Spedifen is indicated for the treatment of the following pain or inflammatory conditions:

·         pain of various origin, especially of acute nature, such as cervical pain, headache, dental pain, muscle and joint pain, spinal column pain, post-traumatic and post-operative inflammations and pains;

·         pain of gynaecological nature, such as dysmenorrhoea

·         gradually recurrent pain in rheumatic conditions of inflammatory and degenerative nature and morning joint stiffness;

·         non-articular rheumatic conditions;

·         fever and pain in infectious diseases (e.g. flu )

Adults and children as from 12 years of age:

The single dose usually amounts to 400-600 mg (maximum 800 mg). The mean daily dose ranges between 1200 and 1800 mg.

In individual cases, when appropriate, the daily dosage may be increased up to a maximum dose of 2400 mg.

 

The daily dose should be divided into 3-4 administration (values expressed in mg are referred to free acid ibuprofen).

Spedifen is not suitable for use in children under 12 years of age. Film-coated tablets should be swallowed with some liquid.

Dissolve the content of one sachet into a glass of water (no sparkling mineral water) and drink immediately.

• Hypersensitivity to the active substance or to any of the excipients. • History of bronchospasm, urticaria or allergic-type symptoms after use of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs. • Third trimester of pregnancy (see “Pregnancy and lactation”). • Active gastric and/or duodenal ulcer or gastrointestinal bleeding. • Inflammatory gastrointestinal diseases (such as Crohn’s disease, ulcerative colitis). • Severe hepatic failure (liver cirrhosis and ascites). • Severe renal failure (creatinine clearance < 30 ml/min). • Severe heart failure (NYHA III-IV). • Treatment of post-operative pain following coronary artery bypass graft surgery (use of a heart-lung machine).

General warnings for the use of systemic non-steroidal anti-inflammatory drugs (NSAIDs): Gastrointestinal ulceration, bleeding or perforation has been reported with non-steroidal anti- inflammatory drugs (NSAIDs), including COX-2 selective inhibitors, at any time during treatment, with or without warning symptoms or a previous history of such events. This risk may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

In placebo-controlled studies, an increased risk of thrombotic cardio- and cerebrovascular complications has been observed with COX-2 selective inhibitors. It is still unknown whether this risk is directly related to COX-1/COX-2 selectivity of each specific NSAID. Since no clinical data relating to the use of maximum doses in long-term treatments is available for ibuprofen to date, this increased risk cannot be excluded. Lacking such clinical information, ibuprofen should be used only after careful assessment of the risk/benefit ratio in the presence of ascertained coronary disease, cerebrovascular disease, and peripheral arterial disease or in patients presenting with significant risk

 

factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). Also in these cases the lowest effective dose for the shortest possible time should be used.

The renal effects of NSAIDs include water retention with oedema and/or arterial hypertension. Therefore caution is required when using ibuprofen in patients with heart failure or other conditions known to possibly cause water retention. A similar careful consideration is required in patients taking concomitantly diuretics or ACE-inhibitors or at increased risk for hypovolaemia.

Elderly patients are exposed to an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.

Other non-steroidal anti-inflammatory drugs and/or glucocorticoids as well as alcohol: Strengthening of gastrointestinal adverse effects, increased risk of gastrointestinal bleeding. Acetylsalicylic acid displaces ibuprofen from protein binding sites.

Probenecid, Sulfinpyrazone: Decreased elimination of ibuprofen; the uricosuric action of probenecid and sulfinpyrazone is weakened.

Oral anticoagulants: The expected increased risk of bleeding reported with other NSAIDs has not been ascertained in several studies for ibuprofen.

Anti-platelet agents and selective serotonin reuptake inhibitors: Increased risk of gastrointestinal bleeding.

Oral antidiabetic agents: No enhancement of the hypoglycemic action has been observed. Aminoglycosides: Non-steroidal anti-inflammatory drugs may reduce aminoglycoside excretion. Diuretics, antihypertensives: Reduced diuretic and antihypertensive effects are to be expected. Histamine -receptor antagonists: No clinically important interactions have been reported with concomitant use of ibuprofen and cimetidine or ranitidine.

Digoxin: Digoxin plasma concentrations may be increased.

Phenytoin: Phenytoin plasma concentrations may be increased.

Lithium: Plasma concentrations of lithium should be carefully monitored.

Methotrexate: Increased methotrexate toxicity.

Baclofen: Increased baclofen toxicity.

Quinolones: The central action of these antibiotics may be increased.

Cyclosporine: Increased risk of nephrotoxicity.

Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding when used concurrently with NSAIDs.

Prostaglandin synthesis inhibition may impair pregnancy evolution           and/or embryo-foetal development.

Results of epidemiologic studies suggest an increased risk of abortion as well as cardiac malformation and gastroschisis after administration of a prostaglandin synthesis inhibitor during the first stages of pregnancy.

It is supposed that the risk is dose- and therapy duration-dependent.

In animals, the administration of prostaglandin synthesis inhibitors was shown to induce pre- and post-implantation loss and embryo/foetal death.

In addition, an increase in the incidence of various malformations, including cardiovascular ones, has been observed in animals which were administered prostaglandin synthesis inhibitors during the organogenesis period.

Spedifen should be administered during the first and second trimester of pregnancy only in case of strict necessity.

Should Spedifen be used in a woman attempting to conceive or during the first and second trimester of pregnancy, the dose should be maintained as low and treatment duration as short as possible.

Spedifen is contraindicated during the third trimester of pregnancy. All prostaglandin synthesis inhibitors may expose:

-  the foetus to:

·         cardiopulmonary toxicity (with premature closing of ductus arteriosus and pulmonary hypertension);

·         renal impairment, which may evolve to renal failure with oligohydramnios;

-  the mother and the newborn to:

·         possible prolongation of bleeding time and antiplatelet effect that may occur at very low doses;

·         inhibition of uterine contractions resulting in labour delay or prolongation.

 

Fertility

Ibuprofen use may impair female fertility and therefore is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigations on infertility, withdrawal of ibuprofen should be considered.

 

Lactation

NSAIDs passes into the breast milk. As precautionary measure, Spedifen should not be used in breast-feeding women. Should the treatment be deemed as strictly necessary, bottle-feeding is to be considered.

By considering the possible undesirable effects, Spedifen may have some influence on the ability to drive and use machines.

Frequency convention: Very common (>10%), Common (>1%, <10%), Uncommon (>0.1%, <1%),

Rare (>0.01%, <0.1%), Very rare (<0.01%).

 

Blood and lymphatic system disorders

Rare: Hematological effects such as agranulocytosis, thrombocytopenia, neutropenia, aplastic anemia, hemolytic anemia

Immune system disorders

Rare: Lupus erythematosus syndrome, aseptic meningitis in patients with autoimmune disorders, such as lupus erythematosus, autoimmune hemolytic anemia.

Psychiatric disorders

Uncommon to common: Depression, anxiety, confusional state.

Very rare: Psychotic conditions.

Nervous system disorders

Uncommon to common: Central nervous system effects such as impairment of reaction capacity (especially with concomitant use of alcohol), headache, dizziness, drowsiness.

Rare: Paresthesia.

Eye disorders

Uncommon to common: Visual disturbances. Such visual disturbances are usually reversible upon discontinuation of treatment.

Rare: Toxic amblyopia, optic neuritis.

Ear and labyrinth disorders

Uncommon to common: Tinnitus, hypoacusis.

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm, risk of acute pulmonary oedema in patients with heart failure.

Gastrointestinal disorders

 

Common: Gastrointestinal effects such as malaise, bloating, heartburn, epigastric pain, anorexia, diarrhoea or constipation, nausea, vomiting, erosive gastritis, occult blood loss (up to anemia).

Rare: Ulcerations in the gastrointestinal tract with bleeding.

Hepatobiliary disorders

Rare: abnormal liver function, hepatic impairment.

Skin and subcutaneous tissue disorders

Common: Hypersensitivity reactions such as urticaria, purpura, itching, exanthem.

Very rare: Stevens-Johnson syndrome, photosensitivity.

Renal and urinary disorders

Rare: Papillary necrosis, interstitial nephritis, renal impairment with oedema.

Individual cases of reversible aseptic meningitis have been reported in patients with lupus erythematosus or collagenosis.

Frequent mild symptoms of overdose are nausea, vomiting, dizziness, drowsiness, tremor; seldom headache, tinnitus, ataxia, tachycardia, myosis and reversible increase in transaminase and bilirubin levels as well as thrombocytopenia are observed.

Severe symptoms are rarely reported and include loss of consciousness (coma), metabolic acidosis, convulsions and acute renal failure; in children under 2 years of age also apnoea may occur.

Severe symptoms may appear starting from doses of 400 mg/kg, whereas doses up to 60 g are tolerated without any problems and with doses up to 100 g survival was reported. In elderly subjects, infants as well as in the presence of liver or renal diseases and chronic alcohol abuse, lower doses may induce severe symptoms.

With doses > 200 mg/kg (infants) or 20 g (adults), activated charcoal (1 g/kg of body weight as water suspension once daily by oral route) should be used. In case of massive overdose, gastric lavage followed by activated charcoal within 1 hour of ingestion of a potentially life-threatening amount should be considered.

Medical surveillance is required with doses from 300 mg/kg and in all patients at high risk. Duration of surveillance: 4 hours; in case of delayed-action preparations 12 hours. Control of laboratory parameters: transaminases, creatinine, bilirubin; in case of symptomatic patients: haemogas-analysis, serum electrolytes, red blood cell count .

ATC code: M01AE01

Spedifen contains the active substance ibuprofen in the form of arginine salt.

Ibuprofen is a non-steroidal anti-inflammatory drug endowed with analgesic, anti-inflammatory and anti-pyretic properties. Its action is mainly based on prostaglandin synthesis inhibition, which plays a major role in inflammation and pain processes.

Ibuprofen arginine shows the same pharmacological properties of ibuprofen, but differs in its higher water solubility.

The onset of action is detectable after about 30 minutes.

Absorption

Granules: Mean peak serum concentrations equal to 25 and 57 mg/ml respectively, are reached 17-

24 minutes after oral administration of 200 and 400 mg ibuprofen (as ibuprofen arginine), respectively.

Film-coated tablets: Mean peak serum concentrations equal to 24 and 40 mg/ml respectively, are reached 28-42 minutes after oral administration of 200 and 400 mg ibuprofen (as ibuprofen arginine), respectively.

When Spedifen is taken after meals, the absorption is slower and peak plasma concentrations are reduced.

Distribution

The serum half-life is 1.5-2 hours. Ibuprofen is about 99% protein bound.

 

Metabolism

Ibuprofen is metabolized in the liver mainly to pharmacologically inactive matabolites, and is then rapidly excreted primarily via the kidneys.

 

Elimination

No accumulation of ibuprofen occurs even in the course of a long-term therapy, as ibuprofen and its metabolites excretion is practically complete within 24 hours of last dosing.

Mutagenic and carcinogenic potential

In-vitro and in-vivo mutagenicity studies (bacteria, human lymphocytes) evidenced no mutagenic action of ibuprofen. In studies investigating the carcinogenic potential of ibuprofen in rats and mice, no evidence of carcinogenic effects was reported.

 

Toxicity to reproduction

Experimental studies performed in two animal species have shown that ibuprofen crosses the placental barrier; anyway no evidence of teratogenic action was provided.

Film-coated tablets: Excipients for tablet coating

Granules: Sodium saccharin, Sucrose, Aspartame, Flavours: Vanillin and others, Excipients per sachet of granules

Warning for diabetic patients: It should be taken into account that each sachet of Spedifen 400 mg and 600 mg contains 1.8 g and 1.3 g of sucrose respectively, corresponding to 30 kJ and 22 kJ or

0.18 and 0.13 carb units, respectively.

N/A

Do not use Spedifen after the expiry date which is stated on the carton after the abbreviation “EXP”.

Store at room temperature (15-25°C) and keep out of the reach of children.

400 mg granule sachets: 12 and 30 sachets* (B)

600 mg granule sachets: 12 and 30 sachets* (B)

400 mg film-coated tablets: 12 and 30 tablets* (B)

N/A