ANTALNOX Gé 550 mg Dry coated tablet Blister/16

Scored film-coated tablet.

White, oval, with a score line on each side.

The tablet can be divided into equal doses.

Anhydrous sodium naproxen ...............................................................................................................550,00 mg

For one scored film-coated tablet.

Excipient(s) with known effect : This medicine contains 50 mg of sodium per tablet.

Excipients:

They stem from the anti-inflammatory activity of naproxen, the significance of the intolerance reactions the medicine gives rise to, and its place among the anti-inflammatory products currently available.

In adults and adolescents from 15 years of age, they are limited to:

• long-term symptomatic treatment of:

• chronic inflammatory rheumatic conditions, in particular rheumatoid arthritis, ankylosing spondylitis or related syndromes such as Fiessinger Leroy-Reiter syndrome and psoriatic rheumatism,
• certain disabling and painful osteoarthritis;

• short-term symptomatic treatment of acute flare-ups of:

• extra-articular rheumatism such as scapulohumeral periarthritis, tendinitis, bursitis,
• osteoarthritis,
• lumbago,
• radiculalgia,
• benign acute post-traumatic conditions of the locomotor system;

• short-term symptomatic treatment of pain during inflammatory manifestations in stomatology. In this indication, the risks incurred, in particular the spread of a concomitant septic process, are those of NSAIDs. They must be assessed against the expected analgesic benefit;

• dysmenorrhoea after etiological investigation.

Dosage

The occurrence of undesirable effects can be minimised by using the lowest possible dose for the shortest treatment duration necessary to relieve symptoms (see section Warnings and precautions).

Elderly patients :

• clinical and biological monitoring is recommended in case of high dosage. A study showed that, in elderly people, the plasma concentration of free naproxen ion is doubled although the total plasma concentration is unchanged.

• a dose reduction should be considered in case of decreased renal elimination.

Adults and adolescents over 15 years :

• Rheumatology, gynaecology :

• Loading treatment: 2 tablets at 550 mg, i.e. 1100 mg per day.
• Maintenance treatment: 1 tablet at 550 mg, i.e. 550 mg per day.

• Stomatology: 1/2 to 2 tablets per day, i.e. 275 mg to 1100 mg every 24 hours.

Frequency of administration

The dose should be divided into 1 or 2 intakes.

Method of administration

Oral use.

The tablets are to be swallowed whole, with a large glass of water, preferably during meals.

This medicine is contraindicated in the following cases:

• hypersensitivity to the active substance or to any of the excipients listed in section Composition,

• history of allergy or asthma triggered by taking naproxen or substances with similar activity such as other NSAIDs, acetylsalicylic acid,

• history of gastrointestinal bleeding or perforation during previous treatment with NSAIDs,

• active peptic ulcer, history of peptic ulcer or recurrent haemorrhage (2 or more distinct episodes of documented haemorrhage or ulceration),

• severe hepatocellular insufficiency,

• severe renal impairment,

• severe heart failure,

• children and adolescents under 15 years.

• pregnancy, from the beginning of the 6th month (24 weeks of amenorrhoea) (see section Fertility, pregnancy and breastfeeding),

Special warnings

The concomitant use of ANTALNOX 550 mg, scored film-coated tablet with other NSAIDs, including selective cyclooxygenase 2 inhibitors (cox-2), should be avoided.

The occurrence of undesirable effects can be minimised by using the lowest possible dose for the shortest treatment duration necessary to relieve symptoms (see section Dosage and administration and the paragraphs "Gastrointestinal effects" and "Cardiovascular and cerebrovascular effects" below).

Patients with asthma associated with chronic rhinitis, sinusitis and/or nasal polyposis have a higher risk of allergic reaction when taking acetylsalicylic acid and/or non-steroidal anti-inflammatory drugs than the rest of the population.

Administration of this medicinal product may cause an asthma attack, particularly in subjects allergic to acetylsalicylic acid or to an NSAID (see section Contraindications).

Elderly subject

Elderly subjects have an increased risk of adverse reactions to NSAIDs, in particular gastrointestinal haemorrhage and potentially fatal perforations (see section Dosage and administration and below).

Gastrointestinal effects

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 history of serious gastrointestinal events.

The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing dose in patients with a history of ulcer, particularly if complicated with bleeding or perforation (see section Contraindications) as well as in elderly subjects. In these patients, treatment should be started at the lowest possible dose. Mucosal protective treatment (for example misoprostol or proton pump inhibitor) should be considered for these patients, as for patients requiring low-dose aspirin treatment or treated with other medicines likely to increase gastrointestinal risk (see below and section Interactions).

Patients with a history of gastrointestinal disorders, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially at the start of treatment.

Particular attention should be paid to patients receiving concomitant treatments that may increase the risk of ulceration or bleeding, such as oral corticosteroids, oral anticoagulants such as warfarin, selective serotonin reuptake inhibitors (SSRIs) and antiplatelet agents such as acetylsalicylic acid (see section Interactions).

If bleeding or ulceration occurs in a patient receiving ANTALNOX 550 mg, film-coated scored tablet, treatment must be stopped.

NSAIDs should be administered with caution and under close supervision in patients with a history of gastrointestinal disease (haemorrhagic proctocolitis, Crohn's disease), due to the risk of aggravation of the condition (see section Adverse effects).

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required in patients with a history of hypertension and/or mild to moderate heart failure, as cases of fluid retention and oedema have been reported in association with NSAID treatment.

Clinical studies and epidemiological data suggest that the use of coxibs and certain NSAIDs (especially when used at high doses and over a long period) may be associated with a slight increase in the risk of arterial thrombotic events (for example, myocardial infarction or stroke). Although these data suggest that the use of naproxen (1000 mg per day) is associated with a lower risk, the risk cannot be completely ruled out.

Patients with uncontrolled hypertension, congestive heart failure, ischaemic heart disease, peripheral arterial disease, and/or a history of stroke (including transient ischaemic attack) should only be treated with naproxen after careful consideration.

Similar attention should be paid before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidaemia, diabetes or smoking).

Skin effects

Serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and Lyell's syndrome have been very rarely reported during treatment with NSAIDs (see section Adverse effects).

The incidence of these undesirable effects appears to be higher at the start of treatment, with onset occurring, in most cases, during the first month of treatment. ANTALNOX 550 mg, film-coated scored tablet must be stopped at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. If the patient has developed Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS during use of ANTALNOX, treatment with ANTALNOX must not be resumed and must be permanently discontinued.

Functional renal failure

NSAIDs, by inhibiting the vasodilatory action of renal prostaglandins, may cause functional renal failure through a decrease in glomerular filtration. This undesirable effect is dose-dependent.

At the start of treatment or after a dose increase, monitoring of urine output and renal function is recommended in patients with the following risk factors:

• elderly subjects,

• associated medicinal products such as: ACE inhibitors, sartans, diuretics (see section Interactions),

• hypovolaemia regardless of its cause,

• heart failure,

• chronic renal failure,

• nephrotic syndrome,

• lupus nephropathy,

• decompensated hepatic cirrhosis.

As naproxen and its metabolites are eliminated largely (95 %) in the urine by glomerular filtration, naproxen should be used with caution in patients with impaired renal function; monitoring of creatinine is recommended. The lowest possible doses should be used in these patients.

Sodium retention

Sodium retention with possible edema, hypertension or worsening of hypertension, worsening of heart failure. Clinical monitoring is necessary from the start of treatment in cases of hypertension or heart failure. A decrease in the effect of antihypertensives is possible (see section Interactions).

Hyperkalaemia

• Hyperkalemia promoted by diabetes or concomitant treatment with hyperkalemic medicinal products (see section Interactions).

• Regular monitoring of serum potassium should be performed in these circumstances.

Precautions for use

This product should be used with caution in conditions of an infectious nature or involving an infectious risk, even if well controlled; indeed:

• naproxen may reduce the body's natural defences against infection,

• naproxen may mask the usual signs and symptoms of infection.

Naproxen causes a decrease in platelet aggregation and a prolongation of bleeding time:

• this must be taken into account when determining bleeding time;

• patients with coagulation disorders or treated with medicinal products interfering with hemostasis must be closely monitored when naproxen is administered.

Rare cases of ophthalmological adverse effects have been reported; it is recommended that, if the physician deems it necessary, an ophthalmological examination be performed in patients who develop visual disturbances during naproxen treatment.

During prolonged treatment, it is recommended to monitor the blood count and formula, hepatic and renal function.

Naproxen, like any drug that inhibits cyclooxygenase and prostaglandin synthesis, may impair fertility. Its use is not recommended in women who wish to conceive a child.

This medicine contains 50 mg of sodium per tablet, which is equivalent to 2.5% of the maximum recommended daily dietary intake by the WHO of 2 g of sodium per adult.

Risk related to hyperkalaemia :

Certain medicinal products or therapeutic classes may promote the occurrence of hyperkalemia: potassium salts, hyperkalemic diuretics, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, non-steroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), immunosuppressants such as ciclosporin or tacrolimus, trimethoprim.

The combination of these medicinal products increases the risk of hyperkalaemia. This risk is particularly important with potassium-sparing diuretics, especially when they are combined with each other or with potassium salts, whereas the combination of an ACE inhibitor and an NSAID, for example, carries a lower risk provided the recommended precautions are implemented.

To learn about the risks and specific levels of constraint for potassium-raising medicinal products, refer to the interactions specific to each substance.

However, certain substances, such as trimethoprim, do not have specific interactions with regard to this risk. Nevertheless, they may act as contributing factors when combined with other medicinal products such as those mentioned above.

Combinations not recommended

+ Other NSAIDs

Increased risk of ulcerogenic and digestive hemorrhage.

+ Acetylsalicylic acid at anti-inflammatory doses (≥ 1 g per dose and/or ≥ 3 g per day), and at analgesic or antipyretic doses (≥ 500 mg per dose and/or < 3 g per day)

Increased risk of ulcerogenic and digestive hemorrhage.

+ Oral anticoagulants

Increased bleeding risk with oral anticoagulants (erosion of the gastroduodenal mucosa by NSAIDs). NSAIDs may increase the effects of anticoagulants, such as warfarin (see section Warnings and precautions).

If the combination cannot be avoided, close clinical and biological monitoring.

+ Acetylsalicylic acid

Clinical pharmacodynamic data suggest that taking naproxen inhibits the effect of acetylsalicylic acid on platelet activity. This inhibition may persist for several days after stopping naproxen. The clinical relevance of this interaction remains unknown.

+ Unfractionated heparins, low molecular weight heparins and related products (at curative doses and/or in elderly subjects)

Increased bleeding risk (aggression of the gastro-duodenal mucosa by NSAIDs). If the combination cannot be avoided, close clinical monitoring.

+ Lithium

Increase in lithaemia that may reach toxic values (decreased renal excretion of lithium). If the combination cannot be avoided, closely monitor lithaemia and adjust the lithium dose during the combination and after discontinuation of the NSAID.

+ Methotrexate, used at doses above 20 mg/week

Increased haematological toxicity of methotrexate (decreased renal clearance of methotrexate by anti-inflammatory drugs).

+ Pemetrexed (patients with low to moderate renal function, creatinine clearance between 45 ml/min and 80 ml/min)

Risk of increased toxicity of pemetrexed (decreased renal clearance by NSAIDs).

Associations requiring precautions for use

+ Ciclosporin, tacrolimus

Risk of additive nephrotoxic effects, particularly in elderly subjects.

Monitor renal function at the start of treatment with the NSAID.

+ Diuretics, Angiotensin-Converting Enzyme (ACE) inhibitors, angiotensin II receptor antagonists

Acute renal failure in at-risk patients (elderly subjects and/or dehydrated) due to decreased glomerular filtration (inhibition of vasodilatory prostaglandins by NSAIDs). Furthermore, reduction of the antihypertensive effect.

Hydrate the patient. Monitor renal function at the start of treatment.

+ Methotrexate, used at doses less than or equal to 20 mg/week

Increased haematological toxicity of methotrexate (decreased renal clearance of methotrexate by anti-inflammatory drugs).

Weekly monitoring of the blood count during the first weeks of the combination.

Increased monitoring in case of impairment (even slight) of renal function, as well as in elderly subjects.

+ Pemetrexed (patients with normal renal function)

Risk of increased toxicity of pemetrexed (decreased renal clearance by NSAIDs).

Biological monitoring of renal function.

Associations to be taken into account

+ Acetylsalicylic acid at antiplatelet doses (from 50 mg to 375 mg per day in 1 or several intakes)

Increased risk of ulcerogenic and digestive hemorrhage.

+ Glucocorticoids (except hydrocortisone as replacement therapy)

Increased risk of ulceration and gastrointestinal bleeding (see section Warnings and precautions)

+ Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal haemorrhage (see section Warnings and precautions).

+ Unfractionated heparins, low molecular weight heparins and related agents (at prophylactic doses)

Increased risk of bleeding.

+ Beta-blockers (except esmolol)

Reduction of antihypertensive effect (inhibition of vasodilatory prostaglandins by NSAIDs and sodium and water retention with pyrazolone NSAIDs).

+ Deferasirox

Increased risk of ulcerogenic and digestive hemorrhage.

Pregnancy

Inhibition of prostaglandin synthesis by NSAIDs may affect the course of pregnancy and/or the development of the embryo or foetus.

Risks associated with use during the 1st trimester

Epidemiological studies suggest that treatment with a prostaglandin synthesis inhibitor during the 1st trimester of pregnancy is associated with an increased risk of miscarriage.

For certain NSAIDs, an increased risk of cardiac malformations and abdominal wall defects (gastroschisis) is also described. The absolute risk of foetal cardiovascular malformation rose from less than 1% to approximately 1,5% with exposure during the 1er trimester. The risk appears to increase with dose and duration of treatment.

In animals, administration of a prostaglandin synthesis inhibitor during the organogenesis phase causes increased pre- and post-implantation loss, increased embryo-foetal lethality and a higher incidence of certain malformations, including cardiovascular ones.

Risks associated with use during the 2th and 3th trimester

• From the 12th week of amenorrhoea

Maternal intake of an NSAID exposes the fetus to a risk of functional renal impairment:

• In utero (onset of fetal diuresis): oligoamnios may occur shortly after the start of treatment. This is generally reversible upon discontinuation of treatment. It may progress to anamnios, particularly with prolonged exposure to an NSAID.
• At birth: renal failure (reversible or not) may be observed, or may even persist, especially in cases of late and prolonged exposure, with a risk of delayed severe hyperkalaemia.

• From the 20th week of amenorrhoea:

In addition to renal functional impairment (see above), maternal intake of an NSAID exposes the foetus to a risk  of constriction of the ductus arteriosus (most often reversible on discontinuation of treatment).

• From the 24th week of amenorrhoea:

The risk of cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary arterial hypertension) becomes greater and may lead to foetal or neonatal right heart failure or even foetal death in utero. This risk is all the greater and less reversible the closer the intake is to term. This effect exists even with a single intake

In late pregnancy (close to term), NSAID intake also exposes the mother and the newborn to:

-       prolonged bleeding time due to an antiaggregant action, which may occur even after administration of very low doses of the medicinal product;

-       inhibition of uterine contractions resulting in delayed labour or prolonged delivery.

Breast-feeding

NSAIDs pass into breast milk, so this medicine is not recommended for women who are breastfeeding.

Fertility

As with all NSAIDs, the use of this medicine may temporarily impair female fertility by affecting ovulation; it is therefore not recommended for women wishing to conceive a child. In women having difficulty conceiving or undergoing fertility testing, discontinuation of treatment should be considered.

Warn patients of the possible occurrence of dizziness, drowsiness and visual disturbances.

Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially when used at high doses and over a long duration) may be associated with a slight increase in the risk of arterial thrombotic events (for example, myocardial infarction or stroke) (see section Warnings and precautions).

The most frequently observed adverse effects are gastrointestinal in nature. Peptic ulcers, perforations or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section Warnings and precautions).

Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, ulcerative stomatitis, abdominal pain, melaena, haematemesis, exacerbation of colitis or Crohn's disease (see section Warnings and precautions) have been reported following administration of NSAIDs. Less frequently, gastritis has been observed.

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

Gastrointestinal effects

• Gastrointestinal disorders have been mainly reported, such as epigastric pain, often mild or moderate, nausea, vomiting, abdominal bloating, dyspepsia, diarrhoea, constipation, ulcerative stomatitis.

• The following have been exceptionally observed: ulcers, gastrointestinal haemorrhages and/or perforations. These digestive haemorrhages are all the more frequent the higher the dose used.

• A few isolated cases of oesophagitis, colitis and pancreatitis have also been reported.

Hypersensitivity reactions

• Dermatological: skin rash, urticaria, worsening of chronic urticaria, pruritus.

• Respiratory: asthma. The occurrence of an asthma attack in some subjects may be linked to an allergy to acetylsalicylic acid or to an NSAID (see section Contraindications).

• General: Quincke's oedema, vasculitis, anaphylactoid reactions to the components.

Skin reactions

• Pruritus, hair loss, photosensitivity reactions including rare cases of "pseudoporphyria" have been observed.

• Purpura, erythema multiforme, fixed pigmented eruption, erythema nodosum and lichen planus have rarely been reported.

• Very rarely, bullous reactions (including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and Lyell's syndrome) have been observed.

Effects on the central nervous system

• Mainly reported: headache, dizziness, drowsiness.

• Also reported: insomnia, difficulty concentrating, disturbances of ideation, aseptic meningitis.

Renal manifestations

• Fluid and sodium retention, hyperkalaemia with possible oedema (see sections Warnings and precautions and Interactions).

• Functional acute renal failure (ARF) in patients with risk factors (see section Warnings and precautions).

• Organic renal damage that may result in ARF: isolated cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome and papillary necrosis have been reported.

Ophthalmic effects

• Visual disturbances, exceptionally papillitis, retrobulbar optic neuritis and papilloedema.

Effects on the auditory apparatus

• Hearing disorders, in particular tinnitus.

Cardiovascular effects

• Moderate peripheral oedema has been reported in patients with compromised cardiac function, worsening of congestive heart failure and hypertension.

Effects on the respiratory system

• Eosinophilic pneumonia.

Haematological manifestations

• Leukopenia (mainly granulocytopenia), thrombocytopenia, bone marrow aplasia and haemolytic anaemia.

Hepatic manifestations

• A few cases of transient and reversible changes in liver biological parameters, jaundice and, exceptionally, severe hepatitis (including one fatal case) have been reported.

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 suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/

Symptoms:

• Clinical signs of overdose : drowsiness, dizziness, disorientation, heartburn, indigestion, nausea or vomiting, apnoea.

• Biological signs of overdose : impaired hepatic and renal function, hypoprothrombinaemia, metabolic acidosis

Management:

• immediate transfer to a hospital setting;
• rapid evacuation of the ingested product, by gastric lavage;
• activated charcoal to reduce absorption of naproxen;
• symptomatic treatment.

Pharmacotherapeutic class: NON-STEROIDAL ANTI-INFLAMMATORY DRUG.

ATC code: M01AE02

Naproxen is a non-steroidal anti-inflammatory drug, derived from aryl-carboxylic acid belonging to the propionic group. It has the following properties:

• anti-inflammatory,

• analgesic,

• antipyretic,

• inhibition of platelet functions.

All of these properties are linked to inhibition of prostaglandin synthesis.

Absorption

Absorption is rapid and complete. The maximum plasma concentration is 77,4 µg/ml after administration of a 275 mg tablet. The maximum plasma level is reached in less than one hour after administration.

At doses above 500 mg, the plasma increase of naproxen is not proportional to the dose ingested.

Distribution

Binding to plasma proteins is approximately 99 %.

Biotransformation

Naproxen is essentially metabolised by the liver in the form of desmethyl-naproxen.

Elimination

Elimination occurs, in unchanged or conjugated form, essentially via the urine:

• 70 % as naproxen.

• 28 % as the desmethylated form.

The plasma clearance of naproxen is approximately 0,13 ml/min/kg.

The plasma half-life is 13 hours.

Physiopathological variations:

Elderly subject, renal insufficiency: see section Warnings and precautions.

4 years.

Store in the original outer packaging, protected from light.

No special requirements.

List II

Marketing authorisation (AMM)

CIP 3400941628115 (Plq/16).

Price:

2,14 euros (Plq/16).

Social security reimbursement at 65% based on the TFR: 2.14 euros (Plq/16).
Collection.