Difenadex 25Mg 10 Capsules

Difenadex 25 Mg 10 Capsules

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 derived from propionic acid. The mechanism of action of non-steroidal anti-inflammatory drugs is related to the decrease in prostaglandin synthesis through non-selective inhibition of cyclooxygenase. In addition, the inhibition of prostaglandin synthesis could have an effect on other inflammatory mediators such as kinins, exerting an indirect action that would be added to their direct action.

PHARMACOKINETICS

- Absorption: it is rapidly absorbed through the gastrointestinal tract after oral administration, obtaining the maximum plasmatic concentration in 0.5-0.75 h (Tmax). Oral absorption is good. Following im administration in humans, Cmax is reached within 20 min (range 10-45 min). For single doses of 25 and 50 mg, the area under the curve has been shown to be proportional to dose after im and iv administration.

- Distribution: Like other drugs with high binding to plasmatic proteins (99%), the volume of distribution has a mean value of less than 0.25 l/Kg, being distributed in the organism selectively. The distribution half-life value was approximately 0.35 h.

- Metabolism: glucuronoconjugation.

- Elimination: it is excreted via the kidneys (80%) in the form of metabolites conjugated with glucuronic acid. After administration of dexketoprofen trometamol, only the S(+) enantiomer is obtained in urine, demonstrating that there is no conversion to the R-(-) enantiomer in humans. The elimination half-life is 1-2.7 hours.

Pharmacokinetics in special situations:

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

INDICATIONS

- Pain of mild or moderate intensity, such as [OSTEOMUSCULAR PAIN], [DYSMENORHEA], [ODONTALGIA].

Parenteral forms: symptomatic treatment of moderate to severe [ACUTE PAIN], when oral administration is inappropriate, such as postoperative pain, moderate to severe renal colic, and low back pain.

POSOLOGY

Orally:

- Adults: 12.5 mg/4-6 h or 25 mg/8 h, without exceeding 75 mg/day.

- Elderly: it is advisable to start with 50 mg daily, being able to increase to the dosage for adults once good tolerability has been verified.

DOSAGE IN RENAL FAILURE

"ORAL"

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

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

DOSAGE IN LIVER FAILURE

"ORAL"

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

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

RULES FOR CORRECT ADMINISTRATION

Administer together with meals to alleviate possible gastric irritation, however, in case of acute pain it may be administered 30 min before meals. Long-term treatments are not recommended.

- Envelopes (powder for oral solution): Dissolve the entire content of an envelope in a glass of water; shake to help dissolve. The solution obtained must be taken immediately after its reconstitution.

- Envelopes (oral solution): press the envelope several times before opening. The oral solution can be taken directly or diluted in a glass of water, taken immediately. Once the envelope has been opened, all its contents must be consumed.

CONTRAINDICATIONS

- Known hypersensitivity to dexketoprofen or [ALLERGY TO NSAIDs].

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

- [DIGESTIVE BLEEDING], [ESOPHAGUS BLEEDING], [PEPTIC ULCERA] active, [CEREBRAL BLEEDING].

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

- Hepatic impairment: patients with severe hepatic dysfunction (Child-Pugh score 10 - 15).

- During the third trimester of pregnancy or lactation.

PRECAUTIONS

- [RENAL INSUFFICIENCY]. It is excreted in the urine, so in case of renal insufficiency accumulation could occur. In addition, it could lead to a decrease in renal blood flow with reversible acute renal failure due to the inhibition of the synthesis of vasodilator prostaglandins, and cases of nephrotic syndrome and acute interstitial nephritis have even been described with prolonged treatments. Patients with the highest risk of renal failure are those with previous renal failure, the elderly, or situations that could reduce renal flow, such as [HYPOVOLEMIA], [DEHYDRATION], low-sodium diets, heart failure, liver failure, liver cirrhosis, or treatment with diuretics, ACE inhibitors, or ARAII. In high-risk patients, during prolonged treatments, It is recommended to determine renal function (serum creatinine, CLcr) before starting treatment, and periodically. In case of worsening renal function, a dose reduction may be necessary.

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

- [LIVER FAILURE]. Due to its hepatic metabolism, accumulation may occur in case of hepatic insufficiency. In patients with mild to moderate insufficiency (Child-Pugh class A or B), an initial dose of no more than 50 mg/day is recommended, carefully monitoring the patient. Use in severe insufficiency (class C or Child-Pugh score 10-15) is contraindicated. On the other hand, the use of NSAIDs has sometimes been related to the appearance of liver symptoms, such as increased transaminases, [JAUNDICE] and [HEPATITIS], which could be serious and even fatal. Due to the risk of toxicity, it is recommended that patients with liver disease use this medication at the lowest effective dose, and periodically check liver function (transaminases,

- Gastrointestinal toxicity. Treatment with NSAIDs has resulted in gastroduodenal ulcers, as well as life-threatening bleeding and perforation. There is a greater risk of ulcer with treatments with high doses or for long periods of time, with a history of peptic ulcer, especially if they have already had bleeding or gastrointestinal perforation due to NSAIDs, as well as in smoking, [CHRONIC ALCOHOLISM] or elderly or debilitated patients. However, short-term treatment is not without risk either.

As a general rule to reduce gastric damage, it is advisable to administer any NSAID with food. In addition, in risk groups it is advisable to start treatment with the lowest possible dose, and always associate an anti-ulcer drug (anti H2 or PPI) whenever possible.

High-risk patients should be closely monitored, as well as those who are being treated with drugs that may favor or aggravate gastrointestinal bleeding, such as oral anticoagulants, antiplatelet agents, corticosteroids or SSRIs. If a peptic ulcer or gastrointestinal bleeding appears, treatment will be discontinued. On the other hand, it should be used with caution in people with [INFLAMATORY BOWEL DISEASE], where NSAIDs could precipitate a crisis.

- Cardiovascular diseases. NSAIDs could lead to fluid retention and edema, which could increase blood pressure and worsen the symptoms of patients with cardiovascular diseases. It is advisable to monitor blood pressure at the start of treatment, as well as periodically throughout it. Its use has been associated with the appearance of thrombotic processes, 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 with diclofenac, while ibuprofen and naproxen have a lower cardiovascular risk. The available data do not allow definitive conclusions to be drawn with other NSAIDs, therefore, cardiovascular risk cannot be ruled out. It is recommended to individually evaluate the benefit/risk ratio in patients with [ARTERIAL HYPERTENSION], [HEART FAILURE], [ISCHEMIC HEART DISEASE], [CEREBRAL ISCHEMIA], [Stroke] or [PERIPHERAL ARTERY DISEASE], as well as in patients with cardiovascular risk factors, such as [DYSLIPEMIA], [DIABETES] or [SMOKING]. NSAIDs should always be used at the lowest effective dose and for the shortest period of time.

- 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 have an early onset, in the first month of treatment. If symptoms of hypersensitivity, mucosal lesions or skin erythema are observed, treatment will be discontinued.

- [HYPERSENSITIVITY REACTIONS]. The administration of any NSAID has been related to the appearance of allergic reactions. Cases of cross hypersensitivity have been reported between different NSAIDs, as well as between NSAIDs and salicylates, so patients with a history of [ALLERGY TO NSAIDs] other than this active ingredient or [ALLERGY TO SALICYLATES] should use this active ingredient with extreme caution.

It is recommended to avoid its use in those patients in whom a salicylate or an NSAID has previously given rise to severe allergic reactions, including asthma, [NASAL POLYPS], [ANGIOEDEMA] or [RHINITIS], due to the increased risk of potentially fatal anaphylaxis.

- [ASTHMA]. Asthmatic patients are more likely to experience bronchospasm when taking an NSAID. In addition, they could be more susceptible to anaphylactic symptoms after the administration of an NSAID. As a general rule, it is advisable to avoid administering NSAIDs and salicylates in asthmatic patients unless the expected benefits outweigh the possible risks. If its use is necessary, the respiratory function and the possible appearance of allergy symptoms will be closely monitored. If there is a reduction in respiratory function or the appearance of allergic symptoms, naproxen will be discontinued and symptomatic treatment will be instituted. Treatment should not be initiated in patients who have previously experienced allergic symptoms or severe bronchoconstriction induced by NSAIDs or salicylates.

- [ALTERATIONS OF COAGULATION]. NSAIDs have antiplatelet activity, although less than that of acetylsalicylic acid. They could increase the bleeding time and favor the appearance of bleeding in patients with alterations in haemostasis or in treatment with anticoagulant drugs or with other antiplatelet agents.

- [ASEPTIC MENINGITIS]. Rare cases of aseptic meningitis have been reported in patients with NSAIDs, with fever and coma, probably due to a hypersensitivity reaction, although cross-allergy between NSAIDs has not been found. This meningitis seems to be more frequent in patients with [COLLAGENOSIS] such as [SYSTEMIC LUPUS ERYTHEMATOSO], although it has also been reported in some patients who did not suffer from these pathologies. In NSAID-treated patients who develop symptoms of meningitis, the possibility of aseptic meningitis should be considered.

- Ophthalmological pictures. NSAIDs have been related to the appearance of ocular reactions, such as blurred vision, loss of vision, alteration in color vision, scotoma or retinal alterations. Sometimes they could be serious, such as papillitis, retrobulbar neuritis or papilledema. These disorders could be asymptomatic, so it is advisable to carry out periodic ophthalmological check-ups, and especially before any change in vision.

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

ADVICE TO THE PATIENT

- The patient must inform his doctor in case of experiencing 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 he has had any asthmatic reaction while taking this medicine.

SPECIAL WARNINGS

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

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

- Masking of symptoms of underlying infections: Dexketoprofen may mask the symptoms of an infection, which may delay the initiation of appropriate treatment and therefore worsen the outcome of the infection. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. When taking this medicine to relieve pain related to an infection, it is recommended to monitor the infection. In non-hospital settings, the patient should see a doctor if symptoms persist or worsen.

INTERACTIONS

- NSAIDs, including low doses of acetylsalicylic acid: the simultaneous use of more than one NSAID should be avoided due to the risk of adverse effects without increasing therapeutic efficacy. Additionally, acetylsalicylic acid produces a decrease in plasmatic levels of piroxicam of up to 80%.

- Alcohol: toxicity can be enhanced.

-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. Described cases with naproxen and alendronate.

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

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

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

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

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

- Antihypertensives (ACEI, 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. Manage with caution. 

- Corticosteroids: possible increase in the incidence of gastric discomfort. However, the concurrent use with glucocorticoids in the treatment of osteoarthritis may provide additional therapeutic benefit and allows the dosage of glucocorticoid to be reduced.

- Digitalis (digoxin): possible increase in plasma concentrations of digitalis (in neonates). There is also a risk of worsening heart failure and reduced kidney 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 potentiation of edema that both glitazones and NSAIDs can cause. Caution and monitor 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 methotrexate plasma levels, with risk of toxicity, sometimes very serious. The severity largely depends on the doses of methotrexate 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 renal effects.

- Zidovudine: increased risk of haematological toxicity, leading to severe anemia a week after starting treatment with the NSAID. Clinical surveillance is advised. Check blood count and reticulocyte count one to two weeks after the start of NSAID treatment.

PREGNANCY

Animal Safety: Animal studies with various NSAIDs have reported cardiovascular malformations during the organogenic period.

Safety in humans: From the 20th week of pregnancy, the use of glucosamine may cause oligohydramnios as a result of fetal renal dysfunction. This can occur soon after the start of treatment and is usually reversible by discontinuing treatment. In addition, there have been reports of constriction of the ductus arteriosus after treatment in the second trimester, most of which resolved after discontinuation of treatment. During the first and second trimesters of pregnancy, glucosamine should not be administered unless strictly necessary. If glucosamine 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. Consideration should be given to prenatal monitoring for oligohydramnios and constriction of the ductus arteriosus after glucosamine exposure for several days from gestational week 20 onwards. Treatment with glucosamine should be discontinued if oligohydramnios or constriction of the ductus arteriosus is found.

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

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction;

the mother and the newborn, at the end of the pregnancy, to:

- possible prolongation of bleeding time, an antiplatelet effect that can occur even at very low doses;

- inhibition of uterine contractions leading to delayed or prolonged labor.

Effects on fertility: the use of NSAIDs can impair female fertility and is not recommended in women trying to conceive. In women having difficulty conceiving or undergoing fertility investigation, dexketoprofen discontinuation should be considered.

LACTATION

Safety in animals: no data available.

Safety in humans: It is unknown if dexketoprofen is excreted in milk, and what consequences it could have for the nursing infant. Contraindicated.

CHILDREN

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

ADVANCED AGE

In elderly patients it is recommended to start treatment with the lowest dose. Use with caution, due to the high probability of adverse reactions. A higher incidence of gastrointestinal adverse reactions to NSAIDs, especially bleeding and perforation, has been observed. In addition, they can suffer renal, hepatic or cardiovascular alterations. May decrease the effect of antihypertensives. Therefore, it should be used with caution in patients >65 years of age.

EFFECTS ON DRIVING

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

ADVERSE REACTIONS

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

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

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

- Nervous system disorders: (0.1-1%): [HEADACHE], [DIZZNESS], [INSOMNIA], [SOMNOLENCE]; (0.01-0.1%): [PARESTHESIS].

- Ocular alterations: (0.1-1%): [BLURRY VISION].

- Alterations of the ear and labyrinth: (0.01-0.1%): [TINNITUS].

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

- Vascular alterations: infrequent (0.1-1%): [HYPOTENSION], [FLASHES]; (0.01-0.1%): [ARTERIAL HYPERTENSION], [MALEOLAR EDEMA], [TROMBOPHLEBITIS] superficial.

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

- Gastrointestinal disturbances: (1-10%): [NAUSEA], [VOMITING]; (0.1-1%): [ABDOMINAL PAIN], [DYSPEPSIA], [DIARRHEA], [CONSTIPATION], [HEMATEMESIS], [DRY MOUTH]; (0.01-0.1%): [GASTRIC ULCER] or [DUODENAL ULCER], [DIGESTIVE 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 [INCREASE IN TRANSAMINASES] mild and transient. Very rarely it manifests as anorexia, asthenia, nausea and [JAUNDICE]; (<0.01%): [HEPATITIS].

- Alterations of the skin and subcutaneous tissue: (0.1-1%): [DERMATITIS], [PRURITUS], [EXANTEMATIC ERUPTIONS] skin, [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 [INCREASE IN UREA NITROGEN] and [INCREASE IN SERUM CREATININE]. In exceptional cases, NSAIDs may be responsible for [ACUTE RENAL FAILURE], [INTERSTITIAL NEPHRITIS], [GLOMERULONEPHRITIS], [RENAL MEDULLARY NECROSIS] or [NEPHROTIC SYNDROME], [PROTEINURIA], [HYPERKOTASEMIA], [HYPONATREMIA], [POLYURIA] and edema. It has been observed in susceptible patients taking high doses of NSAIDs for prolonged periods of time. Patients at risk are 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.

- Changes in the reproductive system: (0.01-0.1%): [MENSTRUAL CYCLE DISORDERS], prostate changes.

- General changes and changes in the administration site: (1-10%): [PAIN AT THE INJECTION POINT]; (0.1-1%): reactions, inflammation, itching or bleeding at the injection site, [HEAT STROKE], [ASTHENIA], [PAIN], [CHILLS]; rare (0.01-0.1%): [LOW BACK PAIN], [SYNCOPE], [CHILLS]; very rare / isolated cases (<0.01%): [ANAPHYLAXIA], [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 haematological reactions ([PURPURA], [APLASTIC ANEMIA] and [HEMOLYTIC ANEMIA], rarely [AGRA NULOCYTOSIS] and [MEDULLARY DEPRESSION]).

OVERDOSE

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

- Treatment of poisoning: stomach emptying, administration of adsorbent carbon (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 functions and detection of possible gastrointestinal bleeding in feces. Dexketoprofen trometamol is dialyzable.

Difenadex 25Mg 10 Capsules Leaflet