ACTION AND MECHANISM

[ANALGESIC], [ANTI-INFLAMMATORY], [ANTIPYRETIC], [PROSTAGLANDIN SYNTHESIS INHIBITOR (CYCLOOXYGENASE)]. Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid, belonging to the family of non-steroidal anti-inflammatory drugs (NSAIDs) derived from propionic acid. The mechanism of action of NSAIDs is related to the reduction of prostaglandin synthesis through the non-selective inhibition of cyclooxygenase. Furthermore, the inhibition of prostaglandin synthesis may affect other inflammatory mediators such as kinins, exerting an indirect action that would be additive to its direct action.

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.

SENIORS

The elderly appear to be more susceptible to the adverse effects of NSAIDs. The risk of developing severe peptic ulcer disease is increased in those over 65 and appears to be dose-dependent. Furthermore, NSAIDs can cause fluid retention, which may lead to cardiovascular complications and reduce the effectiveness of antihypertensive treatments. Caution is advised when using them.

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

- Known hypersensitivity to dexketoprofen or [NSAID ALLERGY].

- Patients with a history of hypersensitivity to acetylsalicylic acid or other NSAIDs, which includes patients who have experienced asthma attacks, acute rhinitis, urticaria or angioneurotic edema after using acetylsalicylic acid or other NSAIDs.

- [DIGESTIVE HEMORRHAGE], [ESOPHAGUS HEMORRHAGE], active [PEPTICA ULCERA], [CEREBRAL HEMORRHAGE].

- Renal insufficiency: patients with moderate to severe renal insufficiency (ClCr < 50 ml/min).

- Liver failure: patients with severe liver dysfunction (Child-Pugh score 10-15).

EFFECTS ON DRIVING

Dexketoprofen may cause mild to moderate dizziness or drowsiness, so patients should avoid operating dangerous machinery, including automobiles, until they are reasonably certain that the drug treatment does not adversely affect them.

PREGNANCY

Animal safety : Animal studies with various NSAIDs have recorded dystocia, increased post-implantation loss, and delayed delivery.

Safety in humans : There are no adequate and well-controlled studies in humans. Occasional use, except shortly before delivery, does not appear to produce adverse fetal effects. However, with chronic use during the third trimester, they could theoretically cause premature closure of the fetal ductus arteriosus by inhibiting prostaglandin synthesis. They may also produce an antiplatelet effect, which could complicate or prolong maternal bleeding and predispose the newborn. Before delivery, they can reduce or even eliminate uterine contractility, delaying labor and prolonging gestation. The use of these drugs, especially during the third trimester, is only acceptable when safer therapeutic alternatives are unavailable.

Effects on fertility : The use of NSAIDs may impair female fertility and is not recommended in women trying to conceive. In women with difficulty conceiving or undergoing fertility investigations, discontinuation of dexketoprofen should be considered.

PHARMACOKINETICS

- Absorption: It is rapidly absorbed from the gastrointestinal tract after oral administration, reaching peak plasma concentrations in 0.5–0.75 h (Tmax). Oral absorption is good. Following intramuscular (IM) administration in humans, Cmax is reached within 20 min (range 10–45 min). For single doses of 25 mg and 50 mg, the area under the curve has been shown to be dose-proportional after IM and IV administration.

- Distribution: Similar to other drugs with high plasma protein binding (99%), the volume of distribution has a mean value of less than 0.25 L/kg, being selectively distributed throughout the body. The distribution half-life was approximately 0.35 h.

- Metabolism: glucuronidation.

- Elimination: It is excreted renally (80%) as glucuronic acid conjugated metabolites. Following administration of dexketoprofen trometamol, only the S(+) enantiomer is found in urine, demonstrating that no conversion to the R-(-) enantiomer occurs in humans. The elimination half-life is 1-2.7 h.

Pharmacokinetics in special situations:

- Elderly: In healthy elderly individuals (65 years or older), exposure was significantly higher than in younger volunteers after single and repeated doses administered orally (up to 55%), while there were no significant differences in Cmax or tmax. The elimination half-life was prolonged after single and repeated doses (up to 48%), and the apparent total clearance was reduced.

INDICATIONS

- Mild or moderate pain, such as [MUSCULOSKELETAL PAIN], [DYSMENORRHEA], [ODONTALGIA].

Parenteral forms: symptomatic treatment of moderate to severe [ACUTE PAIN], when oral administration is not appropriate, such as postoperative pain, moderate to severe renal colic, and lower back pain.

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. Additionally, aspirin can decrease plasma levels of piroxicam by up to 80%.

- Alcohol: toxicity may be increased.

-Aliskiren: possible reduction of the antihypertensive effect of aliskiren (NSAIDs act on the renin-angiotensin system). In patients with compromised 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.

- Alendronic acid, bisphosphonates: possible increased risk of esophagitis and gastric ulcer. Cases have been described with naproxen and alendronate.

- Quinolone antibacterials: there are isolated reports of seizures that may have been due to the concomitant use of quinolones and 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.

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

- Antidiabetic agents: no interaction has been observed. However, there are isolated cases of both hypoglycemic and hyperglycemic effects from diclofenac that required adjusting the dosage of the hypoglycemic agents.

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

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

- 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: possible increase in plasma methotrexate levels, with a risk of toxicity, sometimes very severe. The severity depends largely on the methotrexate dose used. The risk of interaction is reduced with low doses of methotrexate, such as those used in psoriasis and rheumatoid arthritis.

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

- Zidovudine: increased risk of hematological toxicity, leading to severe anemia within one week of starting NSAID treatment. Clinical monitoring is advised. Check blood counts and reticulocyte counts one to two weeks after starting NSAID treatment.

LACTATION

Animal studies have revealed that milk concentrations are 4-5% of plasma concentrations. There are no data on excretion in breast milk. Caution is advised when using this product in breastfeeding mothers.

CHILDREN

Safety and efficacy have not been established in this age group. Use not recommended.

GUIDELINES FOR PROPER ADMINISTRATION

Administer with meals to alleviate possible gastric irritation; however, in cases of acute pain, it may be administered 30 minutes before meals. Long-term treatment is not recommended.

- Sachets (powder for oral solution): Dissolve the entire contents of one sachet in a glass of water; stir to help dissolve. The resulting solution should be taken immediately after reconstitution.

- Sachets (oral solution): Press the sachet several times before opening. The oral solution can be taken directly or diluted in a glass of water and taken immediately. Once opened, the entire contents of the sachet must be consumed.

POSOLOGY

Oral route:

- Adults: 12.5 mg/4-6 h or 25 mg/8 h, not to exceed 75 mg/day.

- Elderly: it is advisable to start with 50 mg daily, and the dosage can be increased to the adult dosage once good tolerability has been verified.

DOSAGE IN HEPATIC INSUFFICIENCY

"ORAL"

- Mild to moderate: the initial dose should not exceed 50 mg/day, with careful monitoring.

- Severe (Child-Pugh score 10-15): Use is not recommended.

DOSAGE IN RENAL INSUFFICIENCY

"ORAL"

- ClCr 50–80 ml/min: the initial dose should not exceed 50 mg/day.

- ClCr <50 ml/min: Use not recommended.

PRECAUTIONS

- [RENAL INSUFFICIENCY]. It is eliminated in the urine, so accumulation could occur in cases of renal insufficiency. Furthermore, it could lead to a decrease in renal blood flow with reversible acute renal failure due to the inhibition of vasodilatory prostaglandin synthesis, and cases of nephrotic syndrome and acute interstitial nephritis have even been reported with prolonged treatment. Patients at higher risk of renal insufficiency are those with pre-existing renal insufficiency, the elderly, or those in conditions that could reduce renal blood flow, such as [HYPOVOLEMIA], [DEHYDRATION], low-sodium diets, heart failure, hepatic insufficiency, hepatic cirrhosis, or treatment with diuretics, ACE inhibitors, or ARBs. In high-risk patients, during prolonged treatment, it is recommended to determine renal function (serum creatinine, CLcr) before starting treatment and periodically thereafter. If renal function worsens, a dose reduction may be necessary.

In patients with mild renal impairment, it is recommended to start treatment with a lower total daily dose, while carefully monitoring the patient. Use in moderate or severe renal impairment (CLcr < 50 ml/min) is contraindicated.

- [HEPATIC INSUFFICIENCY]. Due to its hepatic metabolism, accumulation may occur in cases of hepatic insufficiency. In patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B), an initial dose not exceeding 50 mg/day is recommended, with careful monitoring of the patient. Use in severe hepatic insufficiency (class C or Child-Pugh score 10-15) is contraindicated. Furthermore, the use of NSAIDs has occasionally been associated with the development of hepatic disorders, such as elevated transaminases, jaundice, and hepatitis, which may become severe and even fatal. Due to the risk of toxicity, it is advised that patients with hepatic disease use this medication at the lowest effective dose and that liver function (transaminases, bilirubin) be monitored periodically to detect any signs of liver damage.

- Gastrointestinal toxicity. Treatment with NSAIDs has resulted in gastroduodenal ulcers, as well as life-threatening bleeding and perforation. The risk of ulcers is higher with high-dose treatments or treatments lasting long periods, in patients with a history of peptic ulcers, especially if they have previously experienced gastrointestinal bleeding or perforation due to NSAIDs, and in smokers, chronic alcoholics, or elderly or debilitated patients. However, short-term treatment is not without risks either.

As a general rule to reduce gastric damage, it is advisable to take any NSAID with food. 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 blocker or PPI).

High-risk patients, as well as those receiving medications that may promote or worsen gastrointestinal bleeding, such as oral anticoagulants, antiplatelet agents, corticosteroids, or SSRIs, should be closely monitored. If a peptic ulcer or gastrointestinal bleeding occurs, treatment should be discontinued. Furthermore, it should be used with caution in individuals with inflammatory bowel disease (IBD), in whom NSAIDs could trigger an attack.

- Cardiovascular diseases. NSAIDs may cause fluid retention and edema, which could increase blood pressure and worsen symptoms in patients with cardiovascular diseases. It is advisable to monitor blood pressure at the start of treatment, as well as periodically throughout its duration. Their use has been associated with the occurrence of thrombotic events, stroke, and myocardial infarction, especially in patients treated with high doses for prolonged periods. Based on the studies carried out, the risks appear to be higher with selective COX-2 inhibitors (coxibs) and diclofenac, while ibuprofen and naproxen have a lower cardiovascular risk. The available data do not allow for definitive conclusions to be drawn with other NSAIDs, so the cardiovascular risk cannot be ruled out. Individual assessment of the benefit/risk ratio is recommended in patients with hypertension, heart failure, ischemic heart disease, cerebral ischemia, stroke, or peripheral artery disease, as well as in patients with cardiovascular risk factors such as dyslipidemia, diabetes, or smoking. NSAIDs should always be used at the lowest effective dose and for the shortest possible duration.

- 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.

- [HYPERSENSITIVITY REACTIONS]. Administration of any NSAID has been associated with the occurrence of allergic reactions. Cases of cross-hypersensitivity between different NSAIDs, as well as between NSAIDs and salicylates, have been reported; therefore, patients with a history of [NSAID ALLERGY] to other than this active ingredient or [SALICYLATE ALLERGY] should use this active ingredient with extreme caution.

It is recommended to avoid its use in patients in whom a salicylate or an NSAID has previously caused severe allergic reactions, including asthma, [NASAL POLYPS], [ANGIOEDEMA] or [RHINITIS], because there is an increased risk of life-threatening anaphylaxis.

[ASTHMA]. Asthmatic patients are more susceptible to bronchospasm when an NSAID is administered. They may also be more susceptible to anaphylactic reactions after NSAID administration. As a general rule, it is advisable to avoid administering NSAIDs and salicylates to asthmatic patients unless the expected benefits outweigh the potential risks. If their use is necessary, respiratory function and the possible development of allergy symptoms should be closely monitored. If a reduction in respiratory function or the development of allergic reactions occurs, naproxen should be discontinued and symptomatic treatment initiated. Treatment should not be initiated in patients who have previously experienced allergic symptoms or severe bronchoconstriction induced by NSAIDs or salicylates.

- [COAGULATION DISORDERS]. NSAIDs have antiplatelet activity, although less than that of acetylsalicylic acid. They could increase bleeding time and promote the occurrence of bleeding in patients with hemostasis disorders or those treated with anticoagulant drugs or other antiplatelet agents.

- [ASEPTIC MENINGITIS]. Rare cases of aseptic meningitis have been reported in patients taking NSAIDs, with fever and coma, probably due to a hypersensitivity reaction, although no cross-allergy between NSAIDs has been found. This meningitis appears to be more frequent in patients with collagen vascular diseases such as systemic lupus erythematosus, 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.

- Ophthalmological conditions. NSAIDs have been associated with the occurrence of ocular reactions, such as blurred vision, vision loss, altered color vision, scotoma, or retinal abnormalities. Occasionally, these can be serious, such as papillitis, retrobulbar neuritis, or papilledema. These disorders may be asymptomatic, so it is advisable to have regular eye exams, especially if you notice any changes in your vision.

- [FEMALE INFERTILITY]: Like other NSAIDs, it may decrease female fertility and is not recommended for use in women who wish to become pregnant. In women who have difficulty conceiving or are being evaluated for infertility, discontinuation of the NSAID should be considered.

PRECAUTIONS RELATING TO EXCIPIENTS

This medicine contains sucrose. Patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

ADVERSE REACTIONS

Adverse reactions reported as at least possibly related to the administration of dexketoprofen trometamol in clinical trials are tabulated below, classified by organ system and ordered by frequency:

- Blood and lymphatic system disorders: infrequent (0.1-1%): [ANEMIA]; very rare / isolated cases (<0.01%): [NEUTROPENIA], [THROMBOCYTOPENIA].

- Metabolism and nutrition disorders: rare (0.01-0.1%): [HYPERGLYCEMIA], [HYPOGLYCEMIA], [HYPERTRIGLYCERIDEMIA].

- Nervous system disorders: (0.1-1%): [HEADACHE], [DIZZINESS], [INSOMNIA], [DROWSY]; (0.01-0.1%): [PARESTHESIA].

- Eye disorders: (0.1-1%): [BLURRED VISION].

- Ear and labyrinth disorders: (0.01-0.1%): [TINNITUS].

- Cardiac alterations: (0.01-0.1%): [EXTRASYSTOLE], [TACHYCARDIA].

- Vascular disorders: infrequent (0.1-1%): [HYPOTENSION], [HOT FLASHES]; (0.01-0.1%): [ARTERIAL HYPERTENSION], [ANELEOLAR EDEMA], superficial [THROMBOPHLEBITIS].

- Respiratory, thoracic and mediastinal disorders: (0.01-0.1%): bradypnea ([RESPIRATORY FAILURE]); very rare / isolated cases (<0.01%): [BRONCHIAL SPASM], [DYSPNEA].

- Gastrointestinal disorders: (1-10%): [NAUSEA], [VOMITING]; (0.1-1%): [ABDOMINAL PAIN], [DYSPEPSIA], [DIARRHEA], [CONSTIPATION], [HEMATEMESIS], [DRY MOUTH]; (0.01-0.1%): [GASTRIC ULCER] or [DUODENAL ULCER], [GASTROINTESTINAL BLEEDING] or [INTESTINAL PERFORATION], [ANOREXIA]; very rare / isolated cases (<0.01%): [PANCREATITIS].

- Hepatobiliary disorders: (0.01-0.1%): NSAID-induced hepatotoxicity is rare and generally mild; it usually manifests as mild and transient [INCREASE IN TRANSAMINASES]. Very rarely it manifests as anorexia, asthenia, nausea and [JAUNDICE]; (<0.01%): [HEPATITIS].

- Skin and subcutaneous tissue disorders: (0.1-1%): [DERMATITIS], [PRURITUS], [SKIN ERUPTIONS], [HYPERHIDROSIS]; (0.01-0.1%): [URTICARIA], [ACNE]; very rare / isolated cases (<0.01%): severe mucocutaneous reactions ([STEVENS-JOHNSON SYNDROME], [TOXIC EPIDERMAL NECROLYSIS]), [ANGIOEDEMA], [PHOTOSENSITIVITY REACTIONS].

- Musculoskeletal, connective tissue and bone disorders: (0.01-0.1%): [MUSCLE STIFFNESS], [JOINT STIFFNESS], [MUSCLE CRAMPS].

- Renal and urinary disorders: May cause increased blood urea nitrogen (BUN) and increased serum creatinine. In rare cases, NSAIDs may cause acute renal failure, interstitial nephritis, glomerulonephritis, renal medullary necrosis, nephrotic syndrome, proteinuria, hyperkalemia, hyponatremia, polyuria, and edema. These have 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.

- Reproductive system disorders: (0.01-0.1%): [MENSTRUAL CYCLE DISORDERS], prostate disorders.

- General and administration site disorders: (1-10%): [PAIN AT THE INJECTION SITE]; (0.1-1%): reactions, inflammation, burning or bleeding at the injection site, [HEAT STROKE], [ASTHENIA], [PAIN], [CHILLS]; rare (0.01-0.1%): [LUMBAR PAIN], [SYNCOPE], [CHILLS]; very rare / isolated cases (<0.01%): [ANAPHYLAXIS], [EDEMA].

- Investigations (laboratory tests): rare (0.01-0.1%): [KETONURIA], [PROTEINURIA].

The following adverse reactions may occur as they have been observed for other non-steroidal anti-inflammatory drugs and may be associated with prostaglandin synthesis inhibitors: [ASEPTIC MENINGITIS], which may predominantly occur in patients with systemic lupus erythematosus or mixed connective tissue disease, and hematological reactions ([PURPURA], [APLASTIC ANEMIA] and [HEMOLYTIC ANEMIA], rarely [AGRANULOCYTOSIS] and [BONE MARROW DEPRESSION]).

ADVERSE REACTIONS RELATED TO EXCIPIENTS

- Because it contains methyl parahydroxybenzoate, it may cause [HYPERSENSITIVITY REACTIONS] (possibly delayed).

OVERDOSE

- Symptoms: The symptoms of overdose are unknown. Similar drugs have produced gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and neurological disturbances (drowsiness, vertigo, disorientation, headache).

- Treatment of poisoning: Gastric emptying, administration of activated charcoal (may be effective if administered within two hours of poisoning), monitoring and maintenance of vital signs, symptomatic treatment of gastrointestinal irritation, hypotension, respiratory depression, and seizures, with monitoring of renal and hepatic function and detection of possible gastrointestinal bleeding in stool. Dexketoprofen trometamol is dialyzable.