ACTION AND MECHANISM

- Analgesic, anti-inflammatory, antipyretic. Ibuprofen is a propionic acid derivative with anti-inflammatory, analgesic, and antipyretic activity. Its mechanisms of action may be due to the inhibition of peripheral prostaglandin synthesis through its competitive and reversible binding to the cyclooxygenase enzyme, which transforms arachidonic acid into prostaglandins.

SPECIAL WARNINGS

- Gastrointestinal risk: NSAIDs are associated with an increased risk of gastrointestinal irritation, ulceration, bleeding, or perforation. Lesions can occur at any time during treatment. The elderly are at higher risk of serious gastrointestinal events. During prolonged treatment, patients should be monitored for signs and symptoms of ulceration or bleeding. A history of esophagitis, gastritis, and/or peptic ulcer should also be reviewed to ensure complete healing before initiating treatment with an NSAID.

- Cardiovascular risk: NSAIDs are associated with an increased risk of cardiovascular events, including myocardial infarction and new or worsening cases of hypertension. This risk may increase with the duration of treatment, particularly in patients with cardiovascular disease or risk factors for cardiovascular disease. Monitor for signs of fluid retention (e.g., edema formation), especially in patients with hypertension or heart failure.

- Risk of severe skin reactions: Severe cases, some fatal, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported rarely in association with NSAID use. Patients may be at increased risk of these reactions at the start of treatment; in most cases, this adverse reaction occurs during the first month of treatment. Acute generalized exanthematous pustulosis (AGEP) has been reported in association with ibuprofen-containing products. Ibuprofen administration should be discontinued at the first signs or symptoms of severe skin reactions, such as rash, mucosal lesions, or any other signs of hypersensitivity.

PATIENT ADVICE

- The patient should inform their doctor if they experience skin rashes, symptoms that could be related to a gastroduodenal ulcer (such as epigastric pain or dark stools), visual disturbances, weight gain, edema, or prolonged headache.

- The patient should notify the doctor if they have had any asthmatic reaction while taking this medication.

CONTRAINDICATIONS

- Hypersensitivity to ibuprofen or any component of the medication. Cases of cross-hypersensitivity reactions with other NSAIDs have been reported; therefore, it should also not be used in cases of salicylate allergy or NSAID allergy. These allergic reactions are especially common in patients with asthma, nasal polyps, or who have experienced rhinitis, angioedema, or urticaria when receiving another NSAID or salicylates.

- Active or recurrent peptic ulcer, active inflammatory bowel disease, or any other condition that increases the risk of gastrointestinal bleeding. Ibuprofen has ulcerogenic effects due to the inhibition of prostaglandin synthesis, which could increase the risk of gastrointestinal bleeding and perforation.

- [COAGULATION DISORDERS]. Ibuprofen has antiplatelet effects, although less potent and longer-lasting than those of acetylsalicylic acid. Therefore, it can increase bleeding time, so it should be used with caution in patients with [HEMORRHAGIC DIATHESIS] or active [HEMORRHAGE], as well as in patients with [THROMBOCYTOPENIA].

- Perioperative pain in the context of coronary bypass surgery.

- Severe renal impairment (CLcr < 30 ml/min). Safety and efficacy have not been evaluated, therefore its use is not advised.

- Severe hepatic impairment (Child-Pugh class C). Safety and efficacy have not been evaluated, therefore use is not advised.

- Severe heart failure (NYHA class III-IV) or uncontrolled high blood pressure. Fluid retention could worsen these conditions.

- Pregnancy. Its use is contraindicated during the third trimester of pregnancy, and its use is not recommended for prolonged periods of time during the first two trimesters.

ADVANCED AGE

No specific problems have been described in elderly patients that would require dosage adjustment. Elderly patients experience a higher incidence of gastrointestinal adverse reactions to NSAIDs, particularly bleeding and perforation. Therefore, it should be used with caution.

EFFECTS ON DRIVING

Patients who experience dizziness, vertigo, visual disturbances, or other central nervous system disorders while taking ibuprofen should refrain from driving or operating machinery. Short-term treatments generally do not require special precautions.

PREGNANCY

Animal safety: no teratogenic effects have been recorded, but significant fetal damage has been observed in some cases, as well as impaired labor.

Safety in humans: * First and second trimester of pregnancy.

From the 20th week of pregnancy onward, ibuprofen can cause oligohydramnios as a consequence of fetal renal dysfunction. This can occur shortly after starting treatment and is generally reversible upon discontinuation. In addition, cases of constriction of the ductus arteriosus have been reported following treatment in the second trimester, most of which resolved after cessation of treatment. Therefore, during the first and second trimesters of pregnancy, ibuprofen should not be administered unless considered strictly necessary. If ibuprofen is used by a woman trying to conceive, or during the first and second trimesters of pregnancy, the dose and duration of treatment should be reduced as much as possible. Prenatal monitoring for oligohydramnios and constriction of the ductus arteriosus should be considered following ibuprofen exposure for several days from the 20th week of gestation onward. Ibuprofen should be discontinued if oligohydramnios or constriction of the ductus arteriosus is found.

2) Third trimester of pregnancy

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

- Cardiopulmonary toxicity (constriction/premature closure of the ductus arteriosus and pulmonary hypertension)

- Renal dysfunction, which may progress to renal failure with oligohydramnios.

- Possible prolongation of bleeding time, due to an antiplatelet effect that can occur even at very low doses.

- Inhibition of uterine contractions, which may cause delay or prolongation of labor (with a greater tendency towards bleeding in the mother and child).

Effects on fertility: Ibuprofen may impair female fertility and is not recommended for women trying to conceive. In women who are having difficulty conceiving or who are undergoing fertility investigations, discontinuation of this medication should be considered.

PHARMACOKINETICS

Ibuprofen acid is a racemic compound, of which the S(+)-enantiomer possesses almost all the pharmacological activity. In vivo, nearly 70% of the R(-)-enantiomer of ibuprofen acid is converted to the pharmacologically active S(+)-enantiomer.

Linear pharmacokinetics in the 200-800 mg dosage range

- Absorption:

INDICATIONS

- Treatment of mild to moderate [PAIN].

INTERACTIONS

"IBUPROFEN-RELATED INTERACTIONS"

- NSAIDs, including low-dose aspirin: the simultaneous use of more than one NSAID should be avoided due to the risk of adverse effects without any increase in therapeutic efficacy. Furthermore, ibuprofen may reduce the antiplatelet efficacy of aspirin when administered together. If both drugs are required, it is advisable to separate the doses (administer ibuprofen 8 hours before or 30 minutes after aspirin).

- Alcohol: toxicity may be increased.

- Aliskiren: possible reduction of the antihypertensive effect of aliskiren (NSAIDs act on the renin-angiotensin system). In patients with impaired renal function (dehydrated or elderly), deterioration of renal function may be precipitated (possible acute renal failure, usually reversible). Caution, especially in the elderly, monitoring the antihypertensive effect and renal function.

- Food: food delays Tmax (from ± 2 h in fasting to ± 3 h after eating), although this has no effect on the amount absorbed.

- Quinolone antibacterials: there are isolated reports of seizures that may have been due to the concomitant use of quinolones and some non-steroidal anti-inflammatory drugs.

- Oral anticoagulants, heparin: possible increase in the anticoagulant effect, with a risk of bleeding. Periodic monitoring of coagulation indices is advised.

- Sulfonylurea antidiabetic drugs (chlorpropamide, glibenclamide, tolbutamide): possible increase in hypoglycemic effects, by reducing renal excretion.

- SSRI antidepressants (fluoxetine, paroxetine, sertraline, citalopram): possible increased risk of bleeding in general, and gastrointestinal bleeding in particular, especially in the elderly and patients with a history of digestive bleeding.

- Antihypertensives (ACE inhibitors, Beta-blockers): possible reduction of the antihypertensive effect.

- Oral bisphosphonates (alendronic acid): possible increased risk of esophagitis and gastric ulcer. Cases have been described with naproxen and alendronate.

- Cyclosporine: the effect of NSAIDs on renal prostaglandins may increase the nephrotoxicity of cyclosporine.

- Antiplatelet agents, including pentoxifylline: there is an increased risk of bleeding in general, and gastrointestinal bleeding in particular. Administer with caution.

- Corticosteroids: possible increase in the incidence of gastric discomfort. However, simultaneous use with glucocorticoids in the treatment of osteoarthritis may provide an additional therapeutic benefit and allows for a reduction in the glucocorticoid dosage.

- Digitalis (digoxin): possible increase in plasma concentrations of the digitalis (in neonates). There is also a risk of worsening heart failure and reduced renal function.

- Diuretics (thiazides, high-ceiling diuretics): risk of reduced natriuretic and diuretic effect. May reduce the antihypertensive action of thiazide diuretics.

- Potassium-sparing diuretics and aldosterone antagonists: possible increased risk of hyperkalemia. Frequent monitoring of serum potassium levels is advised.

- Glitazones (pioglitazone, rosiglitazone): theoretical risk of potentiating edema, which both glitazones and NSAIDs can cause. Caution is advised, and patients should monitor for possible signs of fluid retention and heart failure (swollen ankles, dyspnea).

- Hydralazine: possible decrease in the hypotensive effect.

- Iloprost: possible increased risk of bleeding.

- Lithium, salts: possible increase in lithium toxicity due to a reduction in its elimination.

- Methotrexate (administered at doses of 15 mg/week or higher): possible increase in plasma methotrexate levels, with a risk of toxicity, sometimes very severe. The severity depends largely on the dose of methotrexate used. The risk of interaction is reduced with low doses of methotrexate, such as those used in psoriasis and rheumatoid arthritis.

- Mifepristone: Non-steroidal anti-inflammatory drugs should not be administered within 8-12 days after the administration of mifepristone as they may reduce its effects.

- Paracetamol: simultaneous and prolonged use of paracetamol and NSAIDs may cause an increased risk of adverse kidney effects.

- Pentoxifylline: In patients receiving ibuprofen treatment in combination with pentoxifylline, the risk of bleeding may increase, so monitoring of bleeding time is recommended.

- Potassium supplements: possible increase in potassium levels, with risk of hyperkalemia.

- Ticlopidine: possible increased risk of bleeding.

- Zidovudine: Possible alteration of reticulocytes, with severe anemia appearing one week after the start of NSAID administration. Blood values ​​should be monitored, especially at the start of treatment.

LACTATION

Animal safety: no data available.

Safety in humans: Ibuprofen and its metabolites are excreted in low concentrations in breast milk. It does not produce serious adverse reactions in children; therefore, it can be used during breastfeeding to treat pain and fever.

CHILDREN

The safety and efficacy of ibuprofen in children under 3 months of age have not been established, therefore its use is not recommended. Ibuprofen should not be self-medicated in children under 12 years of age.

GUIDELINES FOR PROPER ADMINISTRATION

Administration with food : administer along with food.

POSOLOGY

- Adults: 400 mg/6-8 h. Maximum dose 1,200 mg/24 h.

- Children and adolescents < 18 years:

* Adolescents from 12 years (> 40 kg): 400 mg/6-8 h. Maximum dose 1,200 mg/24 h.

* Children < 12 years (< 40 kg): use presentations adapted to this age.

- Elderly: may require a dose reduction.

Administration with food : administer along with food.

Duration of treatment : consult with the doctor and/or pharmacist if symptoms worsen or persist for more than 5 days (pain) or 3 days (fever).

Missed dose : Take the next dose at the usual time. Do not double the next dose.

DOSAGE IN HEPATIC INSUFFICIENCY

- Mild to moderate hepatic impairment (Child-Pugh classes A and B): use with caution at the lowest possible dose.

- Severe hepatic impairment (Child-Pugh class C): contraindicated.

DOSAGE IN RENAL INSUFFICIENCY

- Mild to moderate renal impairment (CLcr 30-90 ml/min): use with caution at the lowest possible dose.

- Severe renal insufficiency (CLcr < 30 ml/min): contraindicated.

PRECAUTIONS

[RENAL INSUFFICIENCY]. Ibuprofen is eliminated in the urine, so in cases of renal insufficiency, accumulation could occur, with a risk of toxicity. Furthermore, it could lead to a decrease in renal blood flow with reversible acute renal failure due to the inhibition of the synthesis of vasodilatory prostaglandins. Cases of nephrotic syndrome and acute interstitial nephritis have even been reported with prolonged treatment. In patients with mild to moderate renal insufficiency (creatinine clearance between 30-90 ml/min), it is recommended to start treatment with a lower dose than that used in patients with normal renal function, while carefully monitoring the patient. Use in severe renal insufficiency (creatinine clearance < 30 ml/min) is contraindicated (See Contraindications).

- [HEPATIC INSUFFICIENCY]. Due to its hepatic metabolism, accumulation and toxicity may occur in cases of hepatic insufficiency. In patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B), it is recommended to initiate treatment with a lower dose than that used in patients with normal hepatic function, while carefully monitoring the patient. Use in severe hepatic insufficiency (Child-Pugh class C) is contraindicated (See Contraindications).

- History of peptic ulcer. The use of an NSAID, including ibuprofen, has resulted in cases of gastroduodenal ulcers, as well as bleeding and perforation, which can be fatal. The risk of ulcer is increased with high doses or prolonged use, in patients with a history of peptic ulcer, especially if they have already experienced gastrointestinal bleeding or perforation, and in the elderly.

As a general rule, it is advisable to take any NSAID with food to reduce gastric damage. Furthermore, in at-risk groups, it is recommended to start treatment with the lowest possible dose and, whenever possible, to combine it with an anti-ulcer drug (H2 antagonists or proton pump inhibitors).

These patients, as well as those being treated with drugs that may promote bleeding, such as oral anticoagulants or antiplatelet agents, should be closely monitored.

If symptoms of an active ulcer or gastrointestinal bleeding appear, treatment should be discontinued. Likewise, ibuprofen treatment should not be initiated in individuals with an active peptic ulcer (see Contraindications).

- [INFLAMMATORY BOWEL DISEASE]. NSAIDs may precipitate symptomatic flare-ups of diseases such as Crohn's disease or ulcerative colitis, so caution is advised when using them, and their use should be avoided in cases of active disease (See Contraindications).

- Cardiovascular effects. NSAIDs may cause fluid retention (especially with prolonged use), due to the inhibition of the synthesis of vasodilatory prostaglandins, which could lead to the onset or worsening of [HIGH BLOOD PRESSURE], particularly in cases where there is no prior treatment, or where it has not been able to control the disease.

Furthermore, the administration of high doses of ibuprofen (≥ 2,400 mg/24 h) has been associated with an increased risk of arterial thrombosis, similar to that of specific COX-2 inhibitors at therapeutic doses. Therefore, it is recommended to avoid the use of these doses in patients with moderate to severe heart failure (NYHA classes II-IV), ischemic heart disease, peripheral artery disease, stroke, or cerebral ischemia.

Before starting long-term treatment with ibuprofen, and especially if high doses are needed, it would be advisable to evaluate other cardiovascular risk factors such as [DYSLIPIDEMIA], [DIABETES] or [SMOKING].

Using reduced doses of ibuprofen (1,200 mg/24 h) for a limited period does not appear to present the same cardiovascular risks. Therefore, as with other NSAIDs, the general recommendation would be to use it at the lowest dose that controls symptoms and for the shortest possible time.

Cases of Kounis syndrome have been reported in patients treated with ibuprofen, which has been defined as cardiovascular symptoms secondary to an allergic or hypersensitivity reaction associated with constriction of the coronary arteries and which may lead to a myocardial infarction.

- Skin reactions. The use of NSAIDs has caused very rare but potentially fatal serious adverse reactions, such as exfoliative dermatitis, toxic epidermal necrolysis, or Stevens-Johnson syndrome. These adverse reactions usually begin early, within the first month of treatment. If symptoms of hypersensitivity, mucosal lesions, or skin erythema are observed, treatment should be discontinued.

- Chronic asthma. Hypersensitivity reactions with bronchospasm are especially common in these patients, so extreme caution is advised. If respiratory function worsens, treatment should be discontinued.

- [ASEPTIC MENINGITIS]. Rare cases of aseptic meningitis have been reported in patients treated with NSAIDs, probably due to a hypersensitivity reaction, although no cross-allergy between NSAIDs has been found. It has been more frequent in patients with [SYSTEMIC LUPUS ERYTHEMATOSUS] and other [COLLAGENOSES], although it has also been reported in some patients without these conditions. In patients treated with NSAIDs who develop symptoms of meningitis, the possibility of aseptic meningitis should be considered.

- Ibuprofen lysine is contraindicated in case of infection or suspected infection in preterm children.

PRECAUTIONS RELATING TO EXCIPIENTS

This medicine contains cochineal red as an excipient. It may cause allergic-type reactions, including asthma, especially in patients with salicylate allergy.

ADVERSE REACTIONS

Adverse reactions are more frequent with doses of 3200 mg/day.

- Gastrointestinal: (>10%): [DYSPEPSIA], [DIARRHEA]. (1-10%): [NAUSEA], [VOMITING], [ABDOMINAL PAIN]. (0.1-1%): [GASTROINTESTINAL HEMORRHAGE], [GASTRIC ULCER], [DUODENAL ULCER], [ORAL APHTHULAE]. (<0.1%): [INTESTINAL PERFORATION], [FLATULENCE], [CONSTIPATION], [ESOPHAGITIS], [ESOPHAGEAL OBSTRUCTION], exacerbation of diverticular disease, nonspecific hemorrhagic colitis, [ULCERATIVE COLITIS] or [CROHN'S DISEASE], [MELENA]. If gastrointestinal bleeding occurs, it could cause anemia and [HEMATEMESIS].

- Dermatological/Hypersensitivity: (1-10%): [SKIN RASHES]. (0.1-1%): [URTICARIA], [PRURITUS], [PURPURA] (including allergic purpura), [ANGIOEDEMA], [RHINITIS], [BRONCHOSPASM]. (<0.1%): [ANAPHYLAXIS]. (<0.01%): [ERYTHEMA MULTIFORME], [TOXIC EPIDERMAL NECROLYSIS], systemic lupus erythematosus, [ALOPECIA], [PHOTOSENSITIVITY REACTIONS], severe skin reactions such as [STEVENS-JOHNSON SYNDROME], [TOXIC EPIDERMAL NECROLYSIS] (Lyell's syndrome) and allergic [VASCULITIS]; unknown frequency [DRESS SYNDROME] (which may include skin rash, lymph node swelling and [EOSINOPHILIA]) and acute generalized exanthematous pustulosis (AGEP).

In most cases where aseptic meningitis has been reported with ibuprofen, the patient suffered from some form of autoimmune disease (such as systemic lupus erythematosus or other collagen vascular diseases), which constituted a risk factor. It manifests as severe headache, nausea, vomiting, fever, neck stiffness, and some confusion, possibly due to a hypersensitivity reaction. Increased intrathecal IgG synthesis has been observed, with the presence of immune complexes in the cerebrospinal fluid.

Anaphylactic or anaphylactoid reactions typically occur in patients with a history of hypersensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). This can also happen in patients who have not previously shown hypersensitivity to these drugs.

In case of severe generalized hypersensitivity reaction, swelling of the face, tongue and larynx, bronchospasm, asthma, tachycardia, hypotension and shock may occur.

- Central nervous system: (1-10%): [ASTHENIA], [DROWSY], [HEADACHE], [DIZZINESS], [VERTIGO]. (0.1-1%): [INSOMNIA], [ANXIETY]. (<0.1%): reaction of [PSYCHOSIS], [NERVOUSNESS], [IRRITABILITY], [DEPRESSION], [CONFUSION] or disorientation.

- Hematological: Bleeding time may be prolonged. The rare cases of hematological disorders observed correspond to [THROMBOCYTOPENIA], [LEUKOPENIA], [GRANULOCYTOPENIA], [PANCYTOPENIA], [AGRANULOCYTOSIS], [APLASTIC ANEMIA], [HEMOLYTIC ANEMIA].

- Cardiovascular: Patients with hypertension or renal disorders appear to be more predisposed to edema. Hypertension or heart failure may occur (especially in elderly patients). Frequency of Kounis syndrome is unknown.

- Renal: [INCREASED BLOOD UREA NITROGEN] and [INCREASED SERUM CREATININE]. In exceptional cases, NSAIDs can cause [ACUTE RENAL FAILURE], [INTERSTITIAL NEPHRITIS], [GLOMERULONEPHRITIS], [RENAL MEDULLARY NECROSIS] or [NEPHROTIC SYNDROME], [PROTEINURIA], [HYPERKALEMIA], [HYPOKALEMIA], and edema. This has been observed in susceptible patients taking high doses of NSAIDs for prolonged periods. Patients at risk include those with heart, kidney, or liver failure, ascites, hyperreninemia, hyperaldosteronemia, shock, sepsis, systemic lupus erythematosus, dehydration, those treated with ACE inhibitors or diuretics, and the elderly.

- Hepatic: In rare cases, [INCREASE TRANSAMINASES], [HEPATITIS] and [JAUNDICE] have been observed.

- Otological: Rarely, [TINNITUS].

- Ophthalmic: Very rarely, optical reactions such as blurred vision, decreased visual acuity, or changes in color perception (dyschromatopsia) have been observed after administration of ibuprofen, which resolve spontaneously. Isolated cases of reversible toxic amblyopia have been reported.

- In very rare cases, inflammations associated with infections could be aggravated.

ADVERSE REACTIONS RELATED TO EXCIPIENTS

This medicine contains sorbitol. Daily doses above 10 g of sorbitol taken orally may have a mild laxative effect and lead to diarrhea.

OVERDOSE

Symptoms: Ibuprofen can cause toxic effects at doses of 80-100 mg/kg, with symptoms appearing after about 4 hours. In cases of mild overdose, symptoms such as abdominal pain, nausea and vomiting, headache, drowsiness, lethargy, nystagmus, tinnitus, and ataxia may occur. More serious symptoms are rare, although gastrointestinal bleeding, hypotension, hypothermia, metabolic acidosis, seizures, kidney failure, coma, adult respiratory distress syndrome, and transient apnea in children may occur after ingesting large quantities.

Treatment: There is no specific antidote.

In cases of mild overdoses, from doses up to 50 mg/kg, which are not expected to cause symptomatic poisoning, water will be administered to mitigate possible gastrointestinal reactions.

In cases of major overdoses, and if less than one hour has passed since ingestion, the elimination of unabsorbed ibuprofen should be promoted by administering activated charcoal and inducing emesis. Induced emesis is contraindicated in children who have ingested more than 400 mg/kg due to the risk of seizures and aspiration pneumonia. Gastric lavage is only recommended for potentially fatal overdoses.

If more than one hour has passed since the overdose, symptomatic treatment should be initiated, especially for hypotension, gastrointestinal bleeding, and metabolic acidosis. Forced diuresis with urine alkalinization may be attempted.

Due to its high binding to plasma proteins, ibuprofen is not expected to be removed by hemodialysis.