Flosteron (Suspension) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

H02AB01 (Betamethasone)

Active Substances

Betamethasone sodium phosphate (BAN)

Betamethasone (Rec.INN)

Dosage Form

Flosteron

Injection suspension 7 mg/1 ml: amp. 1 ml 1 or 5 pcs.

Dosage Form, Packaging, and Composition

Suspension for injection in the form of a colorless, slightly viscous liquid containing easily resuspendable white particles, free from foreign inclusions.

Excipients: disodium phosphate dihydrate – 2.5 mg, sodium chloride – 5 mg, disodium edetate – 0.1 mg, polysorbate 80 – 0.5 mg, benzyl alcohol – 9 mg, methylparahydroxybenzoate – 1.3 mg, propylparahydroxybenzoate – 0.2 mg, croscarmellose sodium – 5 mg, macrogol (polyethylene glycol) – 20 mg, hydrochloric acid solution 1M – q.s., water for injection – up to 1 ml.

1 ml – ampoules (1) – blister packs (1) – cardboard boxes.
1 ml – ampoules (5) – blister packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Injectable corticosteroids – combination of depot form and rapid-acting form

Pharmacotherapeutic Group

Glucocorticosteroid

Pharmacological Action

Betamethasone is a synthetic glucocorticosteroid that inhibits the release of interleukin-1, interleukin-2, and gamma-interferon from lymphocytes and macrophages. It has anti-inflammatory, anti-allergic, desensitizing, anti-shock, antitoxic, and immunosuppressive effects. It suppresses the release of ACTH and beta-lipotropin from the pituitary gland but does not reduce the level of circulating beta-endorphin. It inhibits the secretion of thyroid-stimulating hormone (TSH) and follicle-stimulating hormone (FSH).

It increases the excitability of the central nervous system, reduces the number of lymphocytes and eosinophils. It increases the number of red blood cells (by enhancing the production of erythropoietins).

It interacts with specific cytoplasmic receptors and forms a complex that penetrates the cell nucleus and stimulates the synthesis of messenger RNA; the latter induces the formation of proteins, including lipocortin, which mediate cellular effects. Lipocortin inhibits phospholipase A2, suppresses the release of arachidonic acid, and inhibits the synthesis of endoperoxides, prostaglandins (Pg), leukotrienes, which contribute to inflammation, allergy, etc.

Protein metabolism: reduces the amount of protein in plasma (due to globulins) with an increase in the albumin/globulin ratio, increases the synthesis of albumins in the liver and kidneys; enhances protein catabolism in muscle tissue.

Lipid metabolism: increases the synthesis of higher fatty acids and triglycerides (TG), redistributes fat (accumulation of fat mainly in the shoulder girdle, face, abdomen), leads to the development of hypercholesterolemia.

Carbohydrate metabolism: increases the absorption of carbohydrates from the gastrointestinal tract; increases the activity of glucose-6-phosphatase, leading to an increase in the release of glucose from the liver into the blood; increases the activity of phosphoenolpyruvate carboxykinase and the synthesis of aminotransferases, leading to the activation of gluconeogenesis.

Water-electrolyte metabolism: retains Na+ and water in the body, stimulates the excretion of K⁺ (mineralocorticosteroid activity), reduces the absorption of Ca²⁺ from the gastrointestinal tract, “leaches” Ca²⁺ from bones, increases the excretion of Ca²⁺ by the kidneys. The anti-inflammatory effect is associated with the inhibition of the release of inflammatory mediators by eosinophils; induction of lipocortin formation and reduction in the number of mast cells producing hyaluronic acid; with a decrease in capillary permeability; stabilization of cell membranes and organelle membranes (especially lysosomal).

The anti-allergic effect develops as a result of suppression of the synthesis and secretion of allergy mediators, inhibition of the release of histamine and other biologically active substances from sensitized mast cells and basophils, T- and B-lymphocytes, mast cells, reduction of effector cell sensitivity to allergy mediators, inhibition of antibody formation, and changes in the body’s immune response.

In COPD, the action is based mainly on the inhibition of inflammatory processes, suppression of the development or prevention of mucosal edema, inhibition of eosinophilic infiltration of the bronchial epithelial submucosal layer, deposition of circulating immune complexes in the bronchial mucosa, as well as on the inhibition of erosion and desquamation of the mucosa. It increases the sensitivity of β-adrenergic receptors of small and medium-caliber bronchi to endogenous catecholamines and exogenous sympathomimetics, reduces mucus viscosity by inhibiting or reducing its production.

The anti-shock and antitoxic action is associated with an increase in blood pressure (due to an increase in the concentration of circulating catecholamines and restoration of sensitivity to them of adrenergic receptors, as well as vasoconstriction), a decrease in vascular wall permeability, membrane-stabilizing properties, and activation of liver enzymes involved in the metabolism of endo- and xenobiotics. The immunosuppressive effect is due to the inhibition of the release of cytokines (interleukin-1, interleukin-2; interferon gamma) from lymphocytes and macrophages. It suppresses the synthesis and secretion of adrenocorticotropic hormone (ACTH) and, secondarily, the synthesis of endogenous glucocorticosteroids. It inhibits connective tissue reactions during the inflammatory process and reduces the possibility of scar tissue formation. Betamethasone sodium phosphate is a readily soluble compound that is well absorbed after parenteral administration into tissues and provides a rapid effect. Betamethasone dipropionate has slower absorption. The combination of these salts makes it possible to create a drug with both short-term (but rapid) and long-term action. Depending on the method of application (IV, IM, intra-articular, periarticular, intradermal), a general or local effect is achieved.

Pharmacokinetics

After intra-articular administration, C_max in plasma is reached after 30 minutes. In plasma, it binds to proteins. It easily passes through histohematic barriers, including the placental barrier. It is metabolized in the liver with the formation of predominantly inactive metabolites. It is excreted by the kidneys, a small amount – with bile, partially – with breast milk.

Indications

Local treatment

• Intra-articular and periarticular administration for inflammatory rheumatic diseases (rheumatoid arthritis, seronegative spondyloarthritis, arthritis in systemic connective tissue diseases), for post-traumatic arthritis, for psoriatic arthritis with multiple joint involvement and tenosynovitis, for crystalline arthritis;
• Intra-articular administration for degenerative rheumatic diseases, especially in the presence of synovitis (not used for hip joint arthrosis);
• Inflammatory lesions of periarticular tissues (bursitis, tendinitis, tenosynovitis, epicondylitis, plantar fasciitis);
• Injection into the lesion site for the treatment of skin diseases in rare cases (if there is no response to other methods of local therapy): sclerosing folliculitis, keloids, granuloma annulare, skin sarcoidosis, diabetic lipodystrophy (liponecrosis), psoriasis, alopecia areata, lichen planus, neurodermatitis, nummular eczema, discoid lupus erythematosus.

Systemic treatment

• The systemic effect of Flosteron is used in some severe allergic diseases: allergic rhinitis, status asthmaticus, angioedema, allergic reactions to drugs and sera, insect bites.

ICD codes

Dosage Regimen

Route of administration – parenteral (intra-articular, periarticular, intradermal injection, injection into the area of affected tissues and, in exceptional situations, IM injection).

The dose for adults and children should be determined individually depending on the size of the joint, severity, nature of the disease, and the patient’s response.

Intra-articular and periarticular administration

• Very large joints (hip) – 1-2 ml;
• Large joints (knee, shoulder, ankle) – 1 ml;
• Medium-sized joints (elbow, wrist) – 0.5-1 ml;
• Small joints (sternoclavicular, metacarpophalangeal, interphalangeal) – 0.25-0.5 ml. For acute gouty arthritis, from 0.5 to 1 ml is used.

Injections into large joints – no more than 3-4 times/year in one joint. Injection into the lesion site (intradermally, but not subcutaneously)

A single dose should not exceed 0.2 ml/cm², and the total weekly dose administered to all affected areas should not be more than 1 ml/week.

Local infiltration

• Bursitis – 0.25-1 ml (in the acute stage up to 2 ml),
• Tenosynovitis, tendinitis – 0.5 ml,
• Fibrositis – 0.5-1 ml.

The drug is repeated every 1-2 weeks.

If necessary, the drug can be mixed in one syringe with a local anesthetic.

Systemic administration for severe allergic diseases.

Only a single dose from 1 to 2 ml can be used (IM, but not IV)

The drug should be injected deep into the muscle in the gluteal region.

Children aged 3 to 5 years initial dose – 2 mg, which corresponds to 0.3 ml of the drug, 6-12 years – 4 mg, which corresponds to 0.5-0.6 ml of the drug.

Adverse Reactions

The frequency and severity of side effects depend on the duration of use, the size of the dose used, and the possibility of observing the circadian rhythm of administration.

From the endocrine system decreased glucose tolerance, steroid diabetes mellitus or manifestation of latent diabetes mellitus, suppression of adrenal function, Itsenko-Cushing’s syndrome (moon face, pituitary-type obesity, “buffalo hump”, hirsutism, increased blood pressure, dysmenorrhea, amenorrhea, muscle weakness, striae), delayed sexual development in children.

From the digestive system nausea, vomiting, pancreatitis, erosive esophagitis, steroid ulcer of the duodenum, bleeding and perforation of the gastrointestinal tract (black stool, vomiting “coffee grounds”), increased or decreased appetite, flatulence, hiccups, increased activity of hepatic transaminases and alkaline phosphatase, oropharyngeal candidiasis, abdominal pain,

From the cardiovascular system arrhythmias, bradycardia (up to cardiac arrest); development (in predisposed patients) or increased severity of heart failure, ECG changes characteristic of hypokalemia, increased blood pressure. In patients with acute and subacute myocardial infarction – spread of the necrosis focus, slowing of scar tissue formation, which can lead to rupture of the heart muscle (with systemic use of the drug), hypercoagulation, venous thrombosis.

From the central and peripheral nervous system manic-depressive psychosis, depression, disorientation, euphoria, hallucinations, paranoia, nervousness or anxiety, insomnia, dizziness, pseudotumor cerebri, headache, increased intracranial pressure, convulsions.

From the sensory organs sudden loss of vision (possibly due to deposition of drug crystals in the eye chambers), posterior subcapsular cataract, increased intraocular pressure with possible damage to the optic nerve, tendency to develop secondary bacterial, fungal or viral eye infections, trophic changes in the cornea, exophthalmos, diplopia.

From metabolism hypocalcemia, weight gain, negative nitrogen balance. Due to mineralocorticoid activity – fluid and sodium retention (peripheral edema), hypernatremia, hypokalemic syndrome (hypokalemia, arrhythmia, myalgia or muscle spasm, unusual weakness and fatigue).

From the musculoskeletal system slowing of growth and ossification processes in children (premature closure of epiphyseal growth zones), osteoporosis (very rarely pathological bone fractures, aseptic necrosis of the humeral and femoral head), muscle tendon rupture, steroid myopathy, decrease in muscle mass (atrophy), weakness of proximal muscles, especially in the arms and legs.

From the skin and mucous membranes petechiae, ecchymoses, hyper- or hypopigmentation, tendency to develop pyoderma and candidiasis, delayed wound healing, skin atrophy, thinning of the skin, steroid acne, striae.

Allergic reactions generalized reactions (skin rash, itching, anaphylactic shock), local allergic reactions, bronchospasm (in patients with bronchial asthma due to the content of metabisulfites), eosinophilia.

Other back pain, development of opportunistic infections (the appearance of this side effect is facilitated by concomitantly used immunosuppressants and vaccination), leukocyturia, leukocytosis, “withdrawal” syndrome after abrupt discontinuation of the drug.

Local burning, numbness, pain, tingling at the injection site, infections at the injection site, necrosis of surrounding tissues, scar formation at the injection site, atrophy of the skin and subcutaneous tissue with IM injection (especially dangerous injection into the deltoid muscle).

Contraindications

• Peptic ulcer of the stomach or duodenum, recently created intestinal anastomosis, diverticulitis;
• Osteoporosis;
• Tuberculosis;
• Glaucoma;
• Diabetes mellitus;
• Thrombophlebitis;
• Acute viral, bacterial, fungal systemic infections (in cases where appropriate therapy is not carried out);
• Itsenko-Cushing’s syndrome;
• Conditions after surgical operations and severe injuries;
• Post-vaccination period (8 weeks before and within 2 weeks after vaccination);
• Idiopathic thrombocytopenic purpura (IM administration);
• Infectious (septic) inflammatory process in the joint and periarticular infections (including in the anamnesis);
• Absence of signs of inflammation in the joint (so-called “dry” joint, for example, in osteoarthritis without synovitis);
• Prior arthroplasty;
• Transarticular bone fracture;
• Severe bone destruction and joint deformity (sharp narrowing of the joint space, ankylosis);
• Joint instability as an outcome of arthritis;
• Injection into the area of the Achilles tendon;
• Aseptic necrosis of the bone epiphyses forming the joint;
• Pathological bleeding (endogenous or caused by the use of anticoagulants);
• Lactation period;
• Flosteron contains benzyl alcohol, therefore the drug is contraindicated in newborns and children under 3 years of age;
• Hypersensitivity to betamethasone or any other ingredient of the drug.

With caution chronic renal failure, liver cirrhosis or chronic hepatitis, hypothyroidism, hyperthyroidism, esophagitis, gastritis, nonspecific ulcerative colitis, psychosis or psychoneurosis, immunodeficiency conditions (including AIDS or HIV infection), diseases of the cardiovascular system, including arterial hypertension, heart failure, recently suffered myocardial infarction, thromboembolism, patients who have not previously had chickenpox, hyperlipidemia, nephrourolithiasis, hypoalbuminemia and conditions predisposing to its occurrence (nephrotic syndrome), myasthenia gravis, epilepsy, obesity (III-IV degree), poliomyelitis (except for the form of bulbar encephalitis), bronchial asthma or allergy in the anamnesis, childhood and old age, pregnancy.

Use in Pregnancy and Lactation

Use only when the potential benefit of their use for the mother outweighs the potential risk of therapy for the fetus. During pregnancy, the use of the smallest doses of glucocorticosteroids that provide control of a particular disease is usually recommended. Children born to mothers who received glucocorticosteroids during pregnancy should be carefully examined to identify possible signs of adrenal insufficiency. Glucocorticosteroids cross the placental barrier and can reach high concentrations in the fetal body.

Glucocorticosteroids pass into breast milk in small amounts. Therefore, breastfeeding during therapy with glucocorticosteroid drugs is not recommended.

Use in Hepatic Impairment

With caution.

Use in Renal Impairment

With caution chronic renal failure.

Pediatric Use

With caution.

Flosteron contains benzyl alcohol, therefore the drug is contraindicated in newborns and children under 3 years of age.

Geriatric Use

With caution.

Special Precautions

Flosteron suspension must not be administered intravenously.

Intra-articular and periarticular administration should be performed by a specially trained specialist.

When using the drug locally, in all cases it is necessary to assess its compatibility with simultaneously administered local anesthetics. Mixing with an equal volume of local anesthetic solutions (1% procaine hydrochloride solution or 1% lidocaine hydrochloride solution) in a syringe is allowed, but not in an ampoule.

It must not be used for the treatment of hyaline membrane disease of newborns, injected into infected areas and intervertebral spaces.

With local (intra-articular) administration of glucocorticosteroids, both local and systemic effects are possible.

Before the start and during steroid therapy, it is necessary to monitor the complete blood count, glycemia and glucosuria, and the content of electrolytes in the blood plasma.

An appropriate examination of the synovial fluid in each joint is necessary to exclude a septic process. A significant increase in pain, accompanied by local swelling, further limitation of joint mobility, fever and malaise, suggests septic arthritis. If the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be carried out. During therapy during intercurrent infections, septic conditions, tuberculosis, antibiotic treatment is carried out simultaneously.

It should not be injected into “unstable” joints, into the area of the Achilles tendon due to the risk of rupture of this tendon.

Vaccination with live virus vaccines is contraindicated during glucocorticosteroid therapy. Immunization with killed virus or bacterial vaccines against the background of glucocorticosteroid use does not provide the expected increase in the number of antibodies and does not give the expected protective effect. Therefore, such drugs should not be prescribed for 8 weeks before and within 2 weeks after vaccination.

In patients who have not had chickenpox and are receiving glucocorticosteroid treatment, the risk of contracting chickenpox or herpes infection increases upon accidental contact with infected individuals. In such cases, passive immunization is recommended.

Caution is necessary in patients after surgery and bone fractures, since glucocorticosteroids can slow down the healing of wounds and fractures.

The effect of glucocorticosteroids is enhanced in patients with liver cirrhosis or hypothyroidism.

When using Flosteron against the background of arterial hypertension, heart failure, diabetes mellitus, epilepsy, thromboembolism, myasthenia gravis, glaucoma, hypothyroidism and severe liver damage, the risk of hypokalemia increases.

The use of Flosteron may change the indicators of hypersensitivity tests.

In children during the growth period, glucocorticosteroids should be used only for absolute indications and under the especially careful supervision of the attending physician.

In patients with acute and subacute myocardial infarction, it is possible to spread the focus of necrosis, slow down the formation of scar tissue and, as a result, rupture of the heart muscle.

Metabisulfites in patients with bronchial asthma or with a history of allergy can cause allergic-type reactions, including anaphylaxis and bronchospasm.

0.6 mg of betamethasone is equivalent to 0.75 mg of dexamethasone, 4 mg of triamcinolone, 4 mg of methylprednisolone and 20 mg of hydrocortisone (according to AMA, 1994).

Effect on the ability to drive vehicles and mechanisms

During the treatment period, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms nausea, vomiting, sleep disorders, euphoria, agitation, depression. With long-term use in high doses – osteoporosis, fluid retention in the body, increased blood pressure, myopathy, Itsenko-Cushing syndrome, suppression of adrenal cortex function. Overdose effects may persist for several weeks.

Treatment in such cases, the dose must be reduced until the drug is gradually withdrawn and symptomatic treatment, maintenance of vital functions, correction of electrolyte balance, antacids, phenothiazines, lithium preparations should be carried out. For Itsenko-Cushing syndrome – aminoglutethimide. There is no specific antidote. Hemodialysis is not effective.

Drug Interactions

Combined use with NSAIDs and ethanol increases the risk of gastrointestinal bleeding and ulcer formation.

Increases the risk of hepatotoxic effects of paracetamol.

The effectiveness of betamethasone is reduced if it is administered simultaneously with rifampicin, carbamazepine, phenobarbital, phenytoin (diphenylhydantoin), primidone, ephedrine and aminoglutethimide.

Increase the risk: antipsychotic drugs, immunosuppressants (increased likelihood of infections, as well as lymphomas and other lymphoproliferative diseases), carbutamide, azathioprine (cataract), M-cholinoblockers, antihistamines, tricyclic antidepressants, nitrates (increased intraocular pressure), digitalis glycosides (arrhythmias associated with hypokalemia).

Glucocorticosteroids reduce the therapeutic effect of antidiabetic agents, antihypertensive agents, anticoagulants (coumarin and indandione derivatives) and natriuretics.

Reduces the effectiveness of anticoagulants (including heparin, streptokinase and urokinase), albendazole and kaliuretics.

With simultaneous use of glucocorticosteroids in high doses and beta₂-adrenomimetics, the risk of hypokalemia increases.

Glucocorticosteroids increase the renal clearance of salicylates, which is why it is sometimes difficult to achieve a therapeutic concentration of salicylates in the blood serum against their background.

When taken simultaneously with androgens, estrogens, steroid anabolics, oral contraceptives, the T_1/2 of glucocorticosteroids may lengthen, their effect may increase, and the frequency of side effects (hirsutism, acne) may increase.

Concomitant use of ritodrine and glucocorticosteroids is contraindicated, since such a combination may lead to the development of pulmonary edema.

When used simultaneously with live antiviral vaccines and against the background of other types of immunization, the risk of virus activation and the development of infections increases.

Reduces the concentration of praziquantel in the blood serum.

Amphotericin B and carbonic anhydrase inhibitors increase the risk of osteoporosis.

Increases the toxicity of asparaginase (its hypoglycemic effect and the risk of neuropathy and impaired erythropoiesis may be enhanced).

Reduces the metabolism of cyclosporine, increases its toxicity.

Increases (with long-term use) the content of folic acid. Increases the metabolism of isoniazid, mexiletine (especially in “fast acetylators”), which leads to a decrease in their plasma concentrations.

Mitotane and other inhibitors of adrenal cortex function may necessitate an increase in the doses of glucocorticosteroids.

Hypokalemia caused by glucocorticosteroids may increase the severity and duration of muscle blockade against the background of muscle relaxants.

Reduces the effect of somatotropin.

Increases the severity of the hyperglycemic effect of streptozocin.

Storage Conditions

Store the drug in a place protected from light, at a temperature not exceeding 25°C (77°F). Keep out of the reach of children.

Shelf Life

Shelf life – 3 years.

Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.