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For intramuscular use Solution for injection Composition: 3ml solution contains: - Diclofenac Sodium BP 75mg - Hydroxocobalamin Acetate BP (equivalent to 10mg Hydroxocobalamin) - Betamethasone Sodium Phosphate BP (equivalent to 2mg Betamethasone). Excipients: - Monobasic Sodium phosphate BP (Anhydrous) - Disodium Hydrogen Phosphate BP (Anhydrous) - Disodium Edetate BP - Sodium Chloride BP - Benzyl Alcohol BP - Propylene Glycol USP - Water for Injection BP Indications: Symptomatic and short-term treatment when monotherapy is ineffective in acute inflammatory conditions associated with neuralgic, musculoskeletal contractures - sciatica. Dosage and administration: Adults Intramuscular injection: one ampoule once a day. If necessary, 1 ampoule can be administered twice a day. Instructions for use of Diclofenac, Hydroxocobalamin and Betamethasone: To avoid local reactions caused by the injection of concentrated solution, the following recommendations must be followed: - Instruments must be absolutely sterile. - The patient must be in a lying position. - Use a needle of sufficient length - 8/0 mm. - Press the plunger slowly. - The injection should be made in the upper outer quadrant of the buttock, perpendicular to the iliac crest. - Massage the injection site with circular movements to improve the distribution and absorption of Diclofenac, Hydroxocobalamin and Betamethasone. - If local pain develops in the leg area, stop the injection, remove the needle, and inject elsewhere. Contraindications: - Hypersensitivity to any of the components. - Active peptic ulcer of the stomach and duodenum. - Progressive liver disease, renal failure. - Live vaccines. - Any infectious condition for which there is no specific indication. - Certain viruses (such as hepatitis, herpes, varicella zoster (VZV)). - Untreated or unmanageable psychotic conditions. - Pregnancy and lactation. - Children under 15 years of age. Special precautions and safety measures: Use the lowest effective dose. Despite the small amount of corticosteroids in the preparation, doses should be adjusted according to the development of the condition and response to treatment, especially in cases of physical or emotional stress, surgery or trauma. The dose should be gradually reduced under medical supervision. Abrupt discontinuation of corticosteroid therapy can cause secondary adrenal insufficiency. To prevent this problem, the preparation should be withdrawn gradually. In any case, a state of relative insufficiency may persist for several months after discontinuation of therapy, so any stress occurring during this period requires renewal of corticosteroid therapy or dose increase. Administration of live vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. When inactivated viral or bacterial vaccines are administered, the expected level of antibodies in the serum may not be achieved. Corticosteroids can mask some signs of infection, and new infections may develop during their use. The body's resistance may be reduced, and it may be impossible to localize the infection. Higher doses of corticosteroids can affect the nitroblue tetrazolium (NBT) test for bacterial infection and cause false-negative results. A double-blind study of cerebral malaria showed that the use of corticosteroids was associated with prolonged coma and increased incidence of gastrointestinal bleeding and pneumonia. Corticosteroids can activate latent amebiasis, so it is recommended to rule out latent or active amebiasis before starting corticosteroid therapy. Prolonged use of corticosteroids can lead to the development of posterior subcapsular cataracts, glaucoma with possible damage to the optic nerve, and can contribute to the development of viral and fungal infections. Patients receiving immunosuppressants are more susceptible to infection than healthy individuals. Similarly, corticosteroids should be administered with great caution in hyperinfection and disseminated disease caused by Strongyloides, which is often accompanied by severe enterocolitis and potentially life-threatening sepsis (Gram- sepsis). If corticosteroid use is indicated in patients with latent tuberculosis or increased reactivity to tuberculin, they must be closely monitored, as reactivation of the disease may occur. During corticosteroid therapy, these patients should undergo chemoprophylaxis. Literature sources indicate a clear link between the use of corticosteroids and rupture of the free wall of the left ventricle after myocardial infarction; therefore, corticosteroid therapy should be administered with caution in these patients. Discontinuation of corticosteroids after prolonged therapy may cause: fever, myalgia, arthralgia, and weakness. This may occur even in the absence of signs of adrenal insufficiency. Corticosteroids are administered with caution in simple ocular herpes, as there is a risk of corneal perforation in such cases. The effect of corticosteroids is enhanced in patients with hypothyroidism or liver cirrhosis. Psychological disorders may develop during corticosteroid therapy, such as euphoria, insomnia, frequent mood swings, depression or personality disorder, and even severe depression or psychosis. In addition, existing emotional lability or psychotic tendencies may be exacerbated by corticosteroid intake. Steroids are administered with caution in non-specific ulcerative colitis if there is a risk of perforation, abscess or other purulent infection, as well as in diverticulitis, new intestinal anastomoses, active or latent peptic ulcer, renal failure, arterial hypertension, osteoporosis, and myasthenia gravis. Effect on the gastrointestinal tract: The combined use of diclofenac and betamethasone in the treatment of arthritis may provide additional therapeutic benefits and allow for a reduction in the dose of glucocorticoids. However, the risk of developing peptic ulcers and gastrointestinal bleeding may increase with the intake of diclofenac and glucocorticoids, so particular caution is required during long-term treatment, even in the absence of serious gastrointestinal symptoms. It is recommended to use the lowest effective dose to achieve a satisfactory therapeutic effect. Patients with a history of serious gastrointestinal side effects and other known risk factors for peptic ulcer disease (alcoholism, smoking) are at increased risk. Elderly or debilitated patients appear to have lower tolerance to ulcers or bleeding. Most spontaneous cases of fatal gastrointestinal disease occur in this population group. Effect on the liver: During treatment with diclofenac, an increase in the activity of one or more liver enzymes may be observed. These abnormalities may progress, remain unchanged, or be temporary with continued therapy. To prevent liver damage, monitoring of GPT is recommended. During long-term treatment with diclofenac, transaminase levels should be measured periodically, as severe hepatotoxicity may develop without characteristic symptoms. The physician should inform the patient about the signs and symptoms of hepatotoxicity that are a cause for concern (e.g., nausea, fatigue, lethargy, itching, jaundice, pain in the upper right quadrant, and "flu-like" symptoms). Allergic reactions: Allergic reactions, including anaphylaxis, have been reported with the use of diclofenac and glucocorticoids. Specific allergic manifestations include swelling of the eyelids, lips, pharynx, and larynx, urticaria, asthma, and bronchospasm, sometimes with a decrease in blood pressure. In some patients, the development of an asthma attack may be associated with allergy to aspirin or other non-steroidal anti-inflammatory drugs. In these cases, the use of the preparation is contraindicated. Fluid retention and edema: Edema and fluid retention have been reported during treatment with glucocorticoids and diclofenac, so the preparation should be administered with caution in patients with a history of decompensation, arterial hypertension, or other factors causing fluid retention. Salt restriction and potassium supplementation may be necessary. Any corticosteroid increases calcium excretion from the body. Effect on the kidney: Rare cases of interstitial nephritis and papillary necrosis have been reported with diclofenac intake. Another form of renal toxicity, often associated with the use of non-steroidal anti-inflammatory drugs, occurs in patients with prerenal conditions that lead to a decrease in renal blood flow or blood volume, where renal prostaglandins play a supportive role in maintaining renal perfusion. In these patients, the intake of non-steroidal anti-inflammatory drugs can lead to a dose-dependent decrease in prostaglandin production and, secondarily, a decrease in renal blood flow, which can lead to acute renal failure. The risk of developing this reaction is highest in patients with impaired renal function, heart failure, impaired liver function, those taking diuretics, as well as in the elderly. Discontinuation of therapy with non-steroidal anti-inflammatory drugs is usually followed by restoration of the clinical condition and laboratory parameters that existed before the start of treatment. Since diclofenac metabolites are mainly excreted by the kidneys, close monitoring of renal function is recommended in patients with impaired renal function. Porphyria: The intake of diclofenac and anti-inflammatory steroids should be avoided in patients with hepatic porphyria. The postulated mechanism for triggering porphyria attacks is the stimulation of the precursor of porphyrin, delta-aminolevulinic acid (ALA). Laboratory tests: Diclofenac slows platelet aggregation without affecting bleeding time, plasma fibrinogen levels, and factors V and VII-XII. However, diclofenac, like any drug that inhibits prostaglandin synthesis, affects platelet function to some extent. Therefore, patients who may be affected by this action should be under close observation. Renal failure and liver damage: Studies in patients with liver or renal failure have not revealed differences in pharmacokinetic parameters compared to healthy subjects. However, close monitoring of these patients is recommended. Children: Indications for use and dosage recommendations in children were developed more than 15 years ago. Elderly: Elderly patients may be more sensitive to non-steroidal anti-inflammatory drugs, so it is recommended to use the lowest effective dose. The risk of developing high blood pressure is higher in the elderly than in young people. Women have a high probability of developing osteoporosis caused by glucocorticoids in the postmenopausal period. Interactions with other drugs: Diclofenac: Diclofenac, like other non-steroidal anti-inflammatory drugs, should not be used with the following drugs: - Aspirin: as it alters the bioavailability of both drugs. - Anticoagulants: as they can affect platelet function. Co-administration with warfarin should be under strict supervision. - Digoxin, methotrexate, cyclosporine: as they can increase the toxicity of these drugs by affecting renal prostaglandins. - Lithium: as it reduces renal clearance and increases plasma lithium levels, increasing the risk of lithium toxicity. - Oral hypoglycemic agents, insulin: the physician should consider that patients with diabetes mellitus may have altered sensitivity to these drugs. - Diuretics: as their activity may be suppressed. Co-administration with potassium-sparing diuretics may be associated with an increase in serum potassium concentration. - Quinolone group antibacterial agents: seizures have been reported with the use of these drugs. - Antihypertensive drugs: Non-steroidal anti-inflammatory drugs, including ACE inhibitors, can reduce the hypotensive effect. Betamethasone: Although betamethasone reduces the mineralocorticoid effect, there is a risk of hypokalemia, which should be considered, especially in the following situations: - When taken with diuretics (lowering blood potassium levels), laxatives, or amphotericin B, or in cases of vomiting or diarrhea. - When the patient is simultaneously taking medications whose toxicity is increased by hypokalemia, such as digoxin and neuromuscular blocking agents. - If there is a risk of developing ventricular tachycardia (torsades de pointes), e.g., in patients with prolonged QT interval, co-administration with other drugs that cause ventricular tachycardia (amiodarone, quinidine, bepridil, intravenous erythromycin, halofantrine, pentamidine, sparfloxacin, sultopride, vincamine, betrilio, disopyramide, sotalol, etc.). Fluid retention may reduce the effect of antihypertensive drugs. It may reduce the effect of interferon alpha. Antacids may reduce steroid absorption, which may require dose adjustment, especially in patients receiving low doses. Betamethasone, like other corticosteroids, should not be used with the following drugs: - Barbiturates, carbamazepine, phenytoin, rifampicin or ephedrine: these drugs enhance corticosteroid metabolism, reducing their therapeutic effect. - Amphotericin B: due to increased potassium deficiency. - Diuretics that cause potassium level reduction (thiazides, furosemide) increase potassium deficiency and the risk of developing severe hypokalemia. - Cardiac glycosides: may increase the likelihood of arrhythmias or enhance digitalis toxicity associated with hypokalemia. Monitoring of serum electrolytes, especially potassium, is necessary. - Anticoagulants: may enhance or reduce the effect, so dose adjustment is necessary. - Somatotropin: suppression of response to this hormone. Pregnancy: The safety of using this preparation during pregnancy has not been established. Therefore, when using it, it is necessary that the potential benefit to the mother outweighs the potential risk to the fetus. The use of drugs known to inhibit prostaglandin synthesis and release (increasing the incidence of premature closure of the ductus arteriosus) is not recommended. Newborns whose mothers received corticosteroids during pregnancy should be monitored for signs of hypoadrenalism. Lactation: Corticosteroids are found in breast milk and can inhibit growth, interfere with endogenous corticosteroid production, or cause other adverse effects. Mothers taking pharmacological doses of corticosteroids should avoid breastfeeding. Side effects (incidence < 1%): - Hematological: low hemoglobin level, leukopenia, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, purpura, allergic purpura. - Cardiovascular: arterial hypertension, congestive heart failure. - Nervous system: dizziness, tremor, insomnia, depression, diplopia, anxiety, irritability, aseptic meningitis. - Sensory organs: blurred vision, taste disturbance, reversible vision loss, scotoma. - Digestive system: vomiting, jaundice, melena, stomatitis, candidiasis, dry mouth, candidiasis and mucosal candidiasis, bloody diarrhea, hepatitis, liver necrosis, appetite changes, pancreatitis with or without concomitant hepatitis, colitis. - Respiratory system: nosebleeds, asthma, laryngeal edema. - Genitourinary system: nephrotic syndrome, proteinuria, oliguria, interstitial nephritis, renal medullary necrosis, acute renal failure. - Skin and appendages: alopecia, urticaria, eczema, dermatitis, bullous rash, erythema multiforme, angioneurotic edema, Stevens-Johnson syndrome. - General: asthenia, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions. (Incidence > 1%): - Digestive system: diarrhea, nausea, constipation, flatulence, liver enzyme level abnormalities, peptic ulcer with or without bleeding and/or perforation, ulcer with or without bleeding. - Skin and appendages: rash, itching. - General: abdominal pain and cramps, headache, fluid retention, bloating. The following side effects have been reported with the use of corticosteroids: - Hydroelectrolytic disorders: sodium retention, potassium loss, hypokalemic alkalosis, fluid retention, congestive heart failure in susceptible patients, arterial hypertension. - Musculoskeletal system: muscle weakness, myopathy, loss of muscle mass, exacerbation of myasthenic symptoms in myasthenia gravis, osteoporosis, vertebral compression fractures, aseptic necrosis of the femoral and humeral heads, pathological fractures of long bones, tendon rupture. - Dermatological: delayed wound healing, skin atrophy and thinning, fragile skin, petechiae and ecchymoses, facial erythema, increased sweating, suppression of reactions to skin tests, allergic dermatitis, urticaria and angioneurotic edema. - Neurological: seizures, increased intracranial pressure with papilledema (pseudotumor cerebri), usually after treatment, dizziness, headache. - Endocrine: menstrual cycle disorders, development of Cushingoid state, intrauterine growth retardation or growth retardation in children, secondary unresponsiveness of the adrenal cortex or pituitary, especially in stressful situations such as trauma, surgery, or illness. Decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased need for insulin or oral hypoglycemic agents in patients with diabetes mellitus. - Ophthalmological: posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos. - Metabolic: negative nitrogen balance due to protein catabolism. - Mental: euphoria, mood swings, severe depression with overt psychotic manifestations, personality changes, increased irritability, insomnia. - Other: anaphylactoid or hypertensive reactions, as well as hypotension or shock-like reactions. Overdose: - Rare cases of toxicity or death due to glucocorticoid overdose have been reported. - In case of overdose of non-steroidal anti-inflammatory drugs, lethargy, drowsiness, nausea, vomiting, and epigastric pain are usually observed, gastrointestinal bleeding may occur, although very rarely, arterial hypertension, acute renal failure, respiratory depression, and coma. Initial treatment for overdose: After a thorough clinical examination of the patient, it is important to determine the time elapsed since the last intake, the amount of poison ingested, and to rule out contraindications for certain procedures, then the specialist will decide on the form of treatment: emesis or gastric lavage, activated charcoal and saline laxative (45-60 minutes after activated charcoal intake), hemodialysis. Pharmacological properties: Pharmacodynamic properties: Diclofenac is a non-steroidal anti-inflammatory drug with analgesic and anti-inflammatory properties, mainly for somatic structures such as muscles and joints, and especially in rheumatic and traumatic processes. This analgesic and anti-inflammatory effect is due to antagonism of bradykinin and inhibition of prostaglandin biosynthesis. Betamethasone reaches the cell membrane, where it binds to specific cytoplasmic receptors. The complex then enters the nucleus, where it binds to other transcription factors and DNA, leading to induction and suppression of genes, which ultimately results in its anti-inflammatory, immunosuppressive, and mineralocorticoid effects. Vitamin B12, in the form of cyanocobalamin or hydroxocobalamin, through its coenzymes, participates in many metabolic processes, including myelin synthesis, a lipoprotein essential for the integrity of the nervous and peripheral systems (antineuritic effect). Pharmacokinetic properties: Diclofenac: Absorption begins immediately after administration. The amount of absorbed preparation is proportional to the dose administered. The pharmacokinetic profile does not change with repeated administration. Cumulation is not observed when recommended intervals between doses are observed. More than 99% is bound to proteins, mainly albumin. Diclofenac penetrates into synovial fluid. Maximum concentration in synovial fluid is observed 2-4 hours after reaching maximum concentration in plasma. Two hours after reaching maximum concentration in blood plasma, the concentration of the active preparation in synovial fluid is higher than in plasma and remains higher for another 12 hours. It is metabolized in the liver, mainly by glucuronidation of the molecule, forming inactive metabolites. The half-life is approximately 1-2 hours. Approximately 60% of the dose is excreted in the urine, less than 1% is excreted unchanged, and the remaining part of the administered dose is excreted as metabolites through bile and feces. Betamethasone: Rapidly absorbed from the gastrointestinal tract. Maximum concentration in blood plasma is reached 1-2 hours after administration. It is strongly bound to plasma proteins, its half-life is 24 hours, and it is excreted in the urine. A significant portion of the preparation is excreted unchanged from the body, while the rest is excreted as conjugated metabolites. Betamethasone crosses the placenta and is excreted in small amounts in breast milk. Vitamin B12: When taken orally, it is rapidly absorbed in the small intestine. Absorption is dependent on the presence of intrinsic factor. When taken parenterally, it is completely absorbed. It has a high affinity for transcobalamin. It is metabolized in the liver and excreted through urine, bile, and secretions. Shelf life: 24 months Special storage conditions: Store at a temperature not exceeding 25°C, in the original packaging. Protect from light. Dispensing rule: Pharmaceutical product group II, dispensed with prescription form №3 Manufacturer: Kwality Pharmaceuticals Ltd India, Amritsar, Nag Kalan, Majitha Road