Spedifen

Ibuprofen (as L-arginine salt).

Each film-coated tablet contains Ibuprofen (as L-arginine salt) 400 mg.
Excipients/Inactive Ingredients: l-arginine, sodium hydrogen carbonate, crospovidone, magnesium stearate, hypromellose (Methocel 5cP), sucrose, titanium dioxide, macrogol 4000.

ATC code: M01AE01.
Pharmacology: Pharmacodynamics: Spedifen contains the active ingredient Ibuprofen in the form of arginine salt.
Ibuprofen is a non-steroidal anti-inflammatory drug with analgesic, antirheumatic and antipyretic properties. Its action is based primarily on a synthesis inhibition of prostaglandins, which play a role in inflammatory and painful processes. Ibuprofen arginine has the same pharmacological properties as ibuprofen but is characterized by higher water solubility.
It is effective after approximately 30 minutes.
Pharmacokinetics: Absorption: The active substance peak concentrations of 24 and 40 μg/ml ibuprofen are achieved in serum 28-42 minutes after oral administration of ibuprofen 200 mg and respectively 400 mg (as ibuprofen arginine).
If Spedifen is taken after meals, the absorption will be slower and the maximum plasma concentrations will be lower.
Distribution: Serum half-life is 1.5-2 hours. Protein binding is approx. 99 %.
Metabolism: After hepatic metabolism, ibuprofen is eliminated rapidly, predominantly in the form of pharmacologically inactive metabolites and especially through the kidneys.
Elimination: Ibuprofen does not accumulate even during long-term therapy, with ibuprofen and its metabolites being almost completely eliminated 24 hours after the last dose.
Toxicology: Preclinical Safety Data: Mutagenicity: In vitro and in vivo studies (bacteria, human lymphocytes) for mutagenicity revealed no evidence of any mutagenic effects of ibuprofen. In studies on the tumorigenic potential of ibuprofen in rats and mice, no evidence of carcinogenic effects of ibuprofen was found.
Reproductive toxicity: Experimental studies in two animal species have shown that ibuprofen crosses the placenta; however, there was no indication of any teratogenic effects.

Pain: headache including migraine, toothache, dysmenorrhoea, neuralgia, osteoarticular and muscular pain, episiotomy and post-partum pain, pain following tooth extraction, post-operative pain, soft tissues injuries and traumatisms.
Rheumatic Inflammatory diseases: rheumatoid arthritis, ankylosing spondylitis, Still's Disease.
Degenerative rheumatic disease: osteoarthritis (cervical, dorsal and lumbar arthritis, gonarthritis, coxarthritis, polyarthritis, etc)
Non-articular rheumatic conditions: tendonitis, fibrositis, bursitis, myalgia, lumbago, scapolohumeral periarthritis, sciatica, radiculoneuritis.

Adults: Initial dose: 1 tablet. 2-4/day according to medical advise. The maximum daily dose should not exceed 1600 mg.
The administration of the first daily dose on awakening (before food) patients can be advantageous to provide relief of the morning stiffness associated with arthritis.
The following daily doses should be taken during or after meals. In elderly, the posology must be carefully assessed by the physician since a reduction of the previously mentioned dosage may be needed.
Mode of Administration: Oral.

Signs and symptoms: Common symptoms of overdose include nausea, vomiting, dizziness, drowsiness, tremors.
Less common are headache, tinnitus, ataxia, tachycardia, miosis and reversible increases in transaminases, bilirubin, and thrombocytopenia.
Severe symptoms are rare and include unconsciousness (coma), metabolic acidosis, seizures, and acute renal insufficiency; also, apnea in children < 2 years.
From 400 mg/kg, severe symptoms are possible, although doses up to 60 g can be easily tolerated and doses up to 100 g have not been fatal. In elderly people and small children, those suffering from liver or kidney disease or from chronic alcohol abuse, severe symptoms may be experienced, even at lower doses.
Treatment: From a dose of > 200 mg/kg (small child) or 20 g (adult), decontamination with activated charcoal (1 g per kg body weight as aqueous suspension administered once orally). In case of excessive overdose use gastric lavage followed by activated charcoal within 1 hour of intake.
Medical monitoring from 300 mg/kg and in all patients at increased risk.
Duration of monitoring: 4 hours, with slow-release preparations 12 hours.
Laboratory tests: Transaminases, creatinine, bilirubin; in symptomatic patients additionally blood gas analysis, electrolytes, platelets.

Hypersensitivity to the active ingredient or to any of the excipients according to the composition.
History of bronchospasms, urticaria or allergy-like symptoms after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs.
History of gastrointestinal haemorrhage or perforation after taking other non-steroidal anti-inflammatory drugs.
Third trimester of pregnancy (see Use in Pregnancy & Lactation).
Active gastric and/or duodenal ulcers or gastrointestinal haemorrhage.
Inflammatory bowel disease (such as Crohn's disease, colitis ulcerosa).
Cerebrovascular bleeding.
Hemorrhagic diathesis.
Severe hepatic impairment (cirrhosis and ascites).
Severe kidney insufficiency (creatinine clearance <30 ml/min).
Severe heart failure (NYHA III-IV).
Treatment of postoperative pain following coronary bypass surgery (incl. use of a heart-lung machine)

General warning for the use of systemic non-steroidal anti-inflammatory drugs (NSAIDs).
Gastrointestinal effects: Gastrointestinal ulceration, haemorrhage or perforation may occur at any time during treatment with non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective or not, also without warning symptoms or history. To reduce risk, the lowest effective dose should be administered over the shortest possible duration of treatment.
Patients with a history of gastrointestinal toxicity, especially those of advanced age, should report any unusual abdominal symptoms (especially gastrointestinal haemorrhage).
If gastrointestinal haemorrhage or ulceration occur in patients taking ibuprofen, treatment has to be discontinued.
Caution is recommended when patients are simultaneously receiving medicines that may increase the risk of ulceration or haemorrhage, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors, or platelet aggregation inhibitors such as acetylsalicylic acid (see also under Interactions).
Cardiovascular or cerebrovascular effects: Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications for certain selective COX-2 inhibitors. It is not yet known if this risk correlates directly with the COX-1/COX-2 selectivity of individual NSAIDs. Clinical studies suggest that the use of ibuprofen, especially at high doses (2,400 mg daily), is associated with a slightly increased risk of arterial thrombotic events (e.g. myocardial infarction and stroke). Overall, according to epidemiological studies, there is no suggestion that low dose ibuprofen (e.g. ≤ 1,200 mg/day) is associated with an increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, heart failure (NYHA II), established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be treated with ibuprofen only after careful evaluation, and high doses (2,400 mg/day) should be avoided.
Careful consideration should also be taken, before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2,400 mg/day) are required.
Renal effects: The renal effects of NSAIDs include fluid retention with edema and/or arterial hypertension. Therefore, in patients with impaired cardiac function or other conditions predisposing them to fluid retention, ibuprofen should be used with caution.
Patients with severe dehydration or postoperative volume shifts should be rehydrated prior to treatment with ibuprofen and closely monitored thereafter. There is a risk of renal impairment, especially in dehydrated children and adolescents.
As with other NSAIDs, renal papillary necrosis and other kidney tissue damage may occur during long-term treatment.
Renal toxicity has also been observed in patients where renal prostaglandins have a supporting role in renal perfusion. In these patients, the administration of NSAIDs may result in a dose-dependent reduction in prostaglandin production in the kidneys, reduce kidney perfusion, and induce overt renal decompensation. These reactions are most common in patients with renal, cardiac, hepatic insufficiency, concomitant use of diuretics or ACE inhibitors, and in the elderly.
Respiratory disorders: Ibuprofen may cause bronchospasms, urticaria or angioedema in patients with or with a history of bronchial asthma, chronic rhinitis, or allergic disease.
Aseptic meningitis: In patients with systemic lupus erythematosus or collagenosis, due to increased risk of aseptic meningitis.
Other NSAIDs: The use of ibuprofen in combination with NSAIDs, including selective cyclo-oxygenase-2 inhibitors, should be avoided.
Severe skin reactions: During treatment with NSAIDs, cases of serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported very rarely (see Side Effects). The highest risk for such reactions seems to be at the beginning of treatment, as in the majority of cases they occurred in the first month of treatment. Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. At the first sign of rash, mucosal lesions or any other signs of hypersensitivity reactions, Spedifen should be discontinued.
Masking of symptoms of underlying infections: Ibuprofen may mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella.
In isolated cases, an exacerbation of infective inflammations (e.g. development of necrotizing fasciitis) has been described in a temporal connection with the use of NSAIDs. When Ibuprofen is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.
Visual disturbances: Patients who experience impaired vision during treatment with ibuprofen should discontinue treatment and have an ophthalmic examination.
Liver function test: NSAIDs may produce an increase of liver function test results.
Excipients of particular interest: Spedifen film-coated tablets contain 83 mg of sodium per tablet, equivalent to 4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product, as the pharmaceutical forms film-coated tablets contain sucrose.
Risk of GI Ulceration, Bleeding and Perforation with NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious GI events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking, and corticosteroid therapy) are at increased risk.
Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneous reports for fatal GI events.
Effects on Ability to Drive and Use Machine: Spedifen may have an effect on the ability to drive and use machines due to potential undesirable effects.
Use in the Elderly: In older patients, there is increased incidence of adverse reactions after taking NSAIDs, especially gastrointestinal haemorrhage and perforation, with fatal outcomes.

Pregnancy: Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-fetal development. Data from epidemiological studies indicates an increased risk of miscarriage, as well as cardiac malformations and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. It is believed that the risk is in directly proportional with the dose and duration of therapy.
In animal studies, it has been shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implanted loss and to embryo fetal lethality. Furthermore, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals receiving prostaglandin synthesis inhibitors during the organogenesis phase.
During the first and second trimesters of pregnancy, Spedifen should only be given if absolutely necessary. If Spedifen is used by women trying to get pregnant or if it is used during the first or second trimester of pregnancy, the dose should be kept as low and the duration of treatment as short as possible.
Spedifen is contraindicated during the third trimester of pregnancy. All prostaglandin synthesis inhibitors can: Expose the fetus to the following risks: Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); Kidney dysfunction, which may progress to renal failure with oligohydramniosis.
Expose mother and child to the following risks: Possible prolongation of bleeding time, an anti-aggregating effect, which may occur even at very low doses; Inhibition of uterine contractions, resulting in delayed or prolonged labour.
Lactation: NSAIDs pass into breast milk. As a precaution, Spedifen should therefore not be taken by breast-feeding women. If treatment is essential, the baby should be switched over to bottle feeding.
Fertility: The use of ibuprofen may affect female fertility and is therefore not recommended in women who wish to become pregnant. In women who have difficulty getting pregnant or who are being tested for infertility, discontinuation of ibuprofen should be considered.

Blood and lymphatic system disorders: Rare: Haematological effects such as agranulocytosis, thrombocytopenia, neutropenia, aplastic anaemia, haemolytic anaemia.
Isolated cases: Anaemia.
Immune system disorders: Uncommon: Allergic reaction.
Rare: Lupus erythematosus syndrome, meningitis aseptic in patients suffering from an autoimmune disease, such as Lupus erythematosus, autoimmune haemolytic anaemia, anaphylaxis.
Isolated cases: Anaphylactic shock.
Psychiatric disorders: Uncommon to common: Depression, anxiety, confusional state.
Very rare: Psychotic state.
Nervous system disorders: Common: Headache, dizziness.
Uncommon to common: Central nervous system side effects such as impaired responsiveness (especially in association with alcohol), sleepiness.
Rare: Paraesthesia.
Eye disorders: Uncommon to common: Visual disturbance.
Visual disturbances are usually reversible when treatment is discontinued.
Rare: Toxic amblyopia, optic neuritis.
Isolated cases: Papilloedema.
Ear and labyrinth disorders: Uncommon to common: Ear disorder, hardness of hearing.
Cardiac disorders: Isolated cases: Cardiac failure.
Vascular disorders: Isolated cases: Arterial thrombosis, hypertension, hypotension.
Respiratory, thoracic and mediastinal disorders: Uncommon: Bronchospasm, asthma, aggravated asthma, dyspnoea.
Rare: Risk of acute pulmonary oedema in patients with cardiac insufficiency.
Isolated cases: Throat irritation.
Gastrointestinal disorders: Very common: Dyspepsia, diarrhoea.
Common: Gastrointestinal side effects such as nausea, abdominal fullness, heartburn, abdominal pain, anorexia, constipation, flatulence, vomiting, gastritis erosive, rectal blood loss (resulting in anaemia).
Uncommon: Peptic ulcer, gastrointestinal haemorrhage, melaena, gastritis.
Rare: Ulcerations or perforations in the gastrointestinal tract with haemorrhage, haematemesis, ulcerative stomatitis, colitis aggravated, Crohn's aggravated.
Hepatobiliary disorders: Rare: Liver disorder, liver failure.
Isolated cases: Liver injury, hepatitis, jaundice.
Skin and sub-cutaneous tissue disorders: Common: Hypersensitivity reactions such as urticaria, purpura, pruritus, exanthem.
Uncommon: Angioedema.
Very rare: Bullous reaction, erythema multiforme, dermatitis exfoliative, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reaction.
Isolated cases: Aggravation of skin reactions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP).
Renal and urinary disorders: Rare: Haematuria, renal papillary necrosis, nephritis interstitial, kidney dysfunction with oedema.
Very rare: Acute renal failure.
General disorders and administration site conditions: Isolated cases: Oedema.
Investigations: Rare: Liver function test abnormal.
Isolated cases: Renal function test abnormal.

Other nonsteroidal anti-inflammatory drugs including COX-2 inhibitors and/or glucocorticoids and alcohol: Augmentation of gastrointestinal side effects, increased risk of gastrointestinal haemorrhage. Salicylic acid displaces ibuprofen from protein binding. Caution is recommended with concomitant use, as this may increase the risk of adverse gastrointestinal effects.
Acetylsalicylic acid (low dosage): Experimental data suggest that ibuprofen may inhibit the efficacy of low dose acetylsalicylic acid on platelet aggregation when used concomitantly. However, the data are limited and the extrapolation of ex vivo data to the clinical situation is uncertain.
Therefore, no clear conclusions can be drawn regarding the regular use of ibuprofen; a clinically relevant effect with the occasional intake of ibuprofen is unlikely (see Properties/Effects).
Probenecid, Sulfinpyrazone: The elimination of ibuprofen is delayed; the uricosuric effect of probenecid and sulfinpyrazone is attenuated.
Oral anticoagulants: Non-steroidal anti-inflammatory drugs may increase the effects of anticoagulants such as warfarin.
Platelet aggregation inhibitors and selective serotonin reuptake inhibitors: Increased risk of gastrointestinal haemorrhage.
Anti-diabetic medicinal products: Ibuprofen enhances the hypoglycemic effect of oral antidiabetic medication and insulin. It may be necessary to adjust the dosage.
Aminoglycosides: NSAID's may decrease the excretion of aminoglycosides.
Diuretics: The efficacy of furosemide and thiazide diuretics can be decreased, probably due to sodium retention, related to an inhibition of prostaglandin synthesis in the kidneys.
Anti-hypertensive agents: A weakening of the efficacy of anti-hypertensive drugs is to be expected. As a result, concomitant treatment with NSAIDs and ACE inhibitors or beta-blocker agents may increase the risk of acute renal insufficiency.
Histamine H2-receptor antagonists: A clinically meaningful interaction of ibuprofen with cimetidine or ranitidine has not been established.
Digoxin: The plasma concentration of digoxin may increase.
Phenytoin: The plasma concentration of phenytoin may increase.
Lithium: The plasma concentration of lithium may increase.
Methotrexate: Increased methotrexate toxicity.
Zidovudine: The concomitant use of zidovudine and ibuprofen increases the risk of haemarthrosis and haematoma in HIV (+) haemophilic patients.
Tacrolimus: The risk of nephrotoxicity may be increased with concomitant use of tacrolimus and ibuprofen.
Voriconazole and Fluconazole: Concomitant use of voriconazole, fluconazole and ibuprofen may lead to an increase in the exposure and plasma concentration of ibuprofen.
Mifepristone: Co-administration of NSAIDs may increase NSAID exposure. A decrease in the efficacy of mifepristone can occur theoretically due to the anti-prostaglandin properties of NSAIDs. Studies suggest that co-administration of ibuprofen on the same day prostaglandins are administered (or as needed), has no adverse influence on the action of mifepristone or on the clinical efficacy of the pregnancy termination.
Baclofen: Increased baclofen toxicity.
Chinolone: Co-administration of NSAIDs may increase the risk of seizures.
Ciclosporin: The toxic effect on kidneys may increase.
Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding associated with NSAIDs.
Interactions with diagnostic tests: Bleeding time (bleeding time may be prolonged until 1 day after discontinuation of therapy);
Serum glucose concentration (may decrease);
Creatinine clearance (may decrease);
Hematocrit or hemoglobin (may decrease);
BUN, serum creatinine concentrations and kaliemia (may increase);
Liver function test (increase in transaminases).

Store at temperature not exceeding 30°C.
Shelf Life: 3 years.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AE01 - ibuprofen ; Belongs to the class of propionic acid derivatives of non-steroidal antiinflammatory and antirheumatic products.

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