NAPROGESIC 250/500
Uncoated Tablet
Naproxen (As Sodium) USP
The active ingredients of the NAPROGESIC is Naproxen (As Sodium). Anti-Inflammatory and anti-rheumatic products, non-steroids. Naproxen is a non-steroidal anti-inflammatory analgesic compound with antipyretic properties
PRESENTATION
Each Packing: 10*10 Blister.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics Properties
Pharmacotherapeutic Group: Anti-Inflammatory and anti-rheumatic products, non-steroids.
Naproxen is a non-steroidal anti-inflammatory analgesic compound with antipyretic properties as has been demonstrated in classical animal test systems.
Mechanism of Action: Naproxen exhibits its anti-inflammatory effect even in adrenalectomised animals, indicating that its action is not mediated through the pituitary-adrenal axis. Naproxen inhibits prostaglandin synthetize (as do other NSAIDs). As with other NSAIDs, however, the exact mechanism of its anti-inflammatory action is not known.
Pharmacokinetic Properties
Naproxen is completely absorbed from the gastro-intestinal tract, and peak plasma levels are reached in 2 to 4 hours. Naproxen is present in the blood mainly as unchanged drug, extensively bound to plasma proteins. The plasma half-life is between 12 and 15 hours, enabling a steady state to be achieved within 3 days of initiation of therapy on a twice daily dose regimen. The degree of absorption is not significantly affected by either foods or most antacids. Excretion is almost entirely via the urine, mainly as conjugated naproxen, with some unchanged drug. Metabolism in children is similar to that in adults. Chronic alcoholic liver disease reduces the total plasma concentration of naproxen but the concentration of unbound naproxen increases. In the elderly, the unbound plasma concentration of naproxen is increased although total plasma concentration is unchanged.
Preclinical Safety Data
Carcinogenicity
Naproxen was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24mg/kg/day. Naproxen was not carcinogenic in rats.
Mutagenicity
Mutagenicity was not seen in Salmonella typhimurium (5 cell lines), Saccharomyces cerevisisae (1 cell line) and mouse lymphoma tests.
Fertility
Naproxen did not affect the fertility of rats when administered orally at doses of 30mg/kg/day to males and 20mg/kg/day to females.
Teratogenicity
Naproxen was not teratogenic when administered orally at doses of 20mg/kg/day during organogenesis to rats and rabbits.
Perinatal/Postnatal Reproduction
Oral administration of naproxen to pregnant rats at doses of 2, 10 and 20mg/kg/day during the third trimester of pregnancy resulted in difficult labor. These are known effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indomethacin.
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
Other Analgesics Including Cyclooxygenase-2 Selective Inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.
Anti-Hypertensive:
Reduced anti-hypertensive effect. Naproxen and other non-steroidal anti-inflammatory drugs can reduce the anti-hypertensive effect of antihypertensive. Concomitant use of NSAIDs with ACE inhibitors or angiotensin-II receptor antagonists may increase the risk of renal impairment, especially in patients with pre-existing poor renal function.
Diuretics:
Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class.
Probenecid:
Probenecid given concurrently increases naproxen plasma levels and extends its plasma half -life considerably.
Cardiac Glycosides:
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium:
Decreased elimination of lithium. Inhibition of renal lithium clearance leading to increase in plasma lithium concentration has been reported.
Methotrexate:
Decreased elimination of Methotrexate. Caution is advised when Methotrexate is administered concurrently because of possible enhancement of its toxicity since naproxen has been reported to reduce the tubular secretion of Methotrexate in the animal model.
Cyclosporine:
Increased risk of Nephrotoxicity.
Mifepristone:
NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Corticosteroids:
Increased risk of GI bleeding or gastrointestinal ulceration.
Anti-Coagulants:
It is considered unsafe to take NSAIDs in combination with anti-coagulants such as warfarin or heparin unless under direct medical supervision, as NSAIDs may enhance the effects of anti-coagulants. Due to the plasma protein binding of naproxen, patients simultaneously receiving anticoagulants should be observed for signs of over dosage of these drugs.
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.
Sulphonamides and Hydantoins:
Due to the 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 over dosage of these drugs.
Patients simultaneously receiving Naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. No interactions have been observed in clinical studies with naproxen and anticoagulants or sulphonylureas (for diabetes), like glimepiride or Glipizide, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class.
Anti-Platelet Agents and Selective Serotonins Reuptake Inhibitors
There is an increased risk of gastrointestinal bleeding when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.
Zidovudine and Ibuprofen
There is an increased risk of hematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and hematoma in HIV (+) hemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Acetylsalicylic Acid:
Clinical pharmacodynamics 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.
Antacid or Colestyramine:
Concomitant administration of antacid or colestyramine 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.
Laboratory Tests
It is suggested that Naproxen therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because naproxen may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.
CLINICAL PARTICULARS
Therapeutic Indications
Adults:
NAPROGESIC is used in the treatment of:
Children:
Juvenile rheumatoid arthritis.
Posology and Method of Administration
Posology
Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
Adults
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis 500mg to 1g taken in 2 doses at 12-hour intervals or alternatively, as a single administration.
In the following cases a loading dose of 750mg or 1g per day for the acute phase is recommended:
a) In patients reporting severe night-time pain/or morning stiffness.
b) In patients being switched to Naproxen from a high dose of another anti-rheumatic compound.
c) In osteoarthritis where pain is the predominant symptom.
Acute Gout
In Acute Gout, an initial dose of 750 mg NAPROGESIC followed by 250 mg every 8 hours until the attack has passed.
Acute Musculoskeletal Disorders and Dysmenorrhea 500 mg may be given initially, followed by 250 mg every 6 to 8 hour intervals as needed, with a maximum daily dose after the first day of 1250mg.
Older People
Studies indicate that although total plasma concentration of Naproxen is unchanged, the unbound plasma fraction of naproxen is increased in older people. The implication of this finding for Naproxen dosing is unknown. The elderly are at increased risk of the serious consequences of adverse reactions. If NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. For the effect of reduced elimination in the elderly. Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.
Pediatrics Population (Over 5 Years)
A dose of 10 mg NAPROGESIC per kg body weight daily, in two divided doses at 12-hour intervals has been used in children over 5 years of age with juvenile Rheumatoid Arthritis. NAPROGESIC is not recommended for use in any other indication in children under 16 years of age.
Renal/Hepatic Impairment
A lower dose should be considered in patients with Renal or Hepatic Impairment. NAPROGESIC is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of naproxen metabolites has been seen in patients with severe renal failure or those on dialysis.
Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.
Method of Administration
For oral administration. To be taken preferably with or after food.
UNDESIRABLE EFFECTS
The following adverse events have been reported with NSAIDs and with naproxen.
Gastrointestinal Disorders: The most commonly-observed adverse events are gastrointestinal in nature. Heartburn, nausea, vomiting, constipation, diarrhea, flatulence, dyspepsia, abdominal discomfort and epigastric distress. More serious reactions which may occur are gastro-intestinal bleeding, which is sometimes fatal, particularly in older people, inflammation, ulceration, perforation, and obstruction of the upper and lower gastrointestinal tract, melena, hematemesis, stomatitis, exacerbation of ulcerative colitis and Crohn's disease, esophagitis, gastritis and pancreatitis.
Immune System Disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs in patients with, or without, a history of previous hypersensitivity reactions to NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiform).
Metabolic and Nutrition Disorders: Hyperkalemia.
Psychiatric Disorders: Insomnia, dream abnormalities, depression, confusion and hallucinations.
Nervous System Disorders: Convulsions, dizziness, headache, lightheadedness, drowsiness, paresthesia, retro bulbar optic neuritis, inability to concentrate and cognitive dysfunction have been reported. Aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematous, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.
Eye Disorders: Visual disturbances, corneal opacity, papillitis and papilledema.
Ear And Labyrinth Disorders: Tinnitus, hearing disturbances including impairment and vertigo.
Cardiac Disorders: Edema, palpations, hypertension, cardiac failure and congestive heart failure, have been reported.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
Vascular Disorders: Hypertension, vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, asthma, eosinophilia pneumonitis and pulmonary edema.
Renal And Urinary Disorders: Nephropathy and nephrotoxicity in various forms, including but not limited to glomerular nephritis, interstitial nephritis, nephrotic syndrome, hematuria, raised serum creatinine, renal papillary necrosis and renal failure.
Hepatobiliary Disorders: Abnormal liver function tests, fatal hepatitis and jaundice.
Blood And Lymphatic System Disorders: Granulocytopenia, thrombocytopenia, neutropenia, agranulocytosis, eosinophilia, leucopenia, aplastic anemia and hemolytic anemia.
Skin And Subcutaneous Tissue Disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymosis, purpura, sweating. Alopecia, erythema multiform, Stevens Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, very rarely toxic epidermal necrolysis, photosensitivity reactions (including cases in which skin resembles porphyria cutanea tarda “pseudo porphyria”) or epidermolysis bullosa-like reactions which may occur rarely.
If skin fragility, blistering or other symptoms suggestive of pseudo porphyria occur, treatment should be discontinued and the patient monitored.
Musculoskeletal and Connective Tissue Disorders: Myalgia and Muscle Weakness.
Reproductive System and Breast Disorders: Female Infertility.
General Disorders And Administration Site Conditions: Thirst, pyrexia, fatigue and malaise.
OVERDOSE
a) Symptoms
Symptoms include headache, nausea, vomiting, indigestion, epigastric pain, gastrointestinal bleeding, rarely diarrhea, heartburn, disorientation, excitation, drowsiness, dizziness, tinnitus, fainting. In cases of significant poisoning acute renal failure and liver damage are possible.
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.
b) Management
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
In All Patients:
Undesirable effects may be minimized by using the lowest 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.
Elderly:
The elderly and/or debilitated patients have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (See section 4.2 – Posology and administration). Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.
The antipyretic and anti-inflammatory activities of Naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Respiratory Disorders:
Caution is required if administered to patients suffering from or with a previous history of, bronchial asthma or allergic disease since NSAIDs have been reported to precipitate bronchospasm in such patients.
Renal Failure Linked To Reduce Prostaglandin Production:
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate Renal Failure. Patients at greatest risk of this reaction are those with Impaired Renal Function, Cardiac Impairment, and Liver Dysfunction, those taking Diuretics, Angiotensin Converting Enzyme Inhibitors, Angiotensin II Receptor Antagonists and the Elderly. Renal function should also be monitored in these patients.
Use in Patients with Impaired Renal Function:
As Naproxen is eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with significantly impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Naproxen is contraindicated in patients having baseline creatinine clearance less than 30ml/minute. Certain patients, specifically those where renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure and pre-existing renal disease should have renal function assessed before and during Naproxen therapy. Some elderly patients, in whom impaired renal function may be expected, as well as patients using diuretics could also fall within this category. A reduction in the daily dosage should be considered to avoid the possibility of excessive accumulation of Naproxen metabolites in the patients.
Hemodialysis does not decrease the plasma concentration of Naproxen because of the high degree of protein binding.
Renal Effects:
There have been reports of Impaired Renal Function, Renal Failure, Acute Interstitial Nephritis, Hematuria, Proteinuria, Renal Papillary Necrosis and occasionally Nephrotic Syndrome associated with Naproxen.
Use in Patients with Impaired Liver Function:
Chronic alcoholic liver disease and probably 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.
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.
Use in Patients with Cardiovascular Impairment:
Caution should be exercised in patients with a history of hypertension and/or heart failure as fluid retention and edema have been reported in association with NSAID therapy.
Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Naproxen.
Gastrointestinal Bleeding, Ulceration and Perforation:
GI 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.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk.
Naproxen has been found to be well tolerated by patients exhibiting dyspepsia with other similar agents. None the less, episodes of gastro-intestinal bleeding have been reported in patients with naproxen therapy.
Patients with a history of GI toxicity, 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 gastro toxicity, or bleeding, such as corticosteroids, or anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be withdrawn.
Naproxen should be given under close supervision to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.
SLE And Mixed Connective Tissue Disease:
In patients with Systemic Lupus Erythematous (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.
Cardiovascular and Cerebrovascular Effects
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and edema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded.
Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with naproxen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. Hypertension, Hyperlipidemias, Diabetes Mellitus, and smoking).
Hematological
Patients who have coagulation disorders or are receiving drug therapy that interferes with hemostasis should be carefully observed if naproxen-containing products are administered.
Patients at high risk of bleeding or those on full anti-coagulation therapies (e.g. dicoumarol derivatives) may be at increased risk of bleeding if given naproxen-containing products concurrently.
Naproxen decreases platelet aggression and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
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.
Steroids
If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of Arthritis.
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 papilledema, 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.
Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring 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.
Combination with other NSAIDs
The combination of Naproxen-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.
Fertility, Pregnancy and Lactation
Pregnancy:
Congenital abnormalities have been reported in associated with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of naproxen on the human fetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labor may be delayed and the duration increased with an increased bleeding tendency in both mother and child by naproxen. Therefore, naproxen should not be used during the first two trimesters of pregnancy or labor unless the potential benefit to the patient outweighs the potential risk to the fetus.
Labor and Delivery:
Naproxen containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit contractions, with an increased bleeding tendency in both mother and child.
Breast Feeding:
In limited studies so far available, Naproxen can appear in breast milk in very low concentrations. The use of naproxen should be avoided in patients who are breastfeeding.
Fertility:
The use of NAPROGESIC, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of naproxen should be considered.
Effects on Ability to Drive and Use Machines
Some patients may experience dizziness, drowsiness, vertigo, insomnia, fatigue and visual disturbances or depression with the use of NAPROGESIC. If patients experience these or similar undesirable effects, they should not drive or operate machinery.
CONTRAINDICATIONS