammatory analgesics.
Furthermore, the effect of other antihypertensive drugs (beta blockers) may be reduced. This should be taken into account at the onset of antihypertensive medication.
Naproxen should not be used concomitantly with other anti-inflammatory analgesics as this may increase adverse effects.
Acetylsalicylic acid: Clinical pharmacodynamic data suggest that concomitant naproxen usage for more than one day consecutively may inhibit the effect of low-dose acetylsalicylic acid on platelet activity and this inhibition may persist for up to several days after stopping naproxen therapy. The clinical relevance of this interaction is not known.
Acetylsalicylic acid displaces naproxen from protein binding sites in plasma, which accelerates the elimination of naproxen.
Corticosteroids: Increased risk of a gastrointestinal ulcer or hemorrhage. If these drugs are used concomitantly, the patient's status should be monitored carefully.
Anticoagulants: Anti-inflammatory analgesics may enhance the effect of anticoagulants, such as warfarin.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.
Significant interactions between naproxen and oral hypoglycaemic drugs or antiepileptics are unlikely. Naproxen has been shown to displace valproic acid from protein binding sites in plasma, but the clinical significance of this phenomenon is likely to be minor.
Serum digoxin concentrations should be monitored in patients with renal failure and on digitalis treatment, and the digoxin dose should be adjusted if needed if naproxen is added to or removed from the medication.
Naproxen slows down the elimination of lithium. Serum lithium concentrations should be monitored and the lithium dosage adjusted if needed, if naproxen is added to or removed from the patient's medication.
Naproxen may slow down the elimination of methotrexate, ciclosporin and aminoglycoside antibiotics (directly dependent on glomerular filtration) and increase their toxicity. Interaction is, however, unlikely in connection with a low-dose (at doses used in the treatment of rheumatic diseases) methotrexate treatment.
Naproxen may change plasma protein binding of tacrolimus and expose to renal toxicity. Caution is advised in combination use, and if possible, the drug doses should be adjusted based on serum concentration determinations.
Naproxen may change the metabolism of zidovudine. The clinical significance of this phenomenon is not known.
Naproxen may interfere with urinary tests for 17-ketogenic steroids and 5-hydroxy-indoleacetic acid (diagnostics in adrenal gland diseases). This is avoided by discontinuing naproxen 72 hours before sampling.

Stored below 30°C.
Shelf Life: 36 months from manufacturing date.
The product should be used within 6 months after opening.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AE02 - naproxen ; Belongs to the class of propionic acid derivatives of non-steroidal antiinflammatory and antirheumatic products.