Flexomitril^® (Solution) Instructions for Use

Marketing Authorization Holder

Action Consulting Limited (Hong Kong)

Manufactured By

Dalkhimpharm, JSC (Russia)

ATC Code

M01AB (Acetic acid derivatives and related compounds)

Active Substances

Diclofenac (Rec.INN registered by WHO)

Betamethasone sodium phosphate (BAN adopted for use in the United Kingdom)

Hydroxocobalamin (Rec.INN registered by WHO)

Dosage Form

Flexomitril®

Solution for intramuscular administration 0.67 mg/ml+3.33 mg/ml+25 mg/ml

Dosage Form, Packaging, and Composition

Solution for intramuscular administration

3 ml – ampoules (10 pcs.) – cardboard packs – By prescription
3 ml – ampoules (5 pcs.) – cardboard packs – By prescription

Pharmacotherapeutic Group

Anti-inflammatory and antirheumatic agents; anti-inflammatory/antirheumatic agents in combination; other anti-inflammatory/antirheumatic agents in combination with other agents

Pharmacological Action

Combined medicinal product. The pharmacological properties of this combination are determined by the properties of its constituent components. It has a pronounced analgesic and anti-inflammatory effect.

Diclofenac is an NSAID, the main mechanism of action is inhibition of prostaglandin biosynthesis. In post-traumatic and postoperative inflammatory phenomena, diclofenac quickly relieves pain, reduces inflammatory edema and postoperative wound edema.

Betamethasone sodium phosphate has high glucocorticoid and insignificant mineralocorticoid activity; it has anti-inflammatory, anti-allergic and immunosuppressive effects, and also has a pronounced and diverse effect on various types of metabolism.

Hydroxocobalamin acts as a coenzyme in several metabolic functions, including lipid and carbohydrate metabolism and protein synthesis. It belongs to the group of water-soluble vitamins and is a metabolite of cyanocobalamin. Unlike cyanocobalamin, in the hydroxocobalamin molecule, the cobalt atom is bound not to a cyano- but to a hydroxy group. It is necessary for the process of hematopoiesis, the formation of epithelial cells, and the functioning of the nervous system (due to its effect on myelin synthesis). In the body, it is converted into the active coenzyme form faster than cyanocobalamin. It remains in the blood longer, as it binds more firmly to plasma proteins and is excreted more slowly in the urine.

Pharmacokinetics

Betamethasone, after intramuscular administration, is rapidly hydrolyzed and absorbed almost immediately from the injection site, which ensures a rapid onset of therapeutic action. Plasma protein binding is 62.5%. It is metabolized in the liver to form predominantly inactive metabolites. It is almost completely eliminated within one day after administration. It is excreted mainly by the kidneys.

After intramuscular administration, hydroxocobalamin is completely absorbed, with C_max in plasma reached approximately in 1 hour. In the systemic circulation, it binds to specific transport proteins, transcobalamins. Plasma protein binding is 99%. Hydroxocobalamin, bound to transcobalamin, quickly leaves the plasma and is distributed preferentially in the parenchymal cells of the liver. It penetrates the placental barrier and is excreted in breast milk. T_1/2 is 500 days. It is excreted with normal renal function – 7-10% by the kidneys, about 50% by the intestines; with reduced renal function – 0-7% by the kidneys, 70-100% by the intestines.

After intramuscular administration of 75 mg of diclofenac, its absorption begins slowly. C_max in plasma is reached in about 20 minutes and averages about 2.5 µg/ml. The amount of active substance absorbed is linearly dependent on the dose. The AUC after intramuscular administration of diclofenac is approximately 2 times greater than after its oral or rectal administration, since in the latter cases about half of the amount of diclofenac is metabolized during the “first pass” through the liver. With subsequent administrations, the pharmacokinetic parameters do not change. Provided that the recommended intervals between diclofenac administrations are observed, no accumulation is noted. Plasma protein binding is 99.7%, mainly with albumin (99.4%). The apparent V_d is 0.12-0.17 l/kg. Diclofenac penetrates into the synovial fluid, where its C_max is reached 2-4 hours later than in plasma. The apparent T_1/2 from the synovial fluid is 3-6 hours. 2 hours after reaching C_max in plasma, the concentration of diclofenac in the synovial fluid is higher than in plasma, and its values remain higher for a period of up to 12 hours. Diclofenac metabolism occurs partially by glucuronidation of the unchanged molecule, but predominantly through single and multiple hydroxylation and methoxylation, leading to the formation of several phenolic metabolites (3′-hydroxy-, 4′-hydroxy-, 5′-hydroxy-, 4′,5-dihydroxy- and 3′-hydroxy-4′-methoxydiclofenac), most of which are converted to glucuronic conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac. The isoenzyme CYP2C9 is involved in the metabolism of the drug. The total systemic plasma clearance of diclofenac is 263 ± 56 ml/min. The terminal T_1/2 is 1-2 hours. The T_1/2 of 4 metabolites, including two pharmacologically active ones, is also short and amounts to 1-3 hours. One metabolite, 3′-hydroxy-4′-methoxydiclofenac, has a longer T_1/2, but this metabolite is completely inactive. About 60% of the diclofenac dose is excreted by the kidneys in the form of glucuronic conjugates of the unchanged active substance, as well as in the form of metabolites, most of which are also glucuronic conjugates. Less than 1% of diclofenac is excreted unchanged. The remainder of diclofenac is excreted as metabolites in the bile. The concentration of diclofenac in plasma is linearly dependent on the applied dose.

Indications

Acute nonspecific low back pain (dorsalgia).

Dosage Regimen

Administer intramuscularly as a deep injection into the upper outer quadrant of the gluteal muscle.

Inject once daily. The recommended duration of treatment is 2 days.

The dose and frequency of administration must be determined individually by the physician based on the patient’s condition and response to therapy.

Do not exceed the prescribed duration of treatment. Re-evaluate the patient if symptoms persist beyond the treatment course.

Aspirate before injection to ensure the needle is not in a blood vessel.

Use strict aseptic technique during preparation and administration.

Do not mix with other medicinal products in the same syringe.

Discard any unused solution remaining in the ampoule.

Adverse Reactions

Infections and infestations very rarely – post-injection abscess; frequency unknown – increased susceptibility to infections and severity of their manifestation with suppression of clinical symptoms and signs.

Blood and lymphatic system disorders very rarely – thrombocytopenia, leukopenia, hemolytic anemia, aplastic anemia, agranulocytosis; frequency unknown – hypercoagulation.

Immune system disorders rarely – hypersensitivity, anaphylactic/anaphylactoid reactions, including decreased blood pressure and shock; very rarely – angioedema (including facial edema); frequency unknown – allergic reactions, anaphylactic shock.

Endocrine disorders frequency unknown – suppression of adrenal and pituitary function, secondary adrenal insufficiency (especially during stress in illness, trauma, surgery), Cushing’s syndrome, decreased glucose tolerance, “steroid” diabetes mellitus or manifestation of latent diabetes mellitus, increased need for insulin or oral hypoglycemic drugs.

Metabolism and nutrition disorders frequency unknown – negative nitrogen balance (due to protein catabolism), lipomatosis (including mediastinal and epidural lipomatosis, which can cause neurological complications), weight gain, increased appetite, hypernatremia, increased excretion of potassium ions, increased excretion of calcium ions, hypokalemic alkalosis, fluid retention in tissues, purine metabolism disorder.

Psychiatric disorders very rarely – disorientation, depression (with pronounced psychotic reactions), insomnia, nightmares, irritability, mental disorders; frequency unknown – euphoria, mood changes, personality disorders, increased irritability, mental agitation.

Nervous system disorders often – headache, dizziness; rarely – drowsiness; very rarely – sensitivity disorders, including paresthesia, memory impairment, tremor, convulsions, anxiety, acute cerebrovascular accidents, aseptic meningitis; frequency unknown – increased intracranial pressure with papilledema (more often after therapy), neuritis, neuropathy.

Eye disorders very rarely – visual disturbances (blurred vision), diplopia, blurred vision; frequency unknown: posterior subcapsular cataract, increased intraocular pressure, glaucoma, exophthalmos.

Ear and labyrinth disorders often – vertigo; very rarely – hearing impairment, tinnitus.

Cardiac disorders infrequently – myocardial infarction, heart failure, palpitations, chest pain; very rarely – increased blood pressure; frequency unknown – Kounis syndrome (allergic acute coronary syndrome), cardiac arrhythmias, bradycardia, tachycardia, cardialgia, myocardial rupture after a recent myocardial infarction, chronic heart failure (in predisposed patients), thromboembolic complications, vasculitis, decreased blood pressure.

Respiratory, thoracic and mediastinal disorders rarely – bronchial asthma (including shortness of breath); very rarely – pneumonitis.

Gastrointestinal disorders often – abdominal pain, nausea, vomiting, diarrhea, dyspepsia, flatulence, decreased appetite, hiccups; rarely – gastritis, gastrointestinal bleeding, vomiting blood, melena, diarrhea with blood; very rarely – stomatitis, glossitis, esophageal lesions, formation of diaphragm-like strictures in the intestine, colitis (nonspecific hemorrhagic colitis, ischemic colitis, exacerbation of ulcerative colitis or Crohn’s disease), constipation, pancreatitis, dysgeusia; frequency unknown – erosive and ulcerative lesions of the gastrointestinal tract (gastric and intestinal ulcers with or without bleeding, stenosis or perforation, with possible development of peritonitis), pancreatitis.

Hepatobiliary disorders often – increased plasma aminotransferase activity; rarely – hepatitis, jaundice, liver function disorders; very rarely – fulminant hepatitis, liver necrosis, liver failure; frequency unknown – hepatomegaly.

Skin and subcutaneous tissue disorders often – skin rash; rarely – urticaria; very rarely – bullous dermatitis, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, pruritus, alopecia, photosensitivity reactions, purpura, Henoch-Schönlein purpura; frequency unknown – impaired wound healing, atrophy and thinning of the skin, petechiae, ecchymoses, purpura, increased sweating, dermatitis, “steroid” acne, striae, tendency to develop pyoderma and candidiasis, decreased response during skin tests, thinning of scalp hair, allergic dermatitis, erythema.

Musculoskeletal and connective tissue disorders frequency unknown – muscle weakness, steroid myopathy, loss of muscle mass, increased myasthenic symptoms in severe pseudoparalytic myasthenia, osteoporosis, compression fracture of the spine, aseptic necrosis of the femoral or humeral head, pathological fractures of long bones, tendon ruptures.

Renal and urinary disorders very rarely – acute kidney injury (acute renal failure), hematuria, proteinuria, tubulointerstitial nephritis, nephrotic syndrome, papillary necrosis.

Reproductive system and breast disorders frequency unknown – menstrual cycle disorders, changes in sperm motility and count.

General disorders and administration site conditions often – pain, induration at the injection site; rarely – edema, necrosis at the injection site, hyper- or hypopigmentation, subcutaneous and skin atrophy, aseptic abscesses, facial flushing after injection, neurogenic arthropathy.

Contraindications

Hypersensitivity to the active substances; erosive and ulcerative lesions of the gastrointestinal tract (in the acute phase), gastrointestinal bleeding, inflammatory bowel diseases in the acute phase (ulcerative colitis, Crohn’s disease); severe hepatic failure; chronic renal failure (creatinine clearance less than 30 ml/min), acute glomerulonephritis; systemic mycoses; viral (including herpetic), bacterial, fungal, mycobacterial infections; simultaneous administration of the drug with live and attenuated vaccines; systemic osteoporosis; hyperkalemia; complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses, and intolerance to acetylsalicylic acid and NSAIDs (including in history); blood formation disorders, hemostasis disorders (including hemophilia), coagulation disorders, thrombocytopenic purpura; uncontrolled arterial hypertension, the period after coronary artery bypass surgery with an increased risk of arterial thrombosis and thromboembolism; chronic heart failure (functional class II-IV according to the NYHA classification), clinically confirmed coronary artery disease, diseases of the peripheral arteries and cerebral vessels; cerebral edema due to traumatic brain injury; polycythemia vera; erythrocytosis; pregnancy, breastfeeding period; children and adolescents under 18 years of age.

With caution

Parasitic and infectious diseases of viral, fungal or bacterial nature (current or recently suffered, including recent contact with a patient) – herpes simplex, herpes zoster (viremic phase), chickenpox; measles, amoebiasis, strongyloidiasis (established or suspected); active and latent tuberculosis; post-vaccination period (a period of 8 weeks before and 2 weeks after vaccination), lymphadenitis after BCG vaccination; immunodeficiency states (including AIDS or HIV infection); gastrointestinal diseases (gastric and duodenal ulcer, esophagitis, gastritis, acute or latent peptic ulcer, recently created intestinal anastomosis, ulcerative colitis with threat of perforation or abscess formation, diverticulitis, abscess or other purulent infections); cardiovascular diseases, including recently suffered myocardial infarction (in patients with acute and subacute myocardial infarction, spread of the necrosis focus, slowing of scar tissue formation and, as a result, rupture of the heart muscle is possible), decompensated chronic heart failure, arterial hypertension, hyperlipidemia; endocrine diseases – decreased glucose tolerance, diabetes mellitus, thyrotoxicosis, hypothyroidism, Cushing’s disease; severe chronic renal failure and/or severe hepatic failure, nephrourolithiasis, liver cirrhosis; hypoalbuminemia and conditions predisposing to its occurrence; systemic osteoporosis, myasthenia gravis, acute psychosis, obesity (III-IV degree), poliomyelitis (except for the form of bulbar encephalitis), open-angle and closed-angle glaucoma, eye diseases caused by Herpes simplex (due to the risk of corneal perforation); precautions are required in elderly patients due to increased sensitivity to corticosteroids, especially in postmenopausal women (high risk of osteoporosis); with convulsive syndrome; angina pectoris; benign and malignant neoplasms accompanied by megaloblastic anemia and vitamin B₁₂ deficiency; tendency to form blood clots.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: severe hepatic failure.

Use in Renal Impairment

Contraindications: severe hepatic failure; chronic renal failure (creatinine clearance less than 30 ml/min), acute glomerulonephritis.

Pediatric Use

Children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

When using this combination, the special instructions and precautions for each component should be taken into account.

Use in severe infectious diseases is permissible only against the background of specific antimicrobial therapy.

With systemic use of corticosteroids, visual disturbances may occur. If a patient has symptoms such as blurred vision or other visual disturbances, it is necessary to recommend that the patient consult an ophthalmologist to identify possible causes of visual disturbances, including cataracts, glaucoma, or rare diseases, for example, central serous chorioretinopathy (CSCR), which have been observed in a number of cases with systemic and local use of corticosteroids.

Patients participating in competitions under the control of the World Anti-Doping Agency (WADA) should familiarize themselves with the WADA rules before starting treatment with the drug, as taking the drug may affect the results of doping control.

The use of this combination may be associated with an increased risk of leakage of an anastomosis located in the gastrointestinal tract. When used after gastrointestinal surgery, careful medical supervision and caution are recommended.

Special caution should be exercised when using diclofenac in patients receiving drugs that increase the risk of gastrointestinal bleeding: systemic corticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including acetylsalicylic acid, clopidogrel) or SSRIs (including citalopram, fluoxetine, paroxetine, sertraline).

The anti-inflammatory effect of diclofenac may complicate the diagnosis of infectious processes.

Effect on ability to drive vehicles and mechanisms

Patients who experience visual disturbances, dizziness, drowsiness, vertigo or other disorders of the central nervous system while using the drug should not drive vehicles or operate machinery. Considering that this combination may cause dizziness, caution should be exercised when engaging in these activities.

Drug Interactions

With simultaneous administration of phenobarbital, rifampicin, phenytoin or ephedrine, acceleration of betamethasone metabolism with a decrease in its therapeutic activity is possible.

With simultaneous use of corticosteroids and estrogens, dose adjustment of betamethasone may be required (due to the risk of overdose).

With simultaneous use of corticosteroids and potassium-excreting diuretics, the likelihood of developing hypokalemia increases.

Concomitant use of corticosteroids (CS) and cardiac glycosides increases the risk of arrhythmia or digitalis intoxication (due to hypokalemia).

Betamethasone may enhance potassium excretion caused by amphotericin B.

When betamethasone and indirect anticoagulants are used concomitantly, changes in blood coagulation are possible, requiring adjustment of the anticoagulant dose.

Combined use of CS with NSAIDs or with ethanol and ethanol-containing drugs may increase the frequency or intensity of erosive and ulcerative lesions of the gastrointestinal tract (GI tract).

When used concomitantly, CS may reduce the plasma concentration of salicylates.

Concomitant administration of CS and somatropin may lead to slowed absorption of the latter (administration of betamethasone doses exceeding 0.3-0.45 mg/m²/day should be avoided).

CS can affect the nitroblue tetrazolium test for bacterial infection and cause a false-negative result.

Aminoglutethimide may cause enhancement or weakening of corticosteroid-induced suppression of adrenal cortex function.

Concomitant use of CS and ketoconazole or itraconazole may increase the systemic adverse reactions of CS.

CS may reduce the effects of cholinesterase inhibitors, which can lead to the development of severe muscle weakness in patients with myasthenia gravis. If possible, cholinesterase inhibitors should be discontinued at least 24 hours before starting CS therapy.

Concomitant use of CS and isoniazid may decrease the plasma concentration of isoniazid. The condition of patients taking isoniazid should be carefully monitored.

Concomitant use of cyclosporine and CS may lead to an increase in the systemic concentration of cyclosporine and enhancement of the effect of CS. There is a high risk of seizures.

Concomitant use of CS with macrolide antibiotics may lead to a significant decrease in the excretion of CS.

Concomitant use with cholestyramine may increase the excretion of CS.

When using betamethasone in patients with diabetes mellitus, adjustment of hypoglycemic therapy may be required.

The risk of developing allergic reactions increases with concomitant use with thiamine.

Aminoglycosides, salicylates, antiepileptic drugs, colchicine, potassium preparations, cimetidine, metformin, oral contraceptives, ranitidine, triamterene, methotrexate reduce the absorption of hydroxocobalamin from the GI tract.

Chloramphenicol reduces the hematopoietic response to hydroxocobalamin.

Hydroxocobalamin should not be combined with drugs that increase blood clotting.

Caution should be exercised when diclofenac is used concomitantly with inhibitors of the CYP2C9 isoenzyme (e.g., voriconazole) due to a possible increase in the serum concentration and exposure of diclofenac.

Diclofenac may increase lithium levels and the plasma concentration of digoxin. Monitoring of serum lithium levels and digoxin concentration is recommended.

When used concomitantly with diuretics and antihypertensive drugs (e.g., beta-blockers, ACE inhibitors), diclofenac may reduce their antihypertensive effect. Therefore, in patients, especially the elderly, with concomitant use of diclofenac and diuretics or antihypertensive agents, blood pressure should be measured regularly, and renal function and hydration status should be monitored (due to an increased risk of nephrotoxicity).

The effect of diclofenac on prostaglandin activity in the kidneys may enhance the nephrotoxicity of cyclosporine and tacrolimus.

Concomitant use of diclofenac with potassium-sparing diuretics, cyclosporine, tacrolimus, and trimethoprim may lead to an increase in plasma potassium levels (if such concomitant use is necessary, this parameter should be monitored frequently).

There are isolated reports of seizures in patients receiving quinolone derivatives and diclofenac concomitantly.

Diclofenac should be used with caution concomitantly with antiplatelet agents and anticoagulants due to the risk of bleeding.

Concomitant use of diclofenac with SSRIs increases the risk of gastrointestinal bleeding.

Concomitant use of diclofenac and hypoglycemic drugs is possible, with the efficacy of the latter remaining unchanged. However, there are isolated reports of both hypoglycemia and hyperglycemia in such cases, which necessitated a change in the dose of hypoglycemic drugs during the use of diclofenac. Therefore, during concomitant use of diclofenac and hypoglycemic drugs, blood glucose monitoring is recommended.

There are isolated reports of the development of metabolic acidosis with concomitant use of diclofenac and metformin, especially in patients with impaired renal function.

Caution should be exercised when using diclofenac less than 24 hours before or 24 hours after taking methotrexate, as in such cases the blood concentration of methotrexate may increase and its toxic effect may be enhanced.

When phenytoin and diclofenac are used concomitantly, the plasma concentration of phenytoin should be monitored due to a possible increase in its systemic exposure.

Caution should be exercised when using diclofenac concomitantly with inducers of the CYP2C9 isoenzyme (such as rifampicin), as this may lead to a significant decrease in the plasma concentration and exposure of diclofenac.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.