• Hypersensitivity to any component.

• Active gastric and duodenal ulcer.

• Progressive liver disease, renal failure.

• Live vaccines.

• Any infectious condition without specific indication.

• Certain viruses (such as hepatitis, herpes, varicella zoster (VZV)).

• Untreated or uncontrolled psychotic conditions.

• Pregnancy and lactation.

• Children under 15 years of age.

Special warnings and precautions:
Use the lowest effective dose. Despite the small amount of corticosteroids contained 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 reduced gradually and under medical supervision.

Rapid discontinuation of corticosteroid therapy may cause secondary adrenal insufficiency. To avoid this problem, the drug should be withdrawn gradually. In any case, a state of relative insufficiency may persist for several months after discontinuation of therapy; therefore, any stress occurring during this period requires resumption of corticosteroid therapy or dose increase.

Administration of live vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. When administering inactivated viral or bacterial vaccines, the expected serum antibody level may not be achieved.

Corticosteroids may mask certain signs of infection, and new infections may develop during their use. The body’s resistance may decrease and localization of infection may become impossible. Larger amounts of corticosteroids may affect the nitroblue tetrazolium (NBT) test for bacterial infection and cause false negative results.

A double-blind study in cerebral malaria showed that the use of corticosteroids was associated with prolonged coma and increased incidence of gastrointestinal bleeding and pneumonia.
Corticosteroids may activate latent amoebiasis; therefore, it is recommended to exclude latent or active amoebiasis before initiating corticosteroid therapy.
Prolonged use of corticosteroids may lead to the development of posterior subcapsular cataract, glaucoma with possible optic nerve damage, and may promote the development of viral and fungal infections.

Patients receiving immunosuppressants are more susceptible to infections than healthy individuals. Similarly, corticosteroids should be prescribed with great caution in cases of hyperinfection and disseminated disease caused by Strongyloides, often accompanied by severe enterocolitis and potentially life-threatening Gram-negative sepsis.

If corticosteroids are indicated in patients with latent tuberculosis or increased reactivity to tuberculin, strict monitoring is necessary due to possible reactivation of the disease. During corticosteroid therapy, such patients should receive chemoprophylaxis.
Literature sources indicate a clear association between corticosteroid use and rupture of the left ventricular free wall after myocardial infarction; therefore, corticosteroid therapy in such patients should be prescribed with caution.

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 should be used with caution in simple ocular herpes due to the risk of corneal perforation. The effect of corticosteroids is enhanced in patients with hypothyroidism or liver cirrhosis.
Psychological disturbances may occur during corticosteroid therapy, such as: euphoria, insomnia, frequent mood changes, depression or personality disorders, and even severe depression or psychosis. In addition, existing emotional instability or psychotic tendencies may be aggravated.

Steroids should be used with caution in nonspecific ulcerative colitis if there is a risk of perforation, abscess or other purulent infection, as well as in diverticulitis, recent intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, arterial hypertension, osteoporosis and myasthenia gravis.

Effect on the gastrointestinal tract: combined use of diclofenac and betamethasone in the treatment of arthritis may provide additional therapeutic benefit and allow reduction of glucocorticoid dose. However, concomitant use of diclofenac and glucocorticoids may increase the risk of peptic ulcer and gastrointestinal bleeding; therefore, special caution is required during prolonged 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 adverse events 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 ulcer or bleeding. Most spontaneous fatal gastrointestinal events occur in this population group.

Effect on the liver: during treatment with diclofenac, elevation of one or more liver enzymes may occur. These abnormalities may progress, remain unchanged, or be transient with continued therapy. Monitoring of GPT is recommended to prevent liver damage. During long-term diclofenac therapy, transaminase levels should be measured periodically, as severe hepatotoxicity may develop without characteristic symptoms. The physician should inform the patient about warning signs and symptoms of hepatotoxicity (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 diclofenac and glucocorticoids. Specific allergic manifestations include swelling of eyelids, lips, pharynx and larynx, urticaria, asthma and bronchospasm, sometimes with decreased blood pressure. In some patients, development of an asthmatic attack may be associated with allergy to aspirin or other nonsteroidal anti-inflammatory drugs. In such cases, use of the product is contraindicated.

Fluid retention and edema: edema and fluid retention have been reported during treatment with glucocorticoids and diclofenac; therefore, the drug should be prescribed 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 kidneys: rare cases of interstitial nephritis and papillary necrosis have been reported with diclofenac use. Another form of renal toxicity often associated with NSAIDs occurs in patients with prerenal conditions leading to decreased renal blood flow or blood volume, where renal prostaglandins play a supportive role in maintaining renal perfusion. In such patients, NSAIDs may cause dose-dependent reduction in prostaglandin formation and, secondarily, reduction in renal blood flow, which may result in acute renal failure. The risk of this reaction is highest in patients with impaired renal function, heart failure, impaired liver function, those taking diuretics, and in the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment clinical state and laboratory parameters. Since diclofenac metabolites are mainly excreted by the kidneys, strict monitoring of renal function is recommended in patients with impaired renal function.

Porphyria: use of diclofenac and anti-inflammatory steroids should be avoided in patients with hepatic porphyria. The postulated mechanism for triggering porphyria attacks is stimulation of the porphyrin precursor delta-aminolevulinic acid (ALA).
Laboratory tests: diclofenac inhibits platelet aggregation without affecting bleeding time, plasma fibrinogen levels, or factors V and VII-XII. However, like any drug that inhibits prostaglandin synthesis, diclofenac affects platelet function to some extent. Therefore, patients who may be affected by this action should be kept under strict supervision.

Renal insufficiency and hepatic impairment: studies conducted in patients with hepatic or renal insufficiency did not reveal differences in pharmacokinetic parameters compared to healthy subjects. However, strict monitoring of these patients is recommended.

Children: indications and dosage recommendations in children were established more than 15 years ago.
Elderly: elderly patients may be more sensitive to NSAIDs; therefore, use of the lowest effective dose is recommended. The risk of developing arterial hypertension is higher in elderly patients than in younger individuals. Women have a higher probability of developing glucocorticoid-induced osteoporosis in the postmenopausal period.

Interaction with other medicinal products:
Diclofenac: like other NSAIDs, diclofenac should not be used concomitantly with:

• Aspirin: as it alters the bioavailability of both drugs.

• Anticoagulants: as they may affect platelet function. Concomitant use with warfarin should be under strict supervision.

• Digoxin, methotrexate, cyclosporine: as diclofenac may 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 diabetic patients may have altered sensitivity to these drugs.

• Diuretics: as their activity may be suppressed. Concomitant use with potassium-sparing diuretics may be associated with increased serum potassium concentration.

• Quinolone antibacterial agents: cases of seizures have been reported with concomitant use.

• Antihypertensive agents: NSAIDs, including ACE inhibitors, may reduce the hypotensive effect.

Betamethasone: although it reduces mineralocorticoid effect, there is a risk of hypokalemia, which should be considered especially in the following situations:

• Concomitant use with diuretics (which lower blood potassium), laxatives or amphotericin B, or in case of vomiting or diarrhea.

• When the patient is simultaneously taking medications whose toxicity increases with hypokalemia, such as digoxin and neuromuscular blocking agents.

• If there is a risk of ventricular tachycardia (torsades de pointes), for example in patients with prolonged QT interval, or concomitant use with other drugs that cause ventricular tachycardia (amiodarone, quinidine, bepridil, intravenous erythromycin, halofantrine, pentamidine, sparfloxacin, sultopride, vincamine, bretylium, disopyramide, sotalol, etc.).
  Fluid retention may reduce the effect of antihypertensive drugs. It may reduce the effect of interferon alfa.
  Antacids may reduce steroid absorption, therefore dose adjustment may be required, especially in patients receiving low doses.
  Betamethasone, like other corticosteroids, should not be used concomitantly with:

• Barbiturates, carbamazepine, phenytoin, rifampicin or ephedrine: these drugs enhance corticosteroid metabolism, reducing their therapeutic effect.

• Amphotericin B: due to increased potassium depletion.

• Diuretics causing potassium loss (thiazides, furosemide): increase potassium deficiency and risk of 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 effect; therefore dose adjustment is required.

• Somatotropin: suppression of response to this hormone.

Pregnancy: the safety of this drug during pregnancy has not been established. Therefore, it should be used only if the potential benefit to the mother outweighs the potential risk to the fetus. Use of drugs known to inhibit prostaglandin synthesis and release (increasing cases 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 may inhibit growth, interfere with endogenous corticosteroid production or cause other undesirable effects. Mothers receiving pharmacological doses of corticosteroids should avoid breastfeeding.

Adverse reactions (frequency < 1%):

• Hematologic: 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.

• Sense organs: blurred vision, taste disturbance, reversible vision loss, scotoma.

• Digestive system: vomiting, jaundice, melena, stomatitis, candidiasis, dry mouth, mucosal candidiasis, bloody diarrhea, hepatitis, liver necrosis, appetite changes, pancreatitis with or without concomitant hepatitis, colitis.

• Respiratory system: epistaxis, 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, angioedema, Stevens-Johnson syndrome.

• General: asthenia, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions.

(Frequency > 1%):

• Digestive system: diarrhea, nausea, constipation, flatulence, liver enzyme disturbances, 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 adverse reactions have been reported with corticosteroid use:

• Hydro-electrolytic disturbances: sodium retention, potassium loss, hypokalemic alkalosis, fluid retention, congestive heart failure in susceptible patients, arterial hypertension.

• Musculoskeletal: muscle weakness, myopathy, loss of muscle mass, worsening of myasthenic symptoms in myasthenia gravis, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathological fractures of long bones, tendon rupture.

• Dermatologic: 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 angioedema.

• Neurologic: seizures, increased intracranial pressure with papilledema (pseudotumor cerebri), usually after treatment, dizziness, headache.

• Endocrine: menstrual irregularities, development of Cushingoid state, intrauterine growth retardation or growth retardation in childhood, secondary adrenocortical or pituitary unresponsiveness, 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 diabetic patients.

• Ophthalmologic: posterior subcapsular cataract, increased intraocular pressure, glaucoma, exophthalmos.

• Metabolic: negative nitrogen balance due to protein catabolism.

• Psychiatric: euphoria, mood swings, severe depression with overt psychotic manifestations, personality changes, increased irritability, insomnia.

• Others: 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 NSAID overdose, lethargy, drowsiness, nausea, vomiting and epigastric pain are usually observed; gastrointestinal bleeding may develop; very rarely, arterial hypertension, acute renal failure, respiratory depression and coma may occur.
Initial management of overdose: after thorough clinical examination of the patient, it is important to determine the time since last intake, the amount of poison taken and to exclude contraindications to certain procedures; then the specialist decides on the form of treatment: induced vomiting or gastric lavage, activated charcoal and saline laxative (45-60 minutes after activated charcoal), hemodialysis.

Pharmacological properties:
Pharmacodynamic properties
Diclofenac is a nonsteroidal anti-inflammatory drug with analgesic and anti-inflammatory properties, mainly in somatic structures such as muscles and joints, particularly in rheumatic and traumatic processes. Its analgesic and anti-inflammatory action is due to bradykinin antagonism and inhibition of prostaglandin biosynthesis.
Betamethasone penetrates the cell membrane where it binds to specific cytoplasmic receptors. The complex then enters the nucleus where it binds to another transcription factor and DNA, leading to gene induction and repression, ultimately resulting 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 central and peripheral nervous systems (antineuritic action).

Pharmacokinetic properties
Diclofenac: absorption begins immediately after administration. The amount absorbed is proportional to the dose taken. The pharmacokinetic profile does not change with repeated administration. No accumulation is observed if recommended intervals between doses are maintained. More than 99% binds to proteins, mainly albumin. Diclofenac penetrates synovial fluid. Maximum concentration in synovial fluid is observed 2-4 hours after reaching maximum plasma concentration. Two hours after reaching maximum plasma concentration, the concentration of active drug 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, producing inactive metabolites. The half-life is approximately 1-2 hours. About 60% of the dose is excreted in urine, less than 1% unchanged, and the remainder is excreted as metabolites in bile and feces.

Betamethasone: rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached 1-2 hours after administration. It binds strongly to plasma proteins, its half-life is 24 hours and it is excreted in urine. A significant portion of the drug is excreted unchanged, and the remainder as conjugated metabolites. Betamethasone crosses the placenta and is excreted in small amounts in breast milk.

Vitamin B12: when administered orally, it is rapidly absorbed in the small intestine. Absorption is associated with the presence of intrinsic factor. When administered parenterally, it is completely absorbed. It has high affinity for transcobalamin. It is metabolized in the liver and excreted in 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 conditions: Pharmaceutical product group II, dispensed by prescription form №3.

Manufacturer:
Kwality Pharmaceuticals Ltd
India, Amritsar, Nag Kalan, Majitha Road