Rx Prescription information
Trade name: Diclofenac-Belmed.
International nonproprietary name: Diclofenac.
Appearance: Transparent, slightly yellowish solution with a faint odor of benzyl alcohol.
Composition per ampoule: active ingredient: diclofenac- - 75.0 mg; excipients: propylene glycol, mannitol, benzyl alcohol, sodium metabisulfite, 1M solution of sodium hydroxide, water for injections.
Dosage form: solution for intramuscular injection, 25 mg/ml.
Pharmacological group: Non-steroidal anti-inflammatory and anti-rheumatic agents. Acetic acid derivatives and their analogues.
ÀÒÑ code: ÌÎ1ÀÂ05.
The product has anti-inflammatory, analgesic and antipyretic effect. Nonselectively inhibiting cyclooxygenase 1 and 2, it interferes with the metabolism of arachidonic acid, and reduces the amount of prostaglandins (Pg) in inflammation area. It is most effective in pain of inflammatory character. As all NSAIDs, the product has antiplatelet activity.
Intramuscular injection of diclofenac is indicated in acute pain, including renal colic, exacerbation of osteoarthritis and rheumatoid arthritis, acute back pain, gout attack, injuries and fractures in the acute period, and postoperative pain.
Dosage and mode administration
Intramuscularly, deeply. The product is used for treatment of acute conditions or relief of chronic disease exacerbation.
Single dose for adults is 75 mg (one ampoule). If necessary, repeated injection is possible, but not earlier than in 12 hours. Maximum daily dose is 150 mg (2 ampoules).
Duration of intramuscular injection of the product should not exceed 2 weeks, for patients over 65 years - no more than 2 days, under close medical supervision, then shift to oral administration.
In order to reduce the risk of adverse events the product should be prescribed in the lowest effective dose for the shortest period.
Dosage in elderly patients. Despite the absence of clinically relevant changes in the pharmacokinetics of diclofenac in elderly patients, non-steroidal anti-inflammatory agents should be used cautiously in patients with increased risk of adverse reactions. The use of the lowest effective dose is recommended in fragile elderly patients or in patients with reduced body weight; it is necessary to control the development of gastrointestinal bleeding in patients upon administration of NSAIDs.
Dosage in renal insufficiency. Diclofenac is contraindicated in patients with severe renal insufficiency. No specific studies among patients with renal insufficiency have been conducted; therefore there are no available dosage recommendations for the product. It is recommended to prescribe diclofenac cautiously in patients with mild or moderate renal insufficiency.
Dosage in hepatic insufficiency. Diclofenac is contraindicated in patients with severe hepatic insufficiency. No specific studies among patients with hepatic insufficiency have been conducted; therefore there are no available dosage recommendations for the product. It is recommended to prescribe diclofenac cautiously in patients with mild or moderate hepatic insufficiency.
Common - 1-10%; uncommon – 0.1-1%; rare – 0.01-0.1%; very rare – less than 0.01%, including individual cases.
Gastrointestinal disorders: common - NSAID gastropathy (stomachalgia, nausea, vomiting, diarrhea, abdominal pain, flatulence), anorexia; uncommon - gastritis, proctitis, gastrointestinal bleeding (vomiting blood, melena, bloody diarrhea), ulcers of the gastrointestinal tract (with or without bleeding or perforation), non-specific colitis with bleeding, dry mouth; very rare -stomatitis, glossitis, esophagus lesions, diaphragm-like intestinal strictures, nonspecific hemorrhagic colitis, exacerbation of ulcerative colitis or Crohn's disease, constipation, pancreatitis.
Hepatic disorders: common - transaminases level increase; rare - toxic hepatitis (jaundice with or without jaundice), fulminant hepatitis, compromised hepatic function; very rare - fulminant hepatitis.
Nervous system disorders: common - headache, dizziness, fatigue; rare - somnolence; very rare - sensitivity disturbance, including paresthesias, memory disorders, tremor, convulsions, anxiety, cerebrovascular disorders, disorientation, depression, insomnia, "nightmares", irritability, mental disorders, aseptic meningitis; unknown - optic neuritis, confusion, hallucinations, malaise.
Sensory organ disorders: common - vertigo; very rare - blurred vision, diplopia, scotoma, decreased hearing, tinnitus.
Skin disorders: common - rash; rare - urticaria; very rare - hematomas, bullous rash, eczema, including multiform and Stevens-Johnson syndrome, Lyell's syndrome, exfoliative dermatitis, pruritus, alopecia, photosensitization, purpura.
Urinary tract disorders: common - nephrotic syndrome (swelling); very rare - acute renal failure, hematuria, proteinuria, oliguria, interstitial nephritis, papillary necrosis, cystitis, electrolyte imbalance as a syndrome resembling inappropriate secretion of antidiuretic hormone, spontaneous hyponatraemia.
Hemopoietic organ disorders: rare - thrombocytopenia, leukopenia, hemolytic and aplastic anemia, agranulocytosis, local spontaneous bleeding and inhibition of platelet aggregation, prolonged bleeding.
Cardiovascular disorders: very rare - palpitations, chest pain, increased blood pressure, hypotension, vasculitis, heart failure, myocardial infarction.
Respiratory disorders: rare - bronchial asthma (including wheezing), very rare - pneumonitis.
Endocrine disorders: very rare - impotency.
Allergic reactions: very rare - anaphylactic/anaphylactoid reactions, including accentuated decrease in blood pressure and shock, angioneurotic edema (including facial).
In intramuscular injection site: common - burning; very rare - infiltration, aseptic necrosis, necrosis of adipose tissue.
Hypersensitivity (including to other NSAIDs); erosive and ulcerative lesions of the gastrointestinal tract (in the exacerbation phase), gastrointestinal bleeding or perforation related to NSAIDs in history; active or recurrent peptic ulcer/bleeding in history (two or more episodes of proven ulcer or bleeding ), bronchial asthma (risk of exacerbation), urticaria or acute rhinitis provoked by administration of aspirin or other non-steroidal anti-inflammatory drugs, severe renal/hepatic and heart insufficiency, disorders of hematopoiesis, pediatric use (under 15 years), pregnancy and lactation.
Diclofenac is contraindicated in patients with established ischemic heart disease, peripheral arterial diseases, or cerebrovascular diseases.
Cautiously: peptic and duodenal ulcer, ulcerative colitis, Crohn's disease, history of hepatic diseases, hepatic porphyria, chronic renal failure, chronic heart failure, hypertension, significant decrease in circulating blood volume (including after massive surgery), elderly patients over 65 years (including receiving diuretics, fragile patients and patients with reduced body weight),concomitant administration of glucocorticoids , anticoagulants, antiplatelet agents , selective serotonin reuptake inhibitors.
Symptoms: dizziness, headache, pulmonary hyperventilation, mental confusion, myoclonic seizures, nausea, vomiting, abdominal pain, bleeding, compromised hepatic and renal function.
Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy aimed at eliminating increased blood pressure, renal impairment, convulsions, gastrointestinal irritation, respiratory depression. Forced diuresis and hemodialysis are ineffective (due to significant protein-binding and intensive metabolism).
In order to reduce the risk of adverse events the product should be prescribed in the lowest effective dose for the shortest period. Simultaneous administration of diclofenac with systemic NSAIDs should be avoided, including selective cyclooxygenase-2 inhibitors, due to the lack of evidence demonstrating synergistic effect, as well as in connection with the potentiating of undesirable effects.
The product should be prescribed cautiously in elderly patients. The use of the lowest effective dose is recommended in fragile elderly patients and in patients with reduced body weight.
As with the use of other NSAIDs, diclofenac may cause allergic reactions, including anaphylactic/anaphylactoid reactions, even without the administration of the product before.
As other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Sodium metabisulphite present in the solution may cause severe hypersensitivity reactions and bronchospasm.
Effect on the gastrointestinal tract. As all NSAIDs, diclofenac may cause gastrointestinal bleeding (vomiting blood, melena), ulcers or perforations (including fatal) at any time during treatment, with or without symptoms, and regardless of the history of gastrointestinal lesions. These complications can have more serious consequences in the elderly age. In the development of bleeding or ulcers of the gastrointestinal tract the product administration should be discontinued. Close medical supervision is necessary when prescribing diclofenac for patients with symptoms of dysfunction of the gastrointestinal tract or the presence of gastric or intestinal ulcers, history of gastrointestinal bleeding or perforation. The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses of diclofenac, as well as in patients with the history of bleeding or perforation.
Increase in the frequency of adverse reactions to NSAIDs was observed in elderly persons, especially of gastrointestinal bleeding and perforation which can be fatal. In order to reduce the risk of gastrointestinal toxicity in patients, especially with the history of bleeding or perforation, as well as in the elderly age, treatment should be started and maintained with the lowest effective dose of the product.
The use of combination therapy with protective agents should be considered in order to reduce the risk of gastrointestinal toxicity (e.g. with misoprostol or proton pump inhibitors), especially in patients requiring concomitant administration of drug products containing low doses of acetylsalicylic acid (ASA/aspirin) or drug products that increase the risk of gastrointestinal tract injury. Patients with the history of gastrointestinal toxicity manifestations, especially elderly persons, should report any unusual abdominal symptoms.
Diclofenac should be used cautiously in patients receiving concomitant products that increase the risk of ulceration or bleeding: systemic corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors (SSRIs) or antiplatelet drugs (acetylsalicylic acid). Close medical supervision and cautiousness are required when prescribing diclofenac for patients with nonspecific ulcerative colitis or Crohn's disease because of the possible development of exacerbation.
Patients with hepatic impairment. When prescribing the product for patients with hepatic diseases deterioration of hepatic function is possible. Development of hepatitis is possible in patients on the background of diclofenac administration without prodromal symptoms. Cautiousness is required when using diclofenac in patients with hepatic porphyria, since the product administration may provoke the attack. During the therapy with diclofenac hepatic enzymes activity may increase. Administration of diclofenac should be discontinued immediately if the increased activity of hepatic enzymes persist or increases.
Patients with renal impairment. The cases of fluid retention and edema occurrence have been registered in patients on the background of NSAIDs administration, including diclofenac. Special cautiousness is required when prescribing diclofenac for patients with impaired cardiac and renal function, hypertension, in elderly patients, in patients receiving concomitant treatment with diuretics or drug products affecting renal function, as well as in patients with significant depletion of extracellular fluid volume regardless of the reason (for example, before or after massive surgery). Monitoring of renal function is recommended as a precautionary measure when using diclofenac. Discontinuation of the therapy usually leads to the restoration of the function to the initial level.
Effect on skin. When using NSAIDs the development of serious adverse skin reactions was rarely observed (including fatal): exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. The highest risk of these reactions was registered in the beginning of the therapy course during the first month of treatment. Diclofenac administration should be discontinued at the first occurrence of skin rash, mucosal lesions or any other signs of hypersensitivity.
Patients with SLE and connective tissue diseases. The increased risk of aseptic meningitis occurrence was registered in patients with systemic lupus erythematosus (SLE) and connective tissue diseases.
Effect on cardiovascular system. State of patients with hypertension and/or mild to moderate chronic cardiac insufficiency requires monitoring due to possible water retention and the appearance of edemas.
Due to the possible increased risk of cardiovascular events during long-term use or at high doses of the product, diclofenac should be prescribed for patients in the lowest effective dose and for the shortest time necessary to reduce the severity of symptoms. Periodical reassessment of the need for relief of symptoms and response to treatment should be conducted. Clinical studies and epidemiological data suggest a possible slight increase in the risk of arterial thrombosis (e.g., myocardial infarction or stroke) when using diclofenac, particularly at high doses (150 mg per day) and during long-term treatment.
In patients with uncontrolled arterial hypertension, chronic cardiac insufficiency, the prescription of diclofenac is possible only after careful evaluation of the benefit/risk ratio. Such evaluation should also be carried out prior to treatment in patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking).
Effect on hemic system. Blood monitoring is recommended during long-term treatment with diclofenac, as with other NSAIDs. Diclofenac can reversibly inhibit platelet aggregation. Patients with hemostasis disorders, hemorrhagic diathesis or hematological disorders should be carefully monitored.
Patients with bronchial asthma. In patients with bronchial asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (including nasal polyps), chronic obstructive pulmonary diseases or chronic respiratory tract infections (especially with allergic rhinitis-like symptoms) reactions to NSAIDs, such as asthma attack (so-called intolerance to analgesics/“aspirin” asthma), angioedema or urticaria are more frequent than in other patients. The product should be used with special cautiousness in such patients, upon availability to provide emergency assistance. This statement is also applicable to patients that are allergic to other substances. As other products that inhibit cyclooxygenase activity, sodium diclofenac and other NSAIDs may cause bronchoconstriction during administering to patients with the history of bronchial asthma.
Effect on fertility in women. The use of diclofenac may impair fertility in women and is not recommended for women planning pregnancy. Diclofenac administration should be discontinued in women experiencing difficulties with conception and with infertility.
Use during pregnancy. Suppression of prostaglandin synthesis may adversely affect the course of pregnancy and fetal development. Data of epidemiological studies suggest increased risk of miscarriage and/or development of cardiac defects and gastroschisis after administration of prostaglandin synthesis inhibitors in early pregnancy. It is believed that the risk increases with the dose and duration of therapy increasing. It has been demonstrated that administration of prostaglandin synthesis inhibitors in animals leads to disruption of embryo implantation. Additionally, in animals treated with prostaglandin synthesis inhibitor in the period of organogenesis, the frequency of occurrence of various malformations, including developmental disorders of the cardiovascular system, increased. The use of diclofenac in pregnant women was not studied. When using prostaglandin synthesis inhibitors during the third trimester of pregnancy the fetus may have:
- premature closure of the ductus arteriosus and pulmonary hypertension;
- renal dysfunction, which progression develops in renal failure with oligohydramnios.
The mother and the fetus/neonate may experience prolonged bleeding; anti-aggregation effect may occur even after administration of very low doses of diclofenac. When administering diclofenac in late pregnancy, the weakness of labor and increase in duration of labor may develop.
Lactation period. As other NSAIDs, diclofenac is excreted in breast milk in small quantities. Diclofenac is contraindicated during lactation period.
Effect on fertility. As other NSAIDs, diclofenac may affect fertility in women. It is not recommended for women planning pregnancy. Women experiencing difficulties with conception and with infertility should discontinue diclofenac administration.
Effect on ability to drive vehicles and use potentially dangerous machines. During treatment period a patient should refrain from driving vehicles and other potentially dangerous activities that require high concentration and speed of psychomotor reactions.
Interaction with other drug products
Lithium. At simultaneous administration with lithium diclofenac may increase lithium concentration in plasma that requires regular monitoring of blood level of the latter.
Digoxin. At simultaneous administration with digoxin diclofenac may increase digoxin concentration in plasma that requires regular monitoring of blood level of the latter.
Diuretics and antihypertensive agents. Simultaneous administration of diclofenac with diuretics and antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme inhibitors (ACE)) may reduce the antihypertensive effect by inhibiting vasodilating prostaglandins synthesis. In this regard this combination should be prescribed with caution, and control of arterial pressure is required, especially in elderly patients. It is required to control the adequacy of hydration and periodically monitor renal function after the start of combination therapy, particularly when administering diuretics and ACE inhibitors due to increased risk of nephrotoxicity.
Drug products which may cause hyperkalemia. Simultaneous treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased level of potassium in blood, which is necessary to control often.
Anticoagulants and antiplatelet agents. Simultaneous administration may lead to increased risk of bleeding. Despite the lack of data of clinical studies confirming the influence of diclofenac on the action of anticoagulants, there are occasional reports of increased risk of bleeding in patients administering diclofenac and anticoagulants simultaneously. At simultaneous prescription careful control of hemostasis is required. As other NSAIDs, diclofenac at a high dose may reversibly inhibit platelet aggregation.
Other NSAIDs, including selective cyclooxygenase-2 inhibitors and corticosteroids. Co-injection of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulcer. Simultaneous prescription of two or more NSAIDs should be avoided.
Selective serotonin neuronal reuptake inhibitors (SSRIs). Simultaneous prescription of diclofenac and SSRIs may lead to increased risk of gastrointestinal bleeding.
Antidiabetic agents. Clinical studies have demonstrated that diclofenac may be used along with oral antidiabetic agents without influencing their clinical effect.However, individual cases are known of both hypoglycemia and hyperglycemia development, which requires dose adjustment of antidiabetic agents during treatment with diclofenac. Such conditions require monitoring of blood glucose levels, which is a precautionary measure during concomitant therapy.
Methotrexate. When injecting NSAIDs less than 24 hours before or after treatment with methotrexate caution is recommended since the increase in the concentration of methotrexate in blood and increase in its toxicity is possible.
Cyclosporine. As other NSAIDs, diclofenac may increase the nephrotoxicity of cyclosporine , due to the effect on prostaglandins secretion in the kidneys. Thus, diclofenac when using with cyclosporine should be administered in smaller doses than in patients that are not administering cyclosporine.
Tacrolimus. Increase of nephrotoxicity is possible at simultaneous administration with diclofenac.
Antibacterial quinolones. There are individual reports regarding seizures, which may be the result of concomitant administration of quinolones and NSAIDs.
Phenytoin. At simultaneous administration of diclofenac and phenytoin monitoring of phenytoin plasma level is required due to increased exposure of phenytoin.
Colestipol and cholestyramine. These products may increase or decrease he absorption of diclofenac. In his regard it is recommended to administer diclofenac not earlier then 4-6 hours after colestipol/cholestyramine administration.
Cardiac glycosides. Simultaneous prescription of cardiac glycosides and NSAIDs may lead to aggravation of heart failure, decreased glomerular filtration rate and increased concentrations of the cardiac glycoside in the plasma.
Mifepristone. NSAIDs, including diclofenac, should not be used during 8-12 days after mifepristone administration due to the possible decrease in mifepristone effect.
Potential ÑYÐ2Ñ9 inhibitors. Care should be taken when prescribing diclofenac with potential ÑYÐ2Ñ9 inhibitors (e.g., voriconazole), which may lead to the increase in peak plasma concentration and exposure of diclofenac due to inhibition of diclofenac metabolism.
Store in protected from light and moisture place at temperature below 25 °Ñ. Keep out of reach of children.
Do not use after expiration of a shelf life indicated on the package.
Ampoules 3 ml, 5 ampoules in a blister, 1 or 2 blisters together with leaflet are placed in a cardboard pack.
Republic of Belarus,
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