Actromadol 660Mg 8 Tablets Modified Release

Actromadol 660 mg Modified Release Tablets ( Naproxen Sodium)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each modified-release tablet contains 660 mg of naproxen sodium (equivalent to 600 mg of naproxen and 60 mg of sodium).

Excipients with known effect:

Each modified-release tablet contains 41.78 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Modified-release tablet.

Oblong blue tablets.

4. CLINICAL DATA
4.1. Therapeutic indications

Actromadol is indicated for the symptomatic relief of occasional mild or moderate pain, such as headaches, dental, menstrual, muscular (contractures) or back (low back pain). Febrile states.

This medicine is indicated in adults 18 to 65 years of age.
4.2. Dosage and method of administration

Posology

Adults (between 18 and 65 years old): 1 tablet every 24 hours. The maximum daily dose is 1 tablet (equivalent to 660 mg of naproxen sodium). The taking of 1 tablet every 24 hours should not be exceeded.

Special populations:

Elderly patients (over 65 years): This medicine is not recommended for use in this population. Older people are more prone to adverse effects, so it is recommended to use lower doses in these patients.

Patients with renal, hepatic or cardiac insufficiency: It is not recommended to use this medicine in this population, since in these patients it is recommended to reduce the dose, using the minimum effective dose that the patient needs (see sections 4.3 and 4.4).

Pediatric population:

Do not administer this medicine in children and adolescents under 18 years of age, because its safety and efficacy in this population have not been established.

Form of administration

This medicine is administered orally.

Take the whole tablet, with a glass of water and without chewing, preferably with food or milk, especially if digestive discomfort is noted.

Taking this medicine with food delays the absorption of this medicine and therefore its onset of action (see section 5.2).

The administration of the preparation is subject to the appearance of painful or feverish symptoms. As these disappear, this medication should be discontinued.

If the pain persists for more than 5 days, the fever for more than 3 days, either worsens or other symptoms appear, the clinical situation should be evaluated.

4.3. Contraindications

Hypersensitivity to naproxen or to any of the excipients listed in section 6.1.
Patients with a history of asthma, urticaria, nasal polyps or allergic reactions due to the administration of salicylates or non-steroidal anti-inflammatory drugs.
History of gastrointestinal bleeding or perforation related to previous treatments with non-steroidal anti-inflammatory drugs (NSAIDs).
Active or recurrent peptic ulcer / gastrointestinal bleeding (two or more different episodes of proven ulceration or bleeding).
Severe kidney, liver or heart failure.
Third trimester of pregnancy.

4.4. Special warnings and precautions for use

Concomitant administration of Actromadol with other NSAIDs, including selective cyclooxygenase-2 inhibitors (Coxib), should be avoided. Adverse reactions may be reduced by using the lowest effective dose for the shortest possible time to control symptoms (see section 4.2).

Naproxen sodium is not indicated for gastrointestinal pain.

Use in the elderly: the elderly experience a higher incidence of adverse reactions to NSAIDs, specifically gastrointestinal bleeding and perforation, which can be fatal (see section 4.2.).

Gastrointestinal risks:

Gastrointestinal bleeding, ulcers and perforations: During treatment with non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen, gastrointestinal bleeding, ulcers and perforations (which can be fatal) have been reported at any time during the treatment, with or without prior warning symptoms and with or without a history of prior serious gastrointestinal events.

The risk of gastrointestinal bleeding, ulcer or perforation is higher when increasing doses of NSAIDs are used, in patients with a history of ulcer, especially if they were ulcers complicated by bleeding or perforation (see section 4.3), and in the elderly. These patients should start treatment with the lowest possible dose. It is recommended to prescribe these patients concomitant treatment with protective agents (eg misoprostol or proton pump inhibitors); such combination therapy should also be considered in the case of patients requiring low dose acetylsalicylic acid or other medicinal products that may increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal toxicity, and especially the elderly, should be advised to immediately report any infrequent abdominal symptoms (especially those of gastrointestinal bleeding) during treatment and particularly in the early stages.

Special precaution should be advised in those patients receiving concomitant treatments that could increase the risk of gastrointestinal ulcer or bleeding such as oral anticoagulants of the dicoumarin type, and antiplatelet drugs of the acetylsalicylic acid type (see section 4.5). Likewise, certain caution should be observed in the concomitant administration of oral corticosteroids and selective serotonin reuptake inhibitor (SSRI) antidepressants.

If gastrointestinal bleeding or ulcer occurs in patients taking Actromadol, treatment should be stopped immediately.

NSAIDs should be administered with caution in patients with a history of ulcerative colitis, or Crohn's disease as they could exacerbate this pathology (see section 4.8, adverse reactions).

The use of naproxen in patients who regularly consume alcohol (three or more alcoholic drinks -beer, wine, liquor, ...- a day) can cause gastric bleeding.

Cardiovascular and cerebrovascular risks:

Special 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 treatment with NSAIDs.

Data from clinical trials and epidemiological studies suggest that the use of some NSAIDs (especially in high doses and in long-term treatments) may be associated with a moderately increased risk of atherothrombotic events (eg myocardial infarction or stroke). Data suggest that the use of naproxen at doses of 1,000 mg daily may be associated with a lower risk than selective cyclo-oxygenase 2 inhibitor drugs (Coxib) and other traditional NSAIDs, although a certain degree of risk cannot be excluded. .

Consequently, patients with hypertension, congestive heart failure, established coronary artery disease, peripheral arterial disease and / or uncontrolled cerebrovascular disease should only be treated with Actromadol if the benefit-risk ratio for the patient is judged favorable by the physician. This same assessment should be carried out before starting long-term treatment in patients with known cardiovascular risk factors (eg hypertension, hyperlipidaemia, diabetes mellitus, smokers).

Naproxen can weaken the antiplatelet effect of acetylsalicylic acid. Patients taking acetylsalicylic acid or planning to take naproxen should consult a doctor.

Risks of serious skin reactions:

In patients treated with NSAIDs, very rare cases of serious skin reactions, some fatal, such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome) have been reported with a very rare frequency, less than 1 case in 10,000 patients (see section 4.8). The maximum risk of reactions of this type appears to occur at the beginning of treatment, since, in most cases, these reactions occurred during the first month of treatment. Actromadol should be discontinued immediately at the first symptoms of skin erythema, mucosal lesions or other signs of hypersensitivity.

Other warnings:

Patients with or without a history of hypersensitivity to acetylsalicylic acid, other NSAIDs or naproxen, may suffer hypersensitivity reactions such as anaphylactic shock. Likewise, it can occur in patients with other allergic manifestations, such as asthma, rhinitis, nasal polyps, allergic reactions (skin reactions, itching or hives). Anaphylactic reactions such as anaphylaxis can be fatal.

As with other NSAIDs, naproxen has reported serious liver reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal). Cross reactivity has been reported.

For information on effects on female fertility, see section 4.6.

This medicine should be administered under close medical supervision in cases of:

patients being treated with other analgesics,
patients receiving steroids,
coagulation disorders or patients receiving medications that may affect hemostasis,
intensive diuretic therapy,
severe renal, hepatic or cardiac insufficiency.

Excipient Warning

This medicine contains lactose. Patients with hereditary galactose intolerance, Lapp lactase deficiency (deficiency seen in certain populations in Lapland) or glucose or galactose malabsorption should not take this medicine.

This medicine contains 60 mg of sodium per tablet equivalent to 3% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.
4.5. Interaction with other medicinal products and other forms of interaction

Naproxen, like other NSAIDs, should always be used with caution in patients treated simultaneously with the following medications:

Cyclosporine: NSAIDs may increase the nephrotoxicity of cyclosporine due to renal prostaglandin-mediated effects. Careful monitoring of renal function is recommended, especially in elderly patients.

Lithium: NSAIDs have been shown to decrease lithium excretion, increasing lithium levels in the blood, which can reach toxic values. The concomitant use of lithium and NSAIDs is not recommended. Lithium blood concentrations should be carefully monitored during the initiation, adjustment and discontinuation of acetylsalicylic acid treatment, if this combination is necessary.

Methotrexate: with concomitant administration of methotrexate at doses of 15 mg / week or more, naproxen decreases the tubular secretion of methotrexate and decreases its binding to plasma proteins, increasing plasma concentrations of the same and therefore its toxicity. For this reason, concomitant use with naproxen is not recommended in patients treated with high doses of methotrexate.

At doses lower than 15 mg / week, the risk of interaction should be taken into account, especially in patients with impaired renal function. In cases where combined treatment is necessary, the blood count and renal function should be monitored, especially the first days of treatment.

Other non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid: the simultaneous administration of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding, due to a synergistic effect.
Low-dose acetylsalicylic acid: Naproxen may attenuate the irreversible platelet-inhibiting effect induced by acetylsalicylic acid. Pharmacodynamic clinical data suggest that concomitant use (on the same day) of naproxen for more than one consecutive day inhibits the antiplatelet effect of acetylsalicylic acid at low doses and this inhibition may persist for several days after naproxen treatment. The clinical relevance of this interaction is unknown. Naproxen treatment in patients with elevated cardiovascular risk may limit the cardiovascular protection of acetylsalicylic acid.

Antiplatelet agents: increase the risk of gastrointestinal bleeding (see section 4.4.).

Low-dose acetylsalicylic acid: Naproxen may attenuate the irreversible platelet-inhibiting effect induced by acetylsalicylic acid.

Acetylsalicylic acid: Pharmacodynamic clinical data suggest that concomitant use of naproxen for more than one consecutive day may inhibit the antiplatelet effect of low-dose acetylsalicylic acid and this inhibition may persist for several days after the end of naproxen treatment. The clinical relevance of this interaction is unknown. Naproxen treatment in patients with elevated cardiovascular risk may limit the cardiovascular protection of acetylsalicylic acid.

Anticoagulants: NSAIDs may increase the effects of dicoumarin-type anticoagulants (see section 4.4.). The simultaneous administration of naproxen with anticoagulants such as heparin and warfarin increases the risk of bleeding and is therefore not recommended. In addition, naproxen displaces oral anticoagulants from plasma protein receptors. Administration of naproxen should be avoided in patients receiving heparin, especially in the presence of thrombocytopenia. Known interactions of naproxen with heparin and coumarin derivatives indicate that these agents should be administered only in the absence of other therapeutic alternatives.

Selective serotonin reuptake inhibitors (SSRIs): their simultaneous administration may increase the risk of gastrointestinal bleeding (see section 4.4.), Therefore their concomitant use should be avoided as far as possible.

Corticosteroids: the simultaneous administration of naproxen with corticosteroids may increase the risk of gastrointestinal ulcers and bleeding, due to a synergistic effect, therefore their concomitant administration is not recommended (see section 4.4).

Diuretics and angiotensin converting enzyme (ACE) inhibitors: they cause a decrease in glomerular filtration as they cause a decrease in the synthesis of renal prostaglandins. Co-administration of naproxen with diuretics can cause acute renal failure, especially in dehydrated patients. In case naproxen and a diuretic are administered simultaneously, it is necessary to ensure correct hydration of the patient and monitor renal function when starting treatment.

No clinically relevant interactions have been found during short-term treatment of naproxen sodium with the concomitant use of the following medications:

- Antacids

- Antidiabetics

- Hydantoin

- Probenecid

- Zidovudine

Interactions with food

Food slows the absorption of naproxen.

Interactions with diagnostic tests:

Naproxen can alter the values ​​of urine analytical determinations of 17-ketogenic steroids and 5-hydroxy-indoleacetic acid.
4.6. Fertility, pregnancy and lactation

Pregnancy

First and second trimesters of pregnancy

Inhibition of prostaglandin synthesis can negatively affect pregnancy and / or the development of the embryo / fetus. Data from epidemiological studies suggest an increased risk of miscarriage and cardiac malformations and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. The risk appears to increase with the dose and duration of treatment. During the first and second trimesters of pregnancy, Actromadol should not be administered unless strictly necessary. If Actromadol is used by a woman trying to become pregnant, or during the first and second trimesters of pregnancy,the dose and duration of treatment should be reduced as much as possible.

Third trimester of pregnancy

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

Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension).
Renal dysfunction, which can progress to renal failure with oligohydramniosis.
Possible prolongation of the bleeding time, due to an antiplatelet-type effect that can occur even at very low doses.
Inhibition of uterine contractions, which can cause delay or prolongation of labor.

Consequently, Actromadol is contraindicated during the third trimester of pregnancy (see section 4.3).

Lactation

Naproxen is excreted through human milk in small amounts. The use of naproxen while breastfeeding should be avoided.

Fertility

The use of Actromadol can impair female fertility and is not recommended in women trying to conceive. In women with difficulties conceiving or undergoing fertility research, discontinuation of this drug should be considered.
4.7. Effects on ability to drive and use machines

Adverse effects such as tiredness, dizziness, dizziness and insomnia have been observed, so caution should be exercised when driving or using machines.

Patients who suffer these effects, visual disturbances or other similar effects during treatment with this medicine, should be cautious when performing activities that require great attention.

4.8. Adverse reactions

The most frequently observed adverse reactions are gastrointestinal in nature. Peptic ulcers, GI perforation or bleeding may occur, in some cases fatal, especially in the elderly (see section 4.4). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have also been reported (see section 4.4 Special warnings and special precautions for use). The appearance of gastritis has been observed less frequently.

Naproxen-related adverse reactions are listed by system or organ class, and have been classified by frequency as: Very common (? 1/10), Common (? 1/100 to? 1/10), Uncommon (? 1 /1,000 to <1/100), Rare (? 1 / 10,000 to <1 / 1,000), Very rare (<1 / 10,000), not known (cannot be estimated from the available data).

Heart disorders

Very rare: congestive heart failure, hypertension, pulmonary edema, palpitations.

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

Data from clinical trials and epidemiological studies suggest that the use of some NSAIDs, especially in high doses and in long-term treatment, may be associated with a moderately increased risk of atherothrombotic events (for example myocardial infarction or stroke; see section 4.4).

Blood and lymphatic system disorders

Very rare: hematopoietic disorders (leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia, hemolytic anemia, eosinophilia).

During long-term treatment, the blood count should be monitored regularly.

Immune system disorders

Very rare: anaphylaxis / anaphylactoid reactions. The signs of these reactions can be the following: facial, lingual and laryngeal edema; dyspnea, tachycardia, and a drop in blood pressure to the point of causing life-threatening shock.

If these phenomena occur, as can happen when using the drug for the first time, immediate medical assistance is required.

Psychiatric disorders

Very rare: psychiatric disorders, depression, sleep abnormalities, poor concentration.

Nervous system disorders

Common: central nervous system disorders such as headache or dizziness.

Uncommon: feeling light-headed, insomnia, drowsiness.

Very rare: aseptic meningitis, cognitive dysfunction, seizures.

Eye disorders

Very rare: visual disturbance, corneal opacity, papillitis, papilledema, optic neuritis.

Ear and labyrinth disorders

Uncommon: vertigo.

Very rare: hearing impairment, tinnitus and hearing disorders.

Vascular disorders

Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders

Very rare: dyspnea, asthma attacks, eosinophilic pneumonitis.

Gastrointestinal disorders

Common: dyspepsia, nausea, burning, stomach pain.

Uncommon: vomiting, constipation or diarrhea.

Rare: gastrointestinal bleeding, peptic ulcers with or without bleeding or perforation, hematemesis and / or melena.

Very rare: stomatitis, esophagitis, pancreatitis, colitis, thrush, intestinal ulcers.

Hepatobiliary disorders

Rare: liver injury.

Very rare: liver damage, hepatitis (could be fatal) and jaundice.

Skin and subcutaneous tissue disorders

Uncommon: hypersensitivity reactions with rash, pruritus, urticaria.

Rare: angioedema.

Very rare: alopecia (usually reversible), sweating, photosensitivity and photosensitivity reactions (including pseudoporphyria), chilblains, exudative erythema multiforme, fixed drug rash, bullous skin reactions including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (Lyell's syndrome ), lichen planus, erythema nodosum, systemic lupus erythematosus, purpura, porphyria, and epidermolysis bullosa.

Renal and urinary disorders

Rare: kidney damage.

Very rare: interstitial nephritis, papillary necrosis, nephrotic syndrome, acute renal failure; hematuria, proteinuria.

Reproductive system and breast disorders

Very rare: infertility in women.

Congenital, familial, and genetic disorders

Very rare: closure of the ductus arteriosus.

General disorders and administration site conditions

Rare: peripheral edema (especially in patients with hypertension or renal failure), fever, chills.

Very rare: edema, thirst, malaise.

Complementary explorations

Very rare: increased serum creatinine levels, elevated liver values, hyperkalaemia.

Reporting of suspected adverse reactions:

It is important to report suspected adverse drug reactions after authorization. This allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are invited to report suspected adverse reactions through the Spanish Pharmacovigilance System for Medicines for Human Use: https: /www.notificaram.es.
4.9. Overdose

Overdose symptoms are characterized by headache, dizziness, drowsiness, and loss of consciousness, as well as epigastric and abdominal pain, burning, dyspepsia, nausea, vomiting, reversible liver disease, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, or disorientation. Some patients have had seizures, but it is unknown whether or not they were related to naproxen administration. Reversible acute renal failure has been described. It is unknown what dose of the drug would be life threatening.

Within an hour of ingestion of a potentially toxic amount, administration of activated charcoal should be considered. In adults, gastric lavage should also be considered within one hour of ingestion of a life-threatening overdose. Hemodialysis does not decrease the plasma concentration of naproxen due to the high degree of protein binding. There is no specific antidote.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs. Derivatives of propionic acid.

ATC code: M01AE02.

Naproxen belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs), with analgesic, anti-inflammatory and antipyretic action. Naproxen is a derivative of propionic acid chemically related to the group of arylacetic acids.

Its anti-inflammatory effect has been proven even in adrenalectomized animals, which indicates that its action is not mediated through the pituitary-adrenal axis.

Like other non-steroidal anti-inflammatory agents, naproxen inhibits prostaglandin synthetase, although the exact mechanism of anti-inflammatory action is unknown for these types of products.

Clinical studies have been conducted to evaluate the 24-hour analgesic safety and efficacy of the modified-release formulation (1 tablet of 660 mg naproxen sodium per day) versus the immediate-release formulation (1 tablet of 220 mg naproxen sodium every 8 hours) in postoperative dental pain. The analgesic efficacy of the modified release formulation was comparable to that of the immediate release formulation within 24 h in relieving postoperative dental pain. The safety profile of both formulations (1 tablet 660 mg vs 1 tablet 220 mg 3 times a day) was similar.

5.2. Pharmacokinetic properties

Absorption

Naproxen sodium modified release 660 mg tablets are bilayer tablets with an immediate release layer containing 264 mg of naproxen sodium and an extended release layer containing 396 mg of naproxen sodium.

The naproxen in the immediate release layer dissolves immediately in the gastric environment and is completely absorbed from the gastrointestinal tract after oral administration. The naproxen in the sustained release layer dissolves slowly and steadily in the gastrointestinal tract over the next 16-18 hours.

Maximum plasma levels are reached at 45-60 minutes (tmax) in the fasting state and allow its action to be exerted for up to 24 hours. The fasting Cmax is approximately 55 µg / ml.

When taken with food, the Cmax is approximately 44 µg / ml and the tmax is delayed (ie, it is approximately 10-12.5 hours). However, the degree of absorption does not vary.

Distribution

After absorption, more than 99% is bound to serum albumin. The volume of distribution is approximately 0.1 l / kg and has a half-life of approximately 14 hours.

Elimination

After its hepatic metabolism, elimination occurs mainly (95%) via the kidneys.

Pharmacokinetic data show linearity at recommended doses. Patients with severe hepatic impairment may have higher free naproxen values. In severe kidney failure, elimination of naproxen may be impaired, but no significant accumulation has been observed at the recommended dose.

5.3. Preclinical safety data

In some reproduction studies in animals, an increase in dystocia and delays in parturition has been observed, related to the inhibitory action of the prostaglandin synthesis of non-steroidal anti-inflammatory drugs.

6. PHARMACEUTICAL INFORMATION

6.1. List of excipients

Microcrystalline cellulose,

Povidone,

Purified water,

Talcum powder,

Magnesium stearate,

Hypromellose 2208,

Lactose monohydrate,

Anhydrous colloidal silica,

Hypromellose 2910,

Titanium dioxide (E171),

Indigo carmine aluminum lake colorant (E132),

Macrogol 8000,

Carnauba wax.
6.2. Incompatibilities

Not applicable.
6.3. Period of validity

3 years.
6.4. Special precautions for storage

It does not require any special storage conditions.
6.5. Nature and contents of container

Packs of 4 and 8 modified-release tablets.

Aluminum / Polyester envelopes containing 4 tablets each.
6.6. Special precautions for disposal and other handling

Disposal of unused medicine and all materials that have been in contact with it will be done in accordance with local regulations, or it will be returned to the pharmacy.

7. MARKETING AUTHORIZATION HOLDER

Bayer Hispania, SL

Av. Baix Llobregat, 3-5

08970 Sant Joan Despí (Barcelona)

Spain
8. MARKETING AUTHORIZATION NUMBER (S)

83.348
9. DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION

August 2018
10. DATE OF REVISION OF THE TEXT

October 2018