Instructions for use Naproxen-Zdorovye film-coated tablets 550 mg No. 10
Composition
active ingredient: naproxen sodium;
1 tablet contains naproxen sodium 550 mg;
excipients: microcrystalline cellulose; povidone; talc; magnesium stearate; indigo carmine (E 132); dry mixture "Opadry white", containing: titanium dioxide (E 171), hypromellose, triacetin (E 1518).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, from light blue to dark blue in color, with a biconvex surface, oval in shape, with a score on one side. On the cut, the tablet is white or almost white.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Naproxen. ATC code M01A E02.
Pharmacological properties
Pharmacodynamics.
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects. Naproxen sodium was developed as a more rapidly absorbed form of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not fully understood, but may involve inhibition of prostaglandin synthetase.
Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations achieved during therapy mimicked the effects in vivo. Prostaglandins are sensitive to afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Since naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be mediated by a reduction in the amount of prostaglandins in peripheral tissues.
Pharmacokinetics.
Naproxen sodium is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The elimination half-life (T½) of naproxen is 12 to 17 hours. Steady-state levels of naproxen are reached after 4-5 days, and the degree of accumulation of naproxen corresponds to the half-life.
Absorption: After oral administration of the drug, peak plasma concentration (Cmax) is reached after 1-2 hours.
Distribution. The volume of distribution of naproxen is 0.16 L/kg. Therapeutic levels of naproxen are more than 99% bound to albumin. At doses of naproxen greater than 500 mg/day, there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (mean minimum Css 36.5, 49.2, and 56.4 mg/L at daily doses of naproxen 500, 1000, and 1500 mg, respectively). The naproxen anion has been detected in the milk of lactating women at concentrations equivalent to approximately 1% of the maximum plasma concentration of naproxen.
Metabolism: Naproxen is extensively metabolized in the liver to 6-O-desmethylnaproxen, and neither the parent compound nor the metabolites induce metabolizing enzymes. Both naproxen and 6-O-desmethylnaproxen undergo further metabolism to their respective acylglucuronide conjugated metabolites.
Elimination: The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of a naproxen dose is excreted in the urine, primarily as naproxen (6-O-desmethylnaproxen) or its conjugates (66-92%). The plasma half-life of naproxen anion in humans is 12-17 hours. The respective half-lives of the metabolites and conjugates of naproxen are less than 12 hours, and their excretion rates closely match the plasma clearance rate of naproxen. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal insufficiency, metabolites may accumulate.
Indication
Symptom relief:
- rheumatoid arthritis;
- osteoarthritis;
- ankylosing spondylitis;
- tendinitis;
- bursitis;
- acute gout;
- pain syndrome therapy;
- primary dysmenorrhea.
Contraindication
The drug is contraindicated in patients with known hypersensitivity to naproxen sodium.
The drug should not be prescribed to patients with a history of asthma, urticaria, or allergic reactions caused by the use of aspirin or other NSAIDs. Acute anaphylactoid reactions to NSAIDs, rarely fatal, have been observed in such patients.
Do not use the drug for the treatment of perioperative pain in coronary artery bypass grafting (CABG).
Interaction with other medicinal products and other types of interactions
Angiotensin-converting enzyme inhibitors (ACE inhibitors)/angiotensin II receptor blockers: NSAIDs may reduce the antihypertensive effect of ACE inhibitors, angiotensin II receptor blockers or β-blockers (including propranolol).
Blood pressure changes should be carefully monitored in patients taking NSAIDs concomitantly with ACE inhibitors, angiotensin II receptor blockers, or β-blockers.
Antacids and sucralfate. Concomitant use of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate may delay the absorption of naproxen.
Aspirin: When the drug is taken with aspirin, the protein binding of naproxen is reduced, although the clearance of free naproxen is not changed. The clinical significance of this interaction is unknown; however, as with other NSAIDs, the simultaneous use of naproxen sodium and aspirin is not recommended due to the possibility of side effects.
It is known that the simultaneous use of NSAIDs and analgesic doses of aspirin does not provide a greater therapeutic effect than the use of NSAIDs alone. The concomitant use of NSAIDs and aspirin was associated with a significantly increased incidence of side effects compared with the use of NSAIDs alone.
Cholestyramine: As with other NSAIDs, concomitant administration of cholestyramine may delay the absorption of naproxen.
Diuretics. There is evidence that the drug may reduce the natriuretic effect of furosemide and thiazides in some patients. This reaction has been associated with inhibition of prostaglandin synthesis in the kidneys. During concomitant therapy with NSAIDs, the patient should be monitored for signs of renal failure, and a diuretic effect should be provided.
Lithium. NSAIDs increase plasma lithium levels and decrease renal lithium metabolism. Mean trough lithium concentrations are increased by 15% and renal clearance is decreased by approximately 20%. These effects have been attributed to NSAID inhibition of renal prostaglandin synthesis. Therefore, if NSAIDs and lithium are administered concomitantly, close attention should be paid to signs of lithium toxicity.
Methotrexate. NSAIDs have been reported to competitively inhibit the accumulation of methotrexate in rabbit kidney slices. Naproxen sodium and other NSAIDs also reduce the tubular secretion of methotrexate in animals. This may indicate that they may increase the toxicity of methotrexate. NSAIDs should be administered with caution when given concomitantly with methotrexate.
Warfarin. The effects of warfarin and NSAIDs on gastrointestinal bleeding are synergistic, so taking both drugs simultaneously increases the risk of serious gastrointestinal bleeding compared with taking either drug alone. No significant interactions have been observed between naproxen and coumarin-type anticoagulants. However, caution is advised in view of the observed interactions with other NSAIDs of this class. The free fraction of warfarin may be significantly increased in some individuals, and naproxen antagonizes platelet function.
Selective serotonin reuptake inhibitors (SSRIs): There is an increased risk of gastrointestinal bleeding when SSRIs are taken in combination with NSAIDs. NSAIDs should be used with caution when used concomitantly with SSRIs.
Digoxin: Concomitant use of naproxen with digoxin has been reported to increase serum concentrations and prolong T½ of digoxin. Serum digoxin levels should be monitored when naproxen is coadministered with digoxin.
NSAIDs and salicylates: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of toxicity, with little or no increase in efficacy.
Pemetrexed: Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-related myelosuppression and toxicity.
When naproxen and pemetrexed are used concomitantly in patients with renal impairment whose creatinine clearance is between 45 and 79 mL/min, myelosuppression and renal toxicity should be monitored.
Other drug interaction information. Naproxen is highly bound to plasma albumin; therefore, it has the theoretical potential to interact with other albumin-binding drugs such as coumarin-type anticoagulants, sulfonylureas, hydantoins, other NSAIDs, and aspirin. Patients receiving naproxen and a hydantoin, sulfonamide, or sulfonylurea concomitantly should have their dosage adjusted as necessary.
Concomitant administration with probenecid increases plasma levels of naproxen anion and significantly prolongs its plasma T½.
Drug/Laboratory Test Interactions: Naproxen may decrease platelet aggregation and increase the risk of bleeding. This should be considered when determining bleeding time.
Naproxen may increase 17-ketosteroid levels due to interaction of the drug and/or its metabolites with m-dinitrobenzene, which is used in this assay. Although 17-hydroxycorticosteroid levels (Porter-Silber test) were not artificially altered, it is recommended that naproxen be temporarily discontinued 72 hours prior to adrenal function testing if the Porter-Silber test is performed.
Naproxen may interfere with the results of urine 5-hydroxyindoleacetic acid tests.
Application features
General information: The drug is not a substitute for corticosteroids and should not be used in the treatment of corticosteroid insufficiency.
In case of any changes or visual disturbances, ophthalmological examinations are recommended.
Liver Effects. Up to 15% of patients taking NSAIDs, including naproxen, have had elevations in one or more liver function tests. Liver function abnormalities are likely to be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, remain virtually unchanged, or be transient with continued use of the drug. The alanine aminotransferase (ALT) test is the most sensitive indicator of liver function abnormalities.
A patient who has symptoms or signs of liver dysfunction, or whose liver function tests are abnormal, should be monitored for the development of a more severe liver reaction while taking the drug.
If clinical signs and symptoms suggest the development of liver disease or in the event of systemic manifestations (e.g. eosinophilia, rash), the drug should be discontinued.
Chronic cirrhosis of the liver and possibly other diseases with reduced or abnormal plasma protein (albumin) levels reduce the total plasma concentration of naproxen, while the concentration of unbound naproxen in the plasma is increased. The drug should be used with caution when high doses are required, and dosage adjustment may be necessary in such patients. The drug should be used at the lowest effective dose.
Effects on hematological parameters. Anemia is occasionally observed in patients receiving NSAIDs, including naproxen. This may be due to fluid retention, occult or massive blood loss in the digestive tract, or due to an incompletely described effect on erythropoiesis. Patients receiving long-term treatment with NSAIDs, including naproxen, should have their hemoglobin and hematocrit levels monitored regularly for any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effects on platelet function are quantitatively smaller, shorter-lived, and reversible. Patients taking naproxen who may develop adverse reactions to altered platelet function (patients with coagulation disorders or patients receiving anticoagulants) should be carefully monitored.
History of asthma. Patients with asthma may have aspirin-induced asthma. The use of aspirin in patients with aspirin-induced asthma may cause severe bronchospasm, which may be fatal. Because of the potential for cross-reactivity, including bronchospasm, between aspirin and other NSAIDs in patients with known hypersensitivity to aspirin, the drug should not be prescribed to such patients, and the drug should be used with caution in patients with a history of asthma.
Laboratory Tests. Because gastrointestinal ulcers and bleeding may occur without warning symptoms, physicians should monitor patients regularly for signs or symptoms of gastrointestinal bleeding. During long-term treatment with NSAIDs, patients should have periodic clinical and biochemical blood tests. Naproxen should be discontinued if clinical signs and symptoms suggestive of hepatic or renal dysfunction occur, or if systemic manifestations (e.g., eosinophilia, rash) occur, or if abnormal liver function tests persist or worsen.
Effect on the cardiovascular system.
Thrombotic cardiovascular events. NSAIDs, both COX-2 selective and non-selective, are associated with an increased risk of serious thrombotic cardiovascular events, myocardial infarction and stroke, which may be fatal. Patients with known or predisposed cardiovascular disease are at increased risk. To minimise the risk of cardiovascular adverse reactions in patients taking NSAIDs, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should be made aware of the possibility of such events, even in the absence of previous cardiovascular symptoms. Patients should be made aware of the signs and/or symptoms of serious cardiovascular events and the steps to take if they occur.
There is no convincing evidence that concomitant use of aspirin reduces the increased risk of serious thrombotic cardiovascular complications associated with NSAID use. Concomitant use of aspirin and NSAIDs increases the risk of serious gastrointestinal complications.
Hypertension. NSAIDs, including naproxen, may induce hypertension or worsen pre-existing hypertension and may increase the incidence of cardiovascular events. Patients receiving thiazide or loop diuretics may experience a decreased effect of these therapies when receiving NSAIDs. NSAIDs, including naproxen, should be used with caution in patients with hypertension. Close monitoring of blood pressure is recommended when initiating NSAID therapy and during therapy.
Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. Naproxen should be used with caution in patients with a tendency to edema, hypertension, or heart failure.
Effects on the digestive tract – risk of ulceration, bleeding, and perforation.
NSAIDs, including naproxen, can cause serious gastrointestinal side effects, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or colon, which can be fatal.
These serious adverse reactions can occur at any time, with or without previous symptoms, in patients taking NSAIDs. Only one in five patients who have serious upper gastrointestinal adverse reactions to NSAIDs are symptomatic. Upper gastrointestinal ulceration, acute bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients taking the drug for 3-6 months and in approximately 2-4% of patients taking the drug for 1 year. This trend is also observed with longer duration of use, which increases the likelihood of developing serious gastrointestinal complications during the course of therapy. However, even short-term therapy does not eliminate the risk. The usefulness of periodic laboratory monitoring has not been demonstrated and has not been adequately evaluated.
NSAIDs should be used with caution in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Patients with a history of peptic ulcer disease and/or gastrointestinal bleeding who are taking NSAIDs have a more than 10-fold increased risk of bleeding compared with patients without any of these risk factors. Other factors that increase the risk of bleeding in patients taking NSAIDs include: concomitant use of oral corticosteroids or anticoagulants, long-term use of NSAIDs, smoking, alcohol consumption, advanced age, and poor general health. The highest number of fatal cases of gastrointestinal complications have been reported in elderly or debilitated patients, so special attention should be paid to this group of patients when treating. To minimize the risk of gastrointestinal adverse reactions in patients taking NSAIDs, the lowest effective dose should be used for the shortest duration possible. Patients and physicians should be informed of the signs and symptoms of gastrointestinal ulceration and bleeding during NSAID use and should seek prompt evaluation and treatment if a serious gastrointestinal adverse reaction is suspected. NSAIDs should be discontinued until a serious adverse reaction has been ruled out. Alternative therapy without NSAIDs should be considered in high-risk patients.
NSAIDs should be prescribed with caution to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease), as their condition may worsen.
Renal effects. Prolonged use of NSAIDs has been associated with renal papillary necrosis and other renal damage. Renal toxicity has also been observed in patients in whom renal prostaglandins have a compensatory function in maintaining renal perfusion. In such patients, the administration of NSAIDs may cause a dose-dependent decrease in prostaglandin formation and a decrease in renal blood flow, which may lead to marked renal decompensation. Patients with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, salt depletion, patients taking diuretics and ACE inhibitors or BAS, and the elderly are at greatest risk of this reaction. Discontinuation of NSAID therapy usually results in a return to the state that existed before treatment.
Progressive renal failure.
Naproxen treatment is not recommended in patients with progressive renal insufficiency. If naproxen therapy must be initiated, careful monitoring of the patient's renal function is recommended, and patients should be adequately hydrated.
Anaphylactoid reactions.
As with other NSAIDs, anaphylactoid reactions may occur in patients who have not previously taken naproxen. Naproxen should not be given to patients with the aspirin triad. This symptom complex usually occurs in patients with asthma who have rhinitis with or without nasal polyps or who develop severe, potentially fatal bronchospasm after taking aspirin or another NSAID. In the event of an anaphylactoid reaction, immediate medical attention should be sought. Anaphylactoid reactions, like anaphylaxis, can be fatal.
Skin reactions.
This medicinal product contains 2.1808 m/mol (or 50.16 mg) per dose (1 tablet) of sodium. Caution should be exercised when administering this medicinal product to patients on a controlled sodium diet.
Use during pregnancy or breastfeeding
The drug can be used during pregnancy in cases where the expected benefit of therapy outweighs the potential risk to the fetus.
Use of naproxen in late pregnancy to delay labor has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in premature infants. Because of the known effects of NSAIDs on the fetal cardiovascular system (premature closure of the ductus arteriosus), the drug should be avoided during pregnancy, starting from the 30th week of gestation (third trimester).
The effect of the drug on labor is unknown. However, naproxen preparations are not recommended for use during labor because, due to its inhibitory effect on prostaglandin synthesis, naproxen may adversely affect fetal circulation and suppress uterine contractions, thereby increasing the risk of uterine hemorrhage.
The naproxen anion has been detected in the milk of lactating women at a concentration equivalent to approximately 1% of the naproxen plasma Cmax. Because of the potential adverse effects of prostaglandin-inhibiting drugs on the newborn, the drug should not be used in nursing mothers.
Ability to influence reaction speed when driving vehicles or other mechanisms
Caution should be exercised in patients whose activities require alertness if they experience drowsiness, dizziness, or depression while taking naproxen.
Method of administration and doses
The potential benefits and risks of the drug and other treatment options should be carefully considered before deciding to use it. Use the lowest effective dose for the shortest duration consistent with the individual patient's treatment goals.
Pain relief may occur within 30 minutes of taking naproxen sodium.
Based on the observation of the effect and/or adverse reactions from the initial dose of the drug, it is recommended to further adjust its dosage. Lower doses are used to treat patients with renal or hepatic insufficiency or elderly patients.
Elderly patients. Although the total plasma concentration of naproxen is not altered in elderly patients, the plasma concentration of unbound naproxen is increased. Caution should be exercised when using high doses in elderly patients and dose adjustment may be necessary. As with other drugs used in the treatment of elderly patients, the lowest effective dose should be used.
Patients with moderate to severe renal impairment: Naproxen is not recommended for use in patients with moderate to severe renal impairment (creatinine clearance <100 mL/min).
For rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, the recommended dose is 550 mg (500 mg naproxen and 50 mg sodium) twice daily.
With prolonged use, the dose of naproxen may be increased or decreased, depending on the clinical effect in the patient. A lower daily dose may be sufficient with prolonged use. There is no need to use the drug more often than 2 times a day.
In patients who tolerate the drug well, the dose of naproxen may be increased to 1375 mg per day for a limited period of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating patients with naproxen at a dose of 1375 mg per day, the physician must observe a significant benefit to the patient that outweighs the potential increased risk.
For pain syndrome, primary dysmenorrhea, acute tendinitis and bursitis, the recommended initial dose is 550 mg of naproxen sodium, followed by 550 mg every 12 hours. The initial total daily dose of naproxen sodium should not exceed 1375 mg. Subsequently, the total daily dose of naproxen sodium should not exceed 1100 mg. Since naproxen sodium is rapidly absorbed, the drug is recommended for the treatment of acute disease states when rapid pain relief is required.
In acute gout, the recommended initial dose of naproxen sodium is 825 mg, then 275 mg every 8 hours until the attack resolves.
Children. The drug in this dosage form is not recommended for use in children.
Overdose
Symptoms and signs. Significant overdosage with naproxen may be characterized by apathy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, dyspepsia, nausea, transient changes in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation, or vomiting. Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression, and coma may occur rarely. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs, and may also occur with overdose. Since naproxen sodium is rapidly absorbed, high and early blood levels are to be expected. A few patients have had convulsions, but their relationship to the drug has not been established. There is no information on the dose of the drug that is life-threatening. When administered orally, the LD50 is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and more than 1000 mg/kg in dogs.
Treatment. Patients should receive symptomatic and supportive care following NSAID overdose. There is no specific antidote. Hemodialysis does not reduce plasma concentrations of naproxen due to its high protein binding. Patients should be induced to vomit and activated charcoal (60-100 g for adults, 1-2 g/kg for children) and/or an osmotic laxative administered within 4 hours of overdose. Forced diuresis, urine alkalinization, or hemoperfusion are not appropriate due to the high protein binding of naproxen.
Adverse reactions
On the part of the digestive tract: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis, flatulence, vomiting, bleeding (sometimes fatal, especially in the elderly), perforation and obstruction of the upper or lower digestive tract, gastric/duodenal ulcer, esophageal ulcer and perforation, inflammation, bleeding, ulcer, perforation, esophagitis, hematemesis, pancreatitis, colitis, exacerbation of inflammatory bowel disease (nonspecific ulcerative colitis, Crohn's disease), dry mouth, gastritis, glossitis, belching.
Hepatobiliary system: jaundice, abnormal liver function tests, hepatitis (in some cases fatal), liver failure.
Central nervous system: headache, dizziness, drowsiness, inability to concentrate, vertigo, depression, sleep disturbances, insomnia, weakness, muscle pain, muscular weakness, aseptic meningitis, cognitive dysfunction, convulsions, anxiety, asthenia, confusion, nervousness, paresthesia, drowsiness, tremor, coma, hallucinations.
Skin and subcutaneous tissue disorders: exfoliative dermatitis, pruritus, skin rash, bruising, sweating, purpura, alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug erythema, lichen planus, pustular reaction, systemic lupus erythematosus, bullous reactions, including Stevens-Johnson syndrome, photosensitivity dermatitis, photosensitivity reactions, including rare cases of chronic hematoporphyria (pseudocorphyria) or epidermolysis bullosa. If skin sensitivity, blistering or other symptoms characteristic of pseudoporphyria appear, treatment with the drug should be discontinued and the patient should be monitored.
From the sensory organs: tinnitus, visual impairment, hearing impairment, hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, optic disc edema, blurred vision, conjunctivitis.
Cardiovascular system: edema, palpitations, congestive heart failure, vasculitis, hypertension, pulmonary edema, tachycardia, fainting, arrhythmia, hypotension, myocardial infarction.
General disorders: dyspnea, thirst, renal dysfunction, anemia, elevated liver enzymes, increased bleeding time, anaphylactoid reactions, angioedema, menstrual disorders, hyperthermia (chills and fever), infection, sepsis, anaphylactic reactions, changes in appetite, fatal outcome.
Blood and lymphatic system disorders: eosinophilia, leukopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia, rectal bleeding, lymphadenopathy, pancytopenia.
Metabolism and nutrition disorders: hyperglycemia, hypoglycemia, weight change.
Respiratory system: eosinophilic pneumonitis, asthma, respiratory depression, pneumonia.
Urinary tract: glomerulonephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, kidney damage, renal failure, renal papillary necrosis, increased serum creatinine.
From the reproductive system (women): infertility.
Urinary tract: cystitis, dysuria, oliguria/polyuria, proteinuria.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
Tablets No. 10 (10x1), No. 20 (10x2) in a blister in a box.
Vacation category
According to the recipe.
Producer
Limited Liability Company "Pharmaceutical Company "Zdorovya".
Ukraine, 61013, Kharkiv region, Kharkiv city, Shevchenko street, building 22.
