Symptomatic treatment of pain and inflammation in                   

·       acute arthritis (including gout attack);

·       chronic arthritis, especially rheumatoid arthritis / chronic polyarthritis;

·       ankylosing spondylitis (Bechterew's disease) and other inflammatory rheumatic diseases of the spine;

·       states of irritation associated with arthroses and spondylarthroses;

·       inflammatory soft tissue rheumatic diseases;

painful posttraumatic swellings or inflammations

Dosage with individual and daily doses

 

Dosage for adults:

The recommended daily dose range for adults, depending on the type and severity of disease (see below), is between 500 and 1250 mg naproxen daily in 1-3 divided doses. A single dose should not exceed 1000 mg naproxen.

 

Unless otherwise prescribed, the following dosage guidelines are recommended:

 

Rheumatic diseases:

The daily dose is generally 1 – 1½ film-coated tablets Proxen 500 mg (equivalent to 500 – 750 mg of naproxen).

 

At the start of treatment, in phases of acute irritation and when changing from another high dose anti-inflammatory medication to Proxen 500 mg film-coated tablets, a dose of 1½ film-coated tablets Proxen 500 mg daily (equivalent to 750 mg naproxen) is recommended, in two divided doses (in the morning 1, in the evening ½ film-coated tablet Proxen 500 mg or vice versa) or as a single dose (in the morning or evening).

In individual cases, the daily dose can be increased to 2 film-coated tablets Proxen 500 mg (equivalent to 1000 mg of naproxen) as required.

The maintenance dose is 1 film-coated tablet Proxen 500 mg (equivalent to 500 mg naproxen per day), which can be given divided into two single doses (in the morning and evening) of ½ Proxen 500 mg film-coated tablet or as a single dose (either in the morning or evening).

 

Acute gout attack:

Start the treatment with a single dose of 1½ film-coated tablets Proxen 500 mg  (equivalent to 750 mg of naproxen), followed by ½ film-coated tablet Proxen 500 mg  (equivalent to 250 mg of naproxen) every 8 hours until remission of symptoms.

 

Posttraumatic swellings and pain

Start the treatment with a single dose of 1 film-coated tablet Proxen 500 mg  (equivalent to 500 mg of naproxen), followed by ½ film-coated tablet Proxen 500 mg  every 6 to 8 hours (equivalent to 250 mg of naproxen).

 

Proxen 500 mg film-coated tablets are not suitable for the treatment of children and adolescents because their active ingredient content is too high.

 

Type and duration of use

Proxen 500 mg film-coated tablets are taken without chewing, with plenty of liquid and preferably before meals (for acute complaints also on an empty stomach). Taking the medication with meals can lead to delayed absorption.

 

The duration of use is decided by the treating physician.

 

Rheumatic diseases may require the long-term use of Proxen 500 mg film-coated tablets.

 

Undesirable effects can be reduced by using the lowest effective dose for the shortest period consistent with control of symptoms (see section 4.4).

 

Special populations

 

Elderly patients:

Clearance is reduced in the elderly. It is therefore recommended to use the lower dose range.

 

Renal impairment:

No dose reduction is required in patients with mild to moderate renal impairment (for patients with severe renal insufficiency see sections 4.3 and 5.2).

 

Hepatic impairment:

No dose reduction is required in patients with mild to moderate hepatic impairment (for patients with severe hepatic dysfunction see sections 4.3 and 5.2).

Film-coated tablets of Proxen 500 mg should not be used in the following cases: • known hypersensitivity to the active substance naproxen or one of the other excipients of the medicinal product mentioned in section 6.1; • known reactions such as bronchospasm, asthma, rhinitis or urticaria after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs in the past. Reactions of this nature can be potentially fatal. Affected patients have been reported to show severe reactions resembling anaphylactic shock. • hematopoietic disorders of undetermined etiology; • existing or past recurrent peptic ulcers or hemorrhages (at least 2 different episodes of proven ulceration or bleeding); • history of gastrointestinal bleeding or perforation associated with previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs); • cerebrovascular or other active bleeding; • severe hepatic or renal impairment; • severe heart failure; • last trimester of pregnancy (see section 4.6). Children and adolescents should not take Proxen 500 mg film-coated tablets because the active substance content is too high.

Gastrointestinal safety

 

The use of Proxen 500 mg film-coated tablets in combination with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

 

Undesirable effects can be reduced by using the lowest effective dose for the shortest period consistent with control of symptoms (see section 4.2 and gastrointestinal and cardiovascular risks below).

 

Elderly patients:

Elderly patients receiving NSAID therapy have a relatively high incidence of undesirable effects, especially gastrointestinal bleeding and perforations, in some cases with fatal outcome (see section 4.2).

 

Gastrointestinal bleeding, ulcers or perforations:

Gastrointestinal bleeding, ulcers or perforations, in some cases with fatal outcome, have been reported for all NSAIDs. These effects have occurred at any time during therapy with or without prior warning symptoms and without a history of serious gastrointestinal events.

 

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID dosage, in patients with a history of ulceration, especially with the complications bleeding or perforation (see section 4.3) and in elderly and debilitated patients. These patients should begin the treatment with the lowest available dose.

For these patients and for patients who require concomitant therapy with low-dose acetylsalicylic acid (ASA) or other drugs that may increase the gastrointestinal risk (see section 4.5), combination therapy with protective medications (e.g. misoprostol or proton pump inhibitors) should be considered (see below and section 4.5).

 

Patients with a history of gastrointestinal toxicity, especially those of advanced age, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly at the start of therapy.       
Caution is advised if the patients are simultaneously receiving medications that can increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or antiplatelet drugs like ASA (see section 4.5).

 

If gastrointestinal bleeding or ulceration occurs in patients taking Proxen 500 mg film-coated tablets, the treatment should be discontinued.

 

NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) since their condition may worsen (see section 4.8).

 

Cardiovascular and cerebrovascular effects

 

Patients with a history of hypertension and/or mild to moderate congestive heart failure should be monitored and advised appropriately, as fluid retention and edema have been reported in association with NSAID therapy.

 

Clinical trials and epidemiological data suggest that use of coxibs and some NSAIDs (particularly in high doses and in long-term treatment) may be associated with a slightly 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, a certain risk of this nature cannot be excluded.

 

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial occlusive disease and/or cerebrovascular disease should only be treated with naproxen after a careful appraisal of the risks and benefits. Similar consideration should be made before initiating longer-term treatment in patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking).

 

Dermatological reactions

 

Serious dermatological reactions, in some cases with a fatal outcome, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported very rarely during NSAID therapy (see section 4.8). The highest risk of such reactions appears to be present at the start of therapy since in the majority of cases these reactions occurred during the first month of treatment. At the first signs of skin rash, mucosal lesions or other signs of hypersensitivity reactions, Proxen 500 mg film-coated tablets should be discontinued.

 

Effect on the kidney

 

Patients whose disease leads to a reduction in blood volume and/or renal blood flow should be treated with caution, since renal prostaglandins have a supportive function in maintaining renal perfusion. In these patients, therefore, the administration of Proxen 500 mg film-coated tablets or other NSAIDs can cause a dose-dependent reduction in the formation of renal prostaglandins and induce a frank impairment or failure of renal function.

The greatest risk of this renal reaction is present in patients:

·       with impaired renal function,

·       with hypovolemia,

·       with congestive heart failure,

·       with impaired hepatic function,

·       with salt deficiency

·       who are taking diuretics

·       and elderly patients.

Discontinuation of treatment with Proxen 500 mg film-coated tablets usually restores the pretreatment condition. Proxen 500 mg film-coated tablets should be used with great caution in these patients and monitoring of serum creatinine and/or creatinine clearance is recommended. A reduction in the daily dose to prevent excessive accumulation of naproxen metabolites should be considered in these patients.

Hemodialysis does not lower the concentration of naproxen in plasma, since naproxen is highly bound to serum proteins.

 

Effect on the liver

 

As with other NSAIDs, the administration of Proxen 500 mg film-coated tablets can also cause an increase in one or more parameters in liver function tests. Hepatic abnormalities may be a result of hypersensitivity reactions instead of direct toxicity. Severe impairments of liver function, including jaundice and hepatitis (some cases of hepatitis take a fatal course), have been reported for Proxen 500 film-coated tablets and for other NSAIDs. Cross-reactions have also been reported.

 

Other information

 

Proxen 500 mg film-coated tablets should only be used after a rigorous risk-benefit analysis in patients with:

·       inducible porphyrias

·       systemic lupus erythematosus (SLE) as well as mixed connective tissue disease (see section 4.8).

 

Particularly close medical supervision is required in the following cases:

·       history of gastrointestinal disorders or chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease);

·       hypertension or heart failure;

·       renal impairment;

·       hepatic impairment;

·       immediately after major surgery;

·       patients suffering from hay fever, nasal polyps or chronic obstructive airway diseases since they have an increased risk of allergic reactions. These may take the form of asthma attacks (analgesic asthma), angioedema or urticaria;

·       patients showing allergic reactions to other substances, because the use of Proxen 500 mg film-coated tablets also represents an increased risk of hypersensitivity reactions in these patients;

·       simultaneous treatment with more than 15 mg methotrexate per week.

 

Severe acute hypersensitivity reactions (for example anaphylactic shock) are observed very rarely. Anaphylactic (anaphylactoid) reactions can occur in patients with and without a history of hypersensitivity reactions or who are taking aspirin or other NSAIDs. At the first signs of a hypersensitivity reaction after taking/administering Proxen 500 mg film-coated tablets, the therapy is to be discontinued. Medically necessary interventions appropriate to the symptoms should be instituted by qualified persons.

 

Headache may develop during prolonged use of analgesics and should not be treated by increasing the medication dose.

 

The habitual use of analgesics, especially in the form of a combination of several analgesic agents, can generally lead to permanent renal damage with the risk of renal failure (analgesic nephropathy). Acute interstitial nephritis, hematuria, proteinuria, papillary renal necrosis and occasionally nephrotic syndrome have been reported in association with naproxen.

 

Patients who develop visual disturbances during treatment with naproxen should have an ophthalmological examination.

 

During the use of NSAIDs, drug-induced undesirable effects, especially those affecting the gastrointestinal tract or the central nervous system, may be intensified by the concomitant use of alcohol.

 

For female fertility see section 4.6.

 

Naproxen, the active substance of Proxen 500 mg film-coated tablets, can temporarily inhibit blood platelet function (platelet aggregation). Patients with coagulation disorders should therefore be closely monitored.

 

During the simultaneous use of Proxen 500 mg film-coated tablets and lithium preparations (drugs for the treatment of mental/psychological illnesses) or certain medications taken to increase urinary excretion (potassium sparing diuretics), monitoring of the lithium and potassium concentration in the blood is required (see section 4.5).

 

During prolonged administration of Proxen 500 mg film-coated tablets, regular monitoring of the liver values, renal function and blood count is necessary.

 

Antipyretic effect

 

The antipyretic and anti-inflammatory properties of naproxen can lower fever and reduce inflammations and thereby reduce their value as diagnostic signals.

 

Concomitant use of Proxen 500 mg film-coated tablets with digoxin, phenytoin or lithium preparations can increase the serum levels of these medications. Monitoring of the serum lithium levels is necessary.

 

Patients simultaneously taking naproxen and a hydantoin or sulfonamide must be monitored to identify the possible need for a dose adjustment.

 

Other NSAIDs including salicylates:

The concurrent use of several NSAIDs can increase the risk of gastrointestinal ulceration and bleeding due to a synergistic effect. The co-administration of naproxen and other NSAIDs is therefore not recommended (see section 4.4).

 

Diuretics, ACE inhibitors and angiotensin II antagonists:

NSAIDs (non-steroidal anti-inflammatory drugs) can weaken the effect of diuretics and antihypertensive drugs. In patients with renal impairment (e.g. exsiccated patients or elderly patients with renal impairment) the simultaneous use of an ACE inhibitor or angiotensin II antagonist with a drug that inhibits cyclooxygenase can lead to a further deterioration in renal function including the possibility of acute renal failure which is usually reversible. A combination should therefore only be used with caution especially in elderly patients. Patients should be encouraged to maintain adequate fluid intake, and regular monitoring of renal values should be considered after starting combination therapy.

The concomitant use of Proxen 500 mg film-coated tablets and potassium sparing diuretics can lead to hyperkalemia. Monitoring of the blood potassium levels is therefore required.

 

Glucocorticoids:

Increased risk of gastrointestinal ulceration or bleeding (see section 4.4)

 

Antiplatelet drugs like acetylsalicylic acid and selective serotonin re-uptake inhibitors (SSRI):

Increased risk of gastrointestinal bleeding (see section 4.4.)

 

The administration of Proxen 500 mg film-coated tablets and other drugs that inhibit prostaglandin synthesis within 24 hours before or after giving methotrexate can lead to an elevated concentration of methotrexate in the blood and an increase in its toxic action.

 

Non-steroidal anti-inflammatory drugs (such as naproxen) can increase the renal toxicity of cyclosporin.

 

Medicines containing probenecid or sulfinpyrazone can delay the excretion of naproxen. Caution is advised during the concomitant use of probenecid, since increases in the plasma concentration and prolongation of the half-life of naproxen have been reported for this combination.

 

The use of antacids or cholestyramine can lead to a reduced rate of absorption of Proxen 500 mg film-coated tablets without influencing the level.

 

NSAIDs can potentiate the action of anticoagulants such as warfarin (see section 4.4.). Monitoring of the coagulation values is recommended during concomitant therapy.

 

Clinical studies have so far shown no interactions between naproxen and oral antidiabetics. Nevertheless, monitoring of the blood glucose values is recommended as a precaution since NSAIDs can increase the effect of antidiabetic sulfonylureas.

 

Note on laboratory diagnostic control tests:

Proxen 500 mg film-coated tablets can influence platelet aggregation, resulting in an increase in the bleeding time. This effect should be considered when determining the bleeding time.

 

A temporary interruption of treatment with Proxen 500 mg film-coated tablets is recommended before performing renal function tests, as naproxen can interfere with the tests for 17-ketogenic steroids. Similarly, treatment with Proxen 500 mg film-coated tablets can influence some urinary tests for 5-hydroxyindolacetic acid (5HIAA).

 

Pregnancy

 

The inhibition of prostaglandin synthesis can adversely impact pregnancy and/or embryofetal development. Data from epidemiological studies show an increased risk of miscarriage as well as cardiac malformations and gastroschisis after using a prostaglandin synthesis inhibitor during early pregnancy. The risk is assumed to increase with the dose and the duration of therapy.

 

Animal studies have shown that the administration of a prostaglandin synthesis inhibitor leads to increased pre- and postimplantation losses and embryofetal mortality. Increased incidences of various birth defects, including cardiovascular malformations, have also been reported in animals which received a prostaglandin synthesis inhibitor during the phase of organogenesis.

 

During the first and second trimester of pregnancy, naproxen should only be given if absolutely necessary. If naproxen is used by a woman planning to become pregnant or if it is used during the first or second trimester of pregnancy, the dose should be kept as low as possible and the period of treatment as short as possible.

 

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can:

·       expose the fetus to the following risks

-      cardiopulmonary toxicity (with premature arterial duct closure and pulmonary hypertension);

-      renal impairment which can progress to renal failure with oligohydramniosis;

·       expose the mother and child to the following risks at the end of pregnancy:

-      possible prolongation of the bleeding time, an antiplatelet effect which can occur even at very low doses;

-      inhibition of uterine contractions resulting in delayed or prolonged childbirth.

 

Naproxen is therefore contraindicated during the third trimester of pregnancy.

 

Proxen 500 mg film-coated tablets should not be used during the puerperium due to possible retardation of uterine involution and intensification of post partum bleeding.

 

Lactation

 

The naproxen anion has been found in the milk of nursing mothers in a concentration of about 1 % of that in plasma. As a precautionary measure, the use of Proxen 500 mg film-coated tablets should therefore be avoided during lactation.

 

Fertility

 

The use of Proxen 500 mg film-coated tablets, like the use of other medicines known to be able to inhibit cyclooxygenase/ prostaglandin synthesis, can impair fertility and is therefore not recommended in women planning to become pregnant. For women experiencing difficulty becoming pregnant or who have been investigated for infertility, discontinuation of Proxen 500 mg film-coated tablets should be considered.

 

Since the use of Proxen 500 mg film-coated tablets in higher dosages can lead to undesirable CNS effects such as fatigue and dizziness, in individual cases reactivity may be affected and the ability to drive or use machines may be impaired. This applies especially in association with alcohol

Undesirable effects have been ranked under headings of frequency using the following convention:

 

Very common               (≥ 10 % of patients)

Common                      (< 10%, but ≥ 1% of patients)

Uncommon                   (< 1%, but ≥ 0.1% of patients)

Rare                             (< 0.1%, but ≥ 0.01% of patients)

Very rare                      (< 0.01% of patients)

Unknown                      (Frequency cannot be estimated from the available data)

 

For the following adverse drug reactions it should be considered that they are predominantly dose-dependent and differ between individuals.

 

The most commonly observed undesirable effects relate to the gastrointestinal tract. Peptic ulcers, perforations or bleeding, sometimes fatal, can occur especially in elderly patients (see section 4.4). Nausea, vomiting, diarrhea, flatulence, constipation, digestive complaints, abdominal pain, tarry stools, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported after the use of this medication. Gastritis has been observed less commonly.

Especially the risk of gastrointestinal bleeding depends on the dose range and duration of use.

 

Edema, hypertension and heart failure have been reported in association with NSAID treatment.

 

Clinical trials and epidemiological data suggest that the use of some NSAIDs (particularly in high doses and in long-term treatment) may be associated with a slightly increased risk of arterial thrombotic events (for example, myocardial infarction or stroke) (see section 4.4).

 

Infections and infestations

Very rare:              Symptoms of aseptic meningitis with severe headache, nausea, vomiting, fever, stiff neck or impairment of consciousness.

 

Very rarely an exacerbation of infectious inflammations (development of necrotic fasciitis) has been observed in association with the systemic use of non-steroidal anti-inflammatory agents.

 

This may possibly be related to the mechanism of action of the non-steroidal anti-inflammatory drugs.

 

If signs of a new infection occur or if an existing infection worsens during the use of Proxen 500 mg film-coated tablets, the patient is recommended to consult a physician immediately. It should be established whether there is an indication for anti-infectious/anti­biotic therapy.

 

Patients with autoimmune diseases (SLE, mixed connective tissue disease) appear to be predisposed.

 

Blood and lymphatic system disorders

Uncommon:          Blood count irregularities, eosinophilia

 

Very rare:              Disorders of blood formation (aplastic anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms may include: fever, sore throat, superficial wounds in the mouth, influenza-like symptoms, severe exhaustion, nose bleeds and bleeding on the skin. The blood count should be monitored regularly during long-term therapy.

                            Hemolytic anemia.

 

Immune system disorders

Common:              Hypersensitivity reactions with exanthem, pruritus, purpura or ecchymoses

 

Very rare:              Severe hypersensitivity reactions (e.g. angioneurotic syndrome). Relevant signs may be: facial, lingual and pharyngeal swelling (edema), dyspnea, tachycardia, severe circulatory disorders or even life-threatening shock.

 

If any of these signs occur, medical assistance should be sought immediately.

 

Metabolism and nutrition disorders

Unknown:             Hyperkalemia

 

Psychiatric disorders

Common:              Depression, abnormal dreams, insomnia

 

Nervous system disorders

Common:              Headache, dizziness, insomnia, excitation, irritability or fatigue.

 

Unknown:             Seizures/convulsions, perception disorders and concentration difficulties, retrobulbar neuritis

 

Eye disorders

Common:              Visual disorders

 

Unknown:             Disc edema, papillary edema, corneal opacity

 

Ear and labyrinth disorders

Common:              Hearing disorders, tinnitus, vertigo

 

Cardiac disorders

Common:              Palpitations

 

Very rare:              Heart failure, hypertension

 

Vascular disorders

Unknown:             Vasculitis

 

Respiratory, thoracic and mediastinal disorders

Common:              Dyspnea

Uncommon:          Asthma attacks (possibly with a fall in blood pressure), bronchospasm, eosinophilic pneumonia

 

Unknown:             Pulmonary edema

 

Gastrointestinal disorders

Very common:      Gastrointestinal symptoms such as nausea, vomiting, heartburn, epigastric distress, bloating, constipation or diarrhea and slight blood loss in the gastrointestinal tract, which in exceptional cases may cause anemia.

 

Common:              Gastrointestinal ulceration (possibly with bleeding and perforation).

 

Uncommon:          Hematemesis, melena or bloody diarrhea; lower abdominal complaints (e.g. bleeding colitis or exacerbation of Crohn's disease/ulcerative colitis), stomatitis, esophageal lesions.

 

The patient should be instructed to stop taking the medication immediately if these symptoms occur and consult a physician.

 

Unknown:             Pancreatitis

 

Hepatobiliary disorders

Uncommon:          Hepatic dysfunction

 

Very rare:              Liver damage, especially during long-term therapy.

 

Unknown:             Hepatitis, jaundice

 

Skin and subcutaneous tissue disorders

Common:              Sweating.

 

Uncommon:          Increased photosensitivity (including formation of blisters), alopecia (usually reversible)

 

Very rare:              Bullous skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).

 

Unknown:             Erythema nodosum, lichen planus, SLE, urticaria.

 

Musculoskeletal and connective tissue disorders

Uncommon:          Myalgia, myasthenia

 

Renal and urinary disorders

Common:              Peripheral edema, especially in patients with hypertension

 

Uncommon:          Reduced urination

                            Acute renal failure, nephrotic syndrome or interstitial nephritis.

 

Very rare:              Renal damage (papillary necroses) especially during long-term therapy, hyperuricemia.

 

Unknown:             Hematuria.

 

Renal function should be monitored regularly.

 

Reproductive system and breast disorders

Unknown:             Female infertility

 

General disorders and administration site conditions

Common:              Thirst

 

Uncommon:          Fever, malaise

 

Unknown:             Papillitis

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any adverse reactions via

 

Bundesinstitut für Arzneimittel und Medizinprodukte

Pharmacovigilance Department

Kurt-Georg-Kiesinger Allee 3

D-53175 Bonn.

Website: http://www.bfarm.de

 

Symptoms of overdose

Symptoms of overdose may comprise central nervous impairments with headache, dizziness or drowsiness, as well as upper abdominal pain and abdominal discomfort, digestive disturbances, nausea, vomiting, transient changes in hepatic function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea and disorientation. Gastrointestinal bleeding may also occur. Hypertension, hypotension, acute renal failure, respiratory depression, cyanosis and coma are also possible.

 

Anaphylactic reactions have been described after treatment with non-steroidal anti-inflammatory drugs and may possibly also occur following an overdose.

 

Naproxen sodium may be rapidly absorbed. High and early active drug concentrations in the blood should be expected. Some patients have suffered seizures/convulsions, although a causal relationship with the naproxen treatment remained uncertain.

 

Management of overdose

There is no specific antidote. Symptomatic therapy should be given. Measures to prevent further absorption (e.g. by giving activated charcoal) may be indicated in patients within four hours after intake or following a large overdose. Forced diuresis, alkalization of urine, hemodialysis or hemoperfusion are unlikely to be helpful due to the high protein binding of naproxen.

 

Pharmacotherapeutic group: non-steroidal anti-inflammatory and antirheumatic drugs, propionic acid derivatives

ATC code: M01A E02

 

Naproxen is a non-steroidal anti-inflammatory drug which has been shown to exert its effect via prostaglandin synthesis inhibition in the usual experimental animal models of inflammation. In humans, naproxen reduces pain, swelling and fever of inflammatory origin.

After oral administration, naproxen is partly absorbed while still in the stomach and then completely from the small intestine. After an oral dose of 250 mg naproxen in a normal release dosage form, peak plasma levels of about 35 – 40 µg/ml are reached after an average 2 to 4 hours. The required therapeutically effective plasma concentration is likely to be 15 µg/ml. The volume of distribution is about 0.09 l/kg.

 

Plasma protein binding is about 99 %.

 

Naproxen crosses the placental barrier and is also excreted in breast milk.

 

Following hepatic biotransformation, the drug is eliminated mainly via the renal route. The extent of biliary excretion is unknown.

 

Following intravenous administration of 100 mg naproxen, about 10 % of the administered dose is excreted intact and about 60 % in conjugated form as a glucuronide via the renal route.

About 28 % are demethylated to inactive 6-oxy-desmethylnaproxen, of which 5 % is recovered intact and 22 % in conjugated form in the urine, with only 0.1 – 3 % present in the feces.

 

The elimination half-life in healthy subjects and renal patients is 10 – 18 hours, but is subject to considerable individual variability in patients with progressive renal dysfunction. Patients with renal impairment tend to have lower plasma concentrations than subjects with healthy kidneys. In subjects with severe renal dysfunction (creatinine clearance 1 to 10 ml/min), the AUC (area under the plasma concentration curve) is reduced by about 50 %.

 

In patients with hepatic impairment, clearance of the naproxen fraction not bound to protein is reduced by about 60 %, the elimination half-life is prolonged and the plasma concentration is increased compared to subjects with normal hepatic function.

 

The absolute bioavailability after oral administration is > 90 %

Acute toxicity

The test for acute toxicity in various animal species revealed no particular sensitivity. For symptoms of intoxication see section 4.9.

 

Chronic toxicity

The test for subchronic and chronic toxicity of naproxen was performed in mice, rats, rabbits, dogs, minipigs and monkeys with daily oral administration in experiments with a duration of 2 weeks to 24 months. Gastrointestinal ulcerations occurred in the toxic range. Renal damage in the form of crystalline deposits in the renal tubuli were observed in several animal species at extremely high dose levels.

 

Mutagenic and tumorigenic potential

No detailed mutagenicity test for mutagenic potential has been performed; tests performed to date produced negative results.

A long-term study in rats produced no evidence of a tumorigenic potential of naproxen.

 

Reproductive toxicity

Studies in three animal species (rat, mouse, rabbit) produced no evidence of a teratogenic potential

Croscarmellose sodium,

Povidone K 90,

Magnesium stearate (Ph. Eur.),

Hypromellose,

Macrogol 400,

Macrogol 6000,

Propylene glycol, 

Polysorbate 80,

Titanium dioxide (E171),

Iron(III)-hydroxide oxide (E172).

None known to date.

The shelf-life is 4 years.

Do not store above 30°C.

20 film-coated tablets

No special requirements