Depiofen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPIOFEN (DEPIOFEN)

Composition:

Active substance: dexketoprofen trometamol;

1 ml of solution contains dexketoprofen trometamol equivalent to dexketoprofen 25 mg (1 ampoule of 2 ml contains dexketoprofen trometamol equivalent to dexketoprofen 50 mg);

Excipients: ethanol 96%, sodium chloride, sodium hydroxide and/or hydrochloric acid diluted, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution free from insoluble solids and foreign particles.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01A E17.

Pharmacological Properties

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl) propionic acid, exerting analgesic, anti-inflammatory, and antipyretic effects and belonging to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of Action

The mechanism of action of NSAIDs is based on reducing the synthesis of prostaglandins by inhibiting the activity of cyclooxygenase. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

Pharmacodynamics

Inhibitory effects of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 have been demonstrated in laboratory animals and in humans.

Clinical Efficacy and Safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol exerts a pronounced analgesic effect. The analgesic effect of dexketoprofen trometamol following intramuscular or intravenous administration to patients with moderate to severe pain intensity has been studied in various pain conditions associated with surgical procedures (orthopedic and gynecological surgeries, abdominal surgeries), as well as musculoskeletal pain (acute low back pain) and renal colic. In these studies, the analgesic effect of the drug began rapidly and reached its maximum within the first 45 minutes. The duration of analgesic action after administration of 50 mg dexketoprofen trometamol is typically 8 hours. Clinical studies have shown that using Depiophen allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. When patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief were also administered dexketoprofen trometamol, they required significantly less morphine (30–45% less) compared to patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen trometamol, maximum concentration is reached approximately within 20 minutes (10–45 minutes). It has been demonstrated that following single intramuscular or intravenous administration of 25–50 mg of the drug, the area under the AUC (concentration–time curve) is proportional to the dose.

Distribution

Similar to other drugs with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages 0.25 L/kg. The distribution half-life is approximately 0.35 hours, and the elimination half-life ranges from 1 to 2.7 hours.

Pharmacokinetic studies with repeated administration of the drug demonstrated that Cmax and AUC after the last intramuscular or intravenous dose did not differ from those after single administration, indicating absence of drug accumulation.

Biotransformation and Elimination

Metabolism of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion. After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating absence of transformation of the drug into the R-(-) optical isomer in humans.

Elderly Patients

Following administration of single and multiple doses, the extent of exposure in elderly healthy volunteers (aged 65 years and older) participating in the study was significantly higher (up to 55%) compared to younger volunteers, although no statistically significant differences in maximum concentration or time to reach it were observed. The mean elimination half-life was prolonged (by up to 48%), and the total clearance was reduced.

Preclinical Safety Data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology—did not reveal any specific hazard for humans. Chronic toxicity studies in animals identified the maximum dose without observed adverse effects as being twice the dose recommended for humans. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and at the highest dose, gastrointestinal tract pathologies such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals, either directly by affecting embryonic or fetal development or indirectly via maternal gastrointestinal tract injury.

Clinical characteristics.

Indications.

Symptomatic treatment of moderate to severe acute pain in cases where oral administration of the drug is not appropriate, e.g., postoperative pain, renal colic, and low back pain.

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product;
• Patients in whom administration of substances with similar action, e.g., acetylsalicylic acid or other NSAIDs, triggers attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema;
• If photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
• Gastrointestinal bleeding or perforation in medical history associated with NSAID therapy;
• Active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations;
• Chronic dyspepsia;
• Active bleeding or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• Severe heart failure;
• Moderate or severe renal impairment (creatinine clearance ≤59 mL/min);
• Severe hepatic impairment (10–15 points on the Child-Pugh scale);
• Hemorrhagic diathesis and other coagulation disorders;
• In case of pronounced dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• Third trimester of pregnancy and breastfeeding period;

Due to the ethanol content in Depiophen, injection solution, it is contraindicated for neuraxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the following agents with NSAIDs is not recommended:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day). Concurrent use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhancing effects;
• Anticoagulants: NSAIDs enhance the effect of anticoagulants, e.g., warfarin, due to high plasma protein binding of dexketoprofen, as well as platelet function inhibition and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under strict medical supervision with monitoring of relevant laboratory parameters;
• Heparins: increased risk of bleeding (due to platelet function inhibition and damage to the gastric and duodenal mucosa). If concomitant use is necessary, it should be performed under medical supervision with careful monitoring of relevant laboratory parameters;
• Corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding;
• Lithium (reports with several NSAIDs): NSAIDs increase lithium blood levels, potentially leading to toxicity (reduced renal excretion of lithium). Therefore, lithium blood levels should be monitored at the start of dexketoprofen therapy, during dose adjustment, or upon discontinuation of the drug;
• High-dose methotrexate (at least 15 mg per week). Due to reduced renal clearance of methotrexate under NSAID therapy, its overall negative effect on the blood system is enhanced;
• Hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Concomitant use of the following agents with NSAIDs requires caution:

• Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients), concomitant use of cyclooxygenase inhibitors with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using dexketoprofen with any diuretic, ensure the patient is not dehydrated and monitor renal function at the beginning of treatment;
• Low-dose methotrexate (less than 15 mg per week): reduced renal clearance of methotrexate under NSAID therapy enhances its overall negative effect on the blood system. During the first weeks of concomitant use, weekly blood tests are required. Treatment should be closely supervised in patients with even mild renal impairment and in elderly patients;
• Pentoxifylline: risk of bleeding. Monitoring should be intensified, and bleeding time should be checked more frequently;
• Zidovudine: risk of increased toxic effect on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use. Blood tests and reticulocyte count should be performed within 1–2 weeks after starting NSAID therapy;
• Sulfonylurea agents: NSAIDs may enhance the hypoglycemic effect of these agents by displacing sulfonylureas from plasma protein binding sites.

Potential interactions should be considered when using the following agents:

• Beta-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting prostaglandin synthesis;
• Cyclosporine and tacrolimus: possible increase in nephrotoxicity due to NSAID effects on renal prostaglandins. Renal function should be monitored during combination therapy;
• Thrombolytic agents: increased risk of bleeding;
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding;
• Probenecid: possible increase in dexketoprofen plasma concentration, likely due to inhibition of renal tubular secretion and glucuronic acid conjugation of the drug, requiring dose adjustment of dexketoprofen;
• Cardiac glycosides: NSAIDs may increase glycoside plasma concentrations;
• Mifepristone: theoretically, there is a risk of altered mifepristone efficacy under the influence of prostaglandin synthetase inhibitors. Limited data suggest that concomitant administration of NSAIDs on the same day as prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of medicinal products for medical termination of pregnancy;
• Quinolone antibiotics: animal studies have shown that high-dose quinolone derivatives in combination with NSAIDs increase the risk of seizures;
• Tenofovir: when used concomitantly with NSAIDs, plasma urea nitrogen and creatinine concentrations may increase; therefore, renal function should be monitored to assess the potential impact of concomitant use of these medicinal products;
• Deferasirox: concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Careful patient monitoring is required when using this medicinal product together with deferasirox;
• Pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using high-dose NSAIDs. Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid NSAID use for two days before and two days after pemetrexed administration.

Special precautions for use.

Use with caution in patients with a history of allergic conditions. Avoid using Depiophen in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, sometimes fatal, have been reported with the use of all NSAIDs at any stage of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment of such patients should begin with the lowest possible dose. As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be treated only if these conditions are in remission. Patients with existing gastrointestinal symptoms or gastrointestinal disorders in their history should be monitored during treatment for possible gastrointestinal complications, particularly gastrointestinal bleeding. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation.

For such patients and for patients taking low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal adverse reactions, concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should inform their physician about any unusual gastrointestinal symptoms, including gastrointestinal bleeding, particularly during the initial stages of treatment.

The drug should be prescribed with caution to patients who are concurrently using agents that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.

Renal safety

The medicinal product should be used with caution in patients with impaired renal function, as NSAIDs may worsen renal function, cause fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or those in whom hypovolemia may occur. During treatment, adequate fluid intake should be maintained to avoid dehydration, which may exacerbate renal toxicity. As with other NSAIDs, the drug may increase plasma concentrations of blood urea nitrogen and creatinine. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic safety

The medicinal product should be used with caution in patients with impaired liver function. As with other NSAIDs, the drug may cause transient and minor elevations in certain liver function tests, as well as marked increases in AST and ALT activity. If such increases occur, therapy should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical advice. Particular caution is required when treating patients with a history of heart disease, especially those with previous episodes of heart failure (the risk of heart failure increases during treatment with this drug), as fluid retention and edema may occur during NSAID therapy. Clinical and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude such a risk with dexketoprofen use are insufficient. Therefore, in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful patient assessment. Similarly careful evaluation is required before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as arterial hypertension, hyperlipidemia, diabetes, smoking).

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. The concomitant use of dexketoprofen trometamol and low-molecular-weight heparin at prophylactic doses in the postoperative period has been studied in clinical trials, and no effect on coagulation parameters was observed. However, patients receiving dexketoprofen trometamol concomitantly with agents affecting hemostasis, such as warfarin, other coumarin derivatives, or heparins, should be closely monitored by a physician. Cardiovascular adverse events occur most frequently in elderly patients.

Skin reactions

There have been very rare reports of serious skin reactions (some fatal) associated with NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk appears highest during the initial stages of treatment, with most cases occurring within the first month. If skin rashes, signs of mucosal involvement, or other symptoms of hypersensitivity occur, Depiophen should be discontinued.

Other information

Particular caution should be exercised when prescribing the medicinal product to patients:

• with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is considered necessary by the physician, regular monitoring of liver and kidney function is recommended.

Very rarely, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after taking Depiophen, treatment should be discontinued. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients suffering from asthma in combination with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. Administration of this drug may trigger asthma attacks or bronchospasm, particularly in patients with hypersensitivity to acetylsalicylic acid or NSAIDs.

Severe infectious complications of the skin and soft tissues may occur during chickenpox. Data to exclude a role of NSAIDs in exacerbating this infectious process are lacking. Therefore, Depiophen is not recommended for use in chickenpox.

Depiophen should be administered with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

As with other NSAIDs, dexketoprofen trometamol may mask symptoms of infectious diseases during its use. In some cases, activation of infectious processes localized in soft tissues has been reported during NSAID use. Therefore, if symptoms of bacterial infection appear or worsen during treatment, patients are advised to seek immediate medical attention.

Each ampoule of Depiophen contains 12.35 vol.% ethanol, i.e., up to 200 mg per dose, equivalent to 5 ml of beer or 2.08 ml of wine per dose. The drug may have adverse effects in individuals suffering from alcoholism. The ethanol content should be considered when administering to pregnant women, breastfeeding women, children, and patients at risk (e.g., those with liver disease) as well as in patients with epilepsy. The medicinal product contains less than 1 mmol of sodium (23 mg) per dose and is therefore practically sodium-free.

Masking of underlying infection symptoms: The drug may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. When the drug is used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding.

Depiophen is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and congenital heart defects and abdominal wall defects in the fetus. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk of such events is considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal developmental abnormalities, including cardiovascular malformations, increased. Nevertheless, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity.

From the 20th week of pregnancy, dexketoprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Dexketoprofen should not be prescribed during the first and second trimesters except in cases of extreme necessity. If dexketoprofen is used by women trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios should be considered after several days of dexketoprofen exposure starting from the 20th week of pregnancy. Dexketoprofen should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors pose risks to the fetus:

• cardiopulmonary toxic syndrome (with closure of the arterial duct and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with oligohydramnios (see above).

Risks for mother and child at the end of pregnancy:

• prolonged bleeding time (due to inhibition of platelet aggregation), which may occur even with low doses;
• delayed uterine contractions, leading to prolonged labor.

Therefore, dexketoprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding

There are no data on the passage of dexketoprofen into breast milk. Depiophen is contraindicated during breastfeeding.

Fertility

As with all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women planning pregnancy. Women experiencing fertility problems or undergoing infertility investigations should consider discontinuing the drug.

Ability to affect reaction speed when driving vehicles or operating machinery.

Dizziness, visual disturbances, or drowsiness may occur during Depiophen use. In such cases, the ability to react quickly, orient in traffic situations, and drive vehicles or operate machinery may be impaired.

Method of Administration and Dosage

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, the dose may be repeated after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use and should be administered only during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. For moderate to severe postoperative pain, the drug may be used as indicated at the same recommended doses in combination with opioid analgesics.

Elderly patients. Dose adjustment is generally not required. However, due to physiological decline in renal function, a lower dose is recommended: the maximum daily dose should be 50 mg in patients with mild renal impairment.

Hepatic impairment. In patients with mild to moderate hepatic impairment (5–9 points on the Child–Pugh scale), the maximum daily dose should be reduced to 50 mg, and liver function should be closely monitored. The drug is contraindicated in patients with severe hepatic impairment (10–15 points on the Child–Pugh scale).

Renal impairment. In patients with mild renal impairment (creatinine clearance 60–89 mL/min), the maximum daily dose should be reduced to 50 mg. The drug is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 59 mL/min).

Children and adolescents. The drug should not be used in children and adolescents due to lack of data on efficacy and safety.

Method of Administration

Intramuscular injection. The contents of one ampoule (2 mL) should be administered slowly by deep intramuscular injection.

Intravenous infusion.

For intravenous infusion, the contents of one 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer’s lactate solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear and transparent. The infusion should be administered intravenously slowly over 10–30 minutes.

Dyphofen, diluted in 100 mL of 0.9% sodium chloride solution or glucose solution, may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine, and theophylline.

Intravenous bolus injection.

If necessary, the contents of one ampoule (2 mL of injection solution) may be administered intravenously slowly over at least 15 seconds. The drug may be mixed in small volumes (e.g., in a syringe) with injection solutions of heparin, lidocaine, morphine, and theophylline.

Dyphofen must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, or hydroxyzine, as precipitation may occur.

Diluted infusion solutions must not be mixed with promethazine or pentazocine.

The drug may only be mixed with medicinal products listed above.

After reconstitution, the drug should be administered immediately when given by intramuscular or intravenous bolus injection.

No changes in active ingredient content due to adsorption have been observed during storage of diluted solutions in polyethylene bags or in administration devices made of ethylene-vinyl acetate, cellulose propionate, low-density polyethylene, or polyvinyl chloride.

Dyphofen is intended for single use only; any unused portion of the prepared solution should be discarded. The solution should be visually inspected before administration to ensure it is clear and colorless. The solution must not be used if particulate matter is present.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Warnings and Precautions for Use").

Children.

The drug should not be used in children and adolescents due to lack of data on efficacy and safety.

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment appropriate to the patient's condition should be initiated immediately. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse Reactions

The table below lists adverse reactions by organ systems and frequency of occurrence, which are considered at least possible in relation to dexketoprofen trometamol according to clinical trial data, as well as adverse reactions reported after marketing authorization of the drug.

Gastrointestinal disorders were observed most frequently.

The development of peptic ulcer disease, perforation, or gastrointestinal bleeding, sometimes with fatal outcome, is possible, especially in elderly patients. Based on available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may occur during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure, which may be caused by NSAID use, have also been reported. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood disorders (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis (very rare), are also possible.

According to results of clinical studies and epidemiological data, the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with a small increased risk of thrombotic events such as myocardial infarction and stroke.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. This allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Store in the original packaging to protect from light. After reconstitution, the solution should be stored for up to 24 hours at 2 to 8 °C in a place protected from light. Keep out of reach of children.

Incompatibilities.

Dipiofen must not be mixed in small volumes (e.g., in a syringe) with dopamine, promethazine, pentazocine, pethidine, or hydroxyzine solutions, as precipitation may occur.

Diluted infusion solutions prepared as described in the section "Administration and dosage" must not be mixed with promethazine or pentazocine.

Packaging. 5 amber glass ampoules in a cassette and in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Normon S.A.

Manufacturer's address and location of its operations.

Ronda de Valdecarrizo, 6, Tres Cantos, 28760 Madrid, Spain.