Diprometa, 7 mg/ml suspension 1 ml

Pharmacotherapeutic group: Glucocorticosteroid (GCS)

ATX code: H02AB01

Pharmacological properties

Pharmacodynamics

p> Betamethasone is a synthetic GCS with high glucocorticosteroid and minor mineralocorticoid activity. Betamethasone has anti-inflammatory, anti-allergic and immunosuppressive effects, and also has a pronounced and diverse effect on various types of metabolism.

It interacts with specific cytoplasmic receptors to form a complex which penetrates the cell nucleus and stimulates synthesis of matrix ribonucleic acid, the latter induces formation of proteins, including lipocortin, which mediate cellular effects. Lipokortin inhibits phospholipase A2, suppresses the release of arachidonic acid and inhibits the synthesis of endoperoxides, prostaglandins, leukotrienes that contribute to the processes of inflammation, allergy, etc. Protein metabolism: reduces the amount of protein in the blood plasma (at the expense of globulins) with increased albumin/globulin ratio, increases the synthesis of albumin in the liver and kidneys, increases protein catabolism in muscle tissue.

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

Carbohydrate metabolism: increases absorption of carbohydrates from the gastrointestinal tract (GIT), increases the activity of glucose-6-phosphatase, leading to increased glucose flow from the liver into the blood, increases the activity of phosphoenolpyruvate carboxylase and aminotransferase synthesis, leading to activation of gluconeogenesis.

Water-electrolyte metabolism: it retains sodium ions and water in the body, stimulates the excretion of potassium ions (mineralocorticoid activity), reduces absorption of calcium from the GI tract, “washes” calcium ions from the bones and increases their excretion by the kidneys.

The anti-inflammatory action is associated with inhibition of release of inflammatory mediators by eosinophils, induction of lipocortin formation and reduction of the number of mast cells producing hyaluronic acid, reduction of capillary permeability, stabilization of cell membranes and organelle membranes (especially lysosomal).

The anti-allergic effect results from suppression of synthesis and secretion of allergy mediators, inhibition of release of histamine and other bioactive substances from sensitized mast cells and basophils, inhibition of maturation and differentiation of T- and B-lymphocytes and mast cells, decrease of sensitivity of effector cells to allergy mediators, suppression of antibody formation, changes in immune response.

It increases sensitivity of beta-adrenoreceptors of small and medium caliber bronchi to endogenous catecholamines and exogenous sympathomimetics, decreases viscosity of bronchial mucosal secretion due to suppression or reduction of its production.

The immunosuppressive action is caused by inhibition of cytokine release (interleukin-1, interleukin-2, gamma-interferon) from lymphocytes and macrophages. It suppresses the synthesis and secretion of ACTH and secondary to the synthesis of endogenous GCS.

Inhibits secretion of thyroid hormone (TSH) and follicle stimulating hormone (FSH).

Suppresses the release of beta-lipotropin, but does not decrease circulating beta-endorphin.

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 the tissues and provides a rapid effect. Betamethasone dipropionate has slower absorption. Combining these betamethasone salts can create a drug with both short-term (but fast) and long-term action. Depending on the route of administration (intramuscular (I/M), intraarticular, periarticular, intradermal (I/D)) a general or local effect is achieved.

Pharmacokinetics

Betamethasone sodium phosphate is highly soluble in water and after intramuscular administration is rapidly hydrolyzed and almost immediately absorbed from the injection site, allowing rapid onset of therapeutic action. It is almost completely eliminated within one day after administration.

Betamethasone dipropionate is slowly absorbed from the depot, is metabolized gradually, which leads to the long-term action of the drug, and is eliminated within more than 10 days.

Betamethasone binds well to plasma proteins (62.5%). It is metabolized in the liver to form mostly inactive metabolites. It is excreted mainly by the kidneys.

Indications

The treatment of conditions and diseases in which GCS therapy achieves the required clinical effect (note that in some diseases GCS therapy is additional and does not replace standard therapy):

Active ingredient

Composition

1 ml (one pre-filled syringe) contains:

The active ingredients:

betamethasone dipropionate – 6.43 mg converted to betamethasone – 5.00 mg;

betamethasone sodium phosphate – 2.63 mg converted to betamethasone – 2.00 mg;

excipients: methyl parahydroxybenzoate, 1.30 mg; propyl parahydroxybenzoate, 0.20 mg; benzyl alcohol, 9.00 mg; macrogol-4000, 20.00 mg; sodium carmellose, 5.00 mg; sodium hydrophosphate dodecahydrate, 5.04 mg; edetate, 0.10 mg; sodium chloride, 5.00 mg; polysorbate 80, 0.625 mg; 1 M hydrochloric acid solution – to pH = 7.4 ± 0.1; water for injection – up to 1.00 ml (1.0127 g).

How to take, the dosage

Intramuscular, intraarticular, periarticular, intrabursal, intradermal, intratissue and intrafocal injections.

The small size of betamethasone dipropionate crystals allows the use of small-diameter needles (26 gauge) for intradermal injection and administration directly into the lesion.

DON’T TAKE INTRODUCTION! NOT SUBJECT!

Strict adherence to asepsis is mandatory when using Dipromet.

The syringe should be shaken before use.

The dosing regimen and route of administration are determined individually depending on the indication, the severity of the disease, and the patient’s response.

In systemic therapy, the starting dose of Dipromet is 1-2 ml in most cases. The administration is repeated as needed, depending on the patient’s condition.

Intramuscular (I/m) injection of the drug should be made deep into the muscle, selecting large muscles and avoiding contact with other tissues (to prevent atrophic tissue changes).

The drug is administered in m/m:

If satisfactory clinical response is not achieved after a sufficient time, Diprometa should be stopped and other therapy prescribed.

In local administration, concomitant use of a local anesthetic is only rarely necessary. If it is desirable, the preparation of Dipromet may be mixed in a syringe with 1% or 2% solution of procaine or lidocaine, not containing methylparaben, propylparaben, phenol and other similar substances. The syringe with the Dipromet preparation is drawn from the ampoule with the local anesthetic and shaken for a short period of time.

In acute bursitis (subdeltoid, scapula, elbow and patellofemoral), injection of 1-2 ml of the drug into the synovial pouch relieves pain and restores joint mobility within a few hours. After relief of exacerbation in chronic bursitis, smaller doses of the drug are used.

In acute tenosynovitis, tendinitis and peritendinitis one injection of the drug Dipromet improves the patient’s condition; in chronic ones the injection is repeated depending on the patient’s reaction. Direct injection of the drug into the tendon should be avoided.

Intra-articular injection of Diprometa in a dose of 0.5-2 ml relieves pain, reduces restriction of joint mobility in rheumatoid arthritis and osteoarthritis within 2-4 hours after injection. The duration of the therapeutic effect varies considerably and may be 4 weeks or more.

The recommended doses of the drug when injected into large joints (e.g., knee or hip) are 1 to 2 ml; in medium (e.g., elbow) 0.5-1 ml; in small (e.g., hand joints) 0.25-0.5 ml.

In dermatological diseases: Dipromet drug should be injected intradermally directly into the lesion. If the drug is not injected directly into the affected tissue, a mild systemic effect of the drug may develop in response to therapy. Diprometa is administered intradermally (not subcutaneously) at a rate of 0.2 ml/cm2. The total amount of Dipromet preparations administered at all sites during each week shall not exceed 1 ml. It is recommended to use a tuberculin syringe with a 26-gauge needle for injection into the lesion site.

Recommended single doses (at 1 week interval between injections): Bursitis beneath the ossicles – 0.25 – 0.5 ml (generally effective
2 injections); bursitis beneath the heel spur – 0.5 ml; bursitis with limited mobility of the big toe – 0.5 ml; synovial cyst – 0.25 – 0.5 ml; tenosynovitis – 0.5 ml; acute gouty arthritis – 0.5 – 1 ml.

A tuberculin syringe with a 25-gauge needle is suitable for most injections.

After therapeutic effect is achieved, the maintenance dose of the drug is adjusted by gradually reducing the dose administered at appropriate intervals. Reduction continues until the minimum effective dose is reached.

If a stressful situation occurs (or threatens to occur) that is not related to an existing disease, it may be necessary to increase the dose of Dipromet.

Cancellation of the drug after long-term therapy is done by gradually reducing the dose.

The patient’s condition should be monitored for at least one year after the end of long-term therapy or high-dose use of Dipromet.

Interaction

GKS (including betamethasone) are metabolized by the CYP3A4 enzyme.

Simultaneous use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, or preparations containing cobicistat) may lead to increased GCS exposure and, consequently, to an increased risk of systemic HP. Co-administration of betamethasone and strong CYP3A4 inhibitors should be avoided unless the expected benefit of GCS therapy exceeds the risk of systemic HF. If concomitant use of betamethasone with strong CYP3A4 inhibitors is necessary, patients should be closely monitored for the risk of systemic HF.

Concomitant use of phenobarbital, rifampicin, phenytoin or ephedrine may accelerate metabolism of betamethasone while reducing its therapeutic activity.

In concomitant use of betamethasone and estrogens, the dose of betamethasone may need to be adjusted (because of the risk of overdose).

The co-administration of betamethasone and potassium-eluting diuretics increases the possibility of hypokalemia.

The concomitant use of GCS and cardiac glycosides increases the risk of arrhythmias or digitalis intoxication (due to hypokalemia). Betamethasone may increase amphotericin B-induced potassium excretion.

In co-administration of betamethasone and oral anticoagulants, changes in blood clotting may occur, requiring adjustment of the dose of anticoagulants.

The combined use of GCS with nonsteroidal anti-inflammatory drugs (NSAIDs) or with ethanol (or ethanol-containing drugs) may increase the frequency or intensity of gastrointestinal erosive ulcers.

When used concomitantly, GCS may decrease plasma concentrations of salicylates.

The simultaneous administration of GCS and somatropin may lead to slower absorption of the latter (doses of betamethasone greater than 0.3-0.45 mg/body surface per day should be avoided).

The GCS may affect the nitrogen blue tetrazole test for bacterial infection and cause a false negative result.

Aminoglutethimide can cause increased or decreased suppression of adrenal cortical function caused by GCS. Aminoglutethimide causes a decrease in adrenal cortisol secretion, with a subsequent increase in pituitary adrenocorticotropic hormone (ACTH) secretion, which can neutralize the blockade of adrenocortical steroid synthesis by aminoglutethimide, resulting in increased adrenal function. Consequently, physicians should be advised to review the information on concomitant use of Dipromet with aminoglutethimide.

The GCS may reduce the effect of cholinesterase inhibitors, which may lead to the development of marked muscle weakness in patients with myasthenia gravis. If possible, cholinesterase inhibitors should be discontinued at least 24 hours before starting GCS therapy.

The concomitant use of GCS and isoniazid may decrease plasma concentrations of isoniazid. The condition of patients taking isoniazid should be monitored carefully.

The concomitant use of cyclosporine and GCS may increase the concentration of cyclosporine and potentiate the effects of GCS. There is a high risk of seizures.

The concomitant use of GCS with macrolide antibiotics may significantly decrease GCS excretion.

Concomitant use with colesteramine may increase GCS excretion.

The use of betamethasone in patients with diabetes may require correction of hypoglycemic therapy.

Special Instructions

Severe nervous system complications (up to and including death) have been reported with epidural and intrathecal administration of GCS (with or without fluoroscopic guidance), including but not limited to spinal cord infarction, paraplegia, quadriplegia, cortical blindness and stroke. Because the safety and efficacy of epidural administration of GCS has not been established, this route of administration is not indicated for this group of drugs.

Preferred routes of administration are listed in the Administration and Dosage section.

The intravascular route of administration must be avoided.

Injection into the intervertebral space is contraindicated due to lack of data regarding the risk of calcification.

Rare cases of anaphylactoid/anaphylactic reactions (up to and including anaphylactic shock) have been reported with parenteral administration of GCS. Necessary precautions should be taken before the drug administration, especially if the patient has a history of allergic reactions to GCS.

The dosing regimen and route of administration are controlled individually depending on the indication, the severity of the disease and the patient’s reaction.

The dose should be as low as possible, and the period of treatment should be as short as possible. The initial dose is adjusted until the desired therapeutic effect is achieved. Then the dose of Dipromet is gradually reduced to the lowest effective maintenance dose. If there is no effect from the current therapy or if the drug is used for a long time, the drug is withdrawn in the same way, gradually reducing the dose.

If a stressful situation occurs or is threatened (not related to the disease), it may be necessary to increase the dose of Dipromet.

The patient’s condition should be monitored for at least one year at the end of long-term therapy or high-dose use.

Injection of the drug into the soft tissues, into the lesion site and intra-articularly may lead to systemic action at the same time if local effects are pronounced.

Diprometa contains two active ingredients, betamethasone derivatives, one of which, sodium betamethasone phosphate, quickly penetrates into the systemic bloodstream, and therefore its possible systemic action should be considered.

The use of Dipromet may exacerbate the patient’s emotional instability or tendency to psychosis.

When using Dipromet in patients with diabetes mellitus, correction of hypoglycemic therapy may be required.

Patients receiving GCS should not be vaccinated against smallpox. Other immunizations should not be performed in patients receiving GCS (especially in high doses) because of possible neurological complications and low immune response (no antibody formation). However, immunization is possible during substitution therapy (e.g., in primary adrenal insufficiency). Patients receiving the drug Diprometa in doses that suppress immunity should be warned about the need to avoid contact with patients with chickenpox and measles (especially important when using the drug in children).

A reaction may be inhibited when skin tests are performed with GCS.

When using Dipromet, it should be noted that GCS may mask the signs of an infectious disease and also reduce the body’s resistance to infection.

Asseptics and antiseptics must be carefully observed when administering the drug.

Cautious use of the drug in patients with a high risk of infection (on hemodialysis or with dentures) is necessary.

The use of the drug Diprometa in active tuberculosis is possible only in cases of fulminant or disseminated tuberculosis in combination with adequate antituberculosis therapy. When using Diprometa in patients with latent tuberculosis or positive reactions to tuberculin, careful medical supervision is necessary in view of the risk of tuberculosis reactivation. Such patients should receive specific chemotherapy in case of prolonged use of GCS. During prophylactic use of rifampicin, the acceleration of hepatic clearance of betamethasone should be considered (correction of its dose may be required).

In the presence of fluid in the joint cavity, a septic process should be excluded. A marked increase in pain, swelling, increased temperature of the surrounding tissues, and further limitation of joint mobility are indicative of septic arthritis. It is necessary to carry out the examination of aspirated joint fluid. If the diagnosis is confirmed, it is necessary to prescribe an appropriate antibiotic therapy. The use of Dipromet drug in septic arthritis is contraindicated.

Repeated injections into the joint in osteoarthritis may increase the risk of joint destruction. Injecting GCS into the tendon tissue gradually causes the tendon to rupture.

After successful intra-articular therapy, the patient should avoid overloading the joint.

Long-term use of GCS may lead to posterior subcapsular cataracts (especially in children), glaucoma with possible optic nerve damage, and may contribute to secondary ocular infections (fungal or viral). Periodic ophthalmologic examination is necessary, especially in patients receiving Diprometa for more than 6 months.

The use of medium and high doses of GCS may lead to increased blood pressure, sodium and fluid retention in the body and increased excretion of potassium from the body (these phenomena are less likely in case of synthetic GCS, unless they are used in high doses). In this case, consider the need to prescribe potassium-containing drugs and a diet with restriction of table salt. All GCS increase calcium excretion.

When concomitant use of Dipromet and cardiac glycosides or drugs that affect electrolyte plasma composition requires control of water-electrolyte balance.

Acetylsalicylic acid in combination with betamethasone in case of hypoprothrombinemia is used with caution.

The effect of GCS is increased in patients with hypothyroidism and cirrhosis.

The development of secondary adrenal insufficiency due to too rapid withdrawal of GCS is possible within a few months after discontinuation of therapy. If there is an occurrence or threat of a stressful situation during this period, therapy with Dipromet should be resumed and a mineralocorticoid should be simultaneously prescribed (due to possible disturbance of mineralocorticoid secretion). Gradual withdrawal of GCS reduces the risk of secondary adrenal insufficiency.

Sperm motility and sperm count may change with GCS use.

A switch from parenteral to oral GCS use may be considered if prolonged GCS therapy is used, based on a benefit/risk assessment.

Perhaps caution should be exercised when using GCS in elderly patients; In patients with ulcerative colitis at risk of perforation, with abscess or other purulent infections, diverticulitis, with recent intestinal anastomoses, active or latent peptic ulcer disease, renal or hepatic insufficiency, arterial hypertension, osteoporosis, myasthenia, confirmed or suspected parasitic infections (e.g., strongyloidosis).

With systemic and local (including intranasal, inhalation, and intraocular) use of GCS, visual disturbances may occur. If a patient presents with symptoms such as blurred vision or other visual disturbances, a referral to an ophthalmologist should be considered for possible causes, including cataracts, glaucoma, or rare conditions such as central serous chorioretinopathy (CCS), which have been seen in some cases with systemic or topical use of GCS.

Pediatric use

Children treated with Dipromet (especially long-term) should be under close medical supervision for possible growth retardation and development of secondary adrenal cortical insufficiency.

Application in athletes

Patients participating in World Anti-Doping Agency (WADA) controlled competitions should read the WADA regulations before starting treatment with the drug, as the use of betamethasone may affect doping control results.

Influence on ability to control vehicles and machinery

There are no data on the effect of betamethasone on the ability to control vehicles and machinery. However, in case of adverse reactions during long-term treatment (blurred vision, dizziness, insomnia) it is necessary to refrain from driving vehicles and mechanisms.

Synopsis

Contraindications

Side effects

The incidence and severity of adverse reactions (ARs), as with other GKS, depend on the dose used and the duration of use. These reactions are usually reversible and may be eliminated or reduced with dose reduction.

Immune system disorders: allergic or anaphylactic reactions, including anaphylactic shock, angioedema.

Nervous system disorders: seizures, increased intracranial pressure with optic disc edema (usually at the end of therapy), dizziness, headache, neuritis, neuropathy, paresthesias, with intrathecal administration – arachnoiditis, meningitis, paresis/paralysis, sensory disorders.

Psychiatric disorders: euphoria, mood changes, depression (with pronounced psychotic reactions), personality disorders, increased irritability, insomnia.

Visual disorders: posterior subcapsular cataract, increased intraocular pressure, glaucoma, exophthalmos; blurred vision; in rare cases – blindness (when the drug is administered in the face and head).

Heart disorders: chronic heart failure (in predisposed patients), heart rhythm disorders, bradycardia, tachycardia, hypertrophic myopathy in premature infants, myocardial rupture after recent myocardial infarction.

Vascular disorders: decreased blood pressure, increased blood pressure, thromboembolic complications, vasculitis.

Endocrine system disorders: Secondary adrenal insufficiency (especially during the stress of illness, injury, surgery); Icenko-Cushing’s syndrome; decreased glucose tolerance; “steroid” diabetes mellitus or manifestation of latent diabetes mellitus; increased need for insulin or oral hypoglycemic drugs; when used during pregnancy – impairment of fetal intrauterine development; delayed growth and sexual development in children; hirsutism; hypertrichosis; suppression of adrenal and pituitary function.

Mechanism and nutrition disorders: hypernatriemia, increased potassium excretion, increased calcium excretion, hypokalemic alkalosis, fluid retention in tissues, negative nitrogen balance (due to protein catabolism), lipomatosis (including mediastinal and epidural lipomatosis which may cause neurologic complications), weight gain, increased appetite.

Gastro-intestinal disorders: gastrointestinal erosive and ulcerative lesions with possible subsequent perforation and bleeding, pancreatitis, flatulence, hiccups, nausea.

Liver and biliary tract disorders: hepatomegaly, increased activity of “liver” enzymes (usually reversible).

Muscular and connective tissue disorders: Muscle weakness, “steroid” myopathy, loss of muscle mass, worsening of myasthenic symptoms in severe pseudoparalytic myasthenia gravis, osteoporosis, spinal compression fracture, aseptic necrosis of the femoral or humerus head, pathological fractures of tubular bones, tendon tears, joint instability (with repeated intraarticular injections).

Skin and subcutaneous tissue disorders: impaired wound healing, skin atrophy and thinning, petechiae, ecchymosis, increased sweating, dermatitis, “steroid” acne, stretch marks, tendency to develop pyoderma and candidiasis, reduced reaction in skin tests, urticaria, rash, thinning of the head hair, allergic dermatitis, erythema.

Gender and mammary gland disorders: menstrual cycle disorders, changes in sperm motility and sperm count.

General disorders and disorders at the injection site: rarely hyper- or hypopigmentation, subcutaneous and cutaneous atrophy, aseptic abscesses, “rush” of blood to the face after injection (or intraarticular injection), neurogenic arthropathy.

Overdose

Symptoms

Acute overdose of betamethasone does not lead to life-threatening situations. Administration of high doses of GCS for several days does not lead to adverse effects (except in cases of very high doses or if the patient has diabetes mellitus, glaucoma, exacerbation of erosive-ulcerative gastrointestinal lesions or concomitant use of cardiac glycosides, indirect anticoagulants or potassium-eluting diuretics).

Treatment

The patient’s condition requires close medical monitoring; optimal fluid intake should be maintained and plasma and urinary electrolyte levels (especially the sodium/potassium ion ratio) should be monitored. Appropriate therapy should be given if necessary.

Pregnancy use

Pregnancy

In the absence of controlled studies of the safety of betamethasone in pregnancy, the use of Dipromethasone during pregnancy or in women with preserved reproductive potential is indicated only when the expected therapeutic benefit to the mother exceeds the risk of possible adverse effects of the drug on the fetus.

Patients with fluid retention or gestosis in the second half of pregnancy (especially severe preeclampsia, eclampsia) should be closely monitored.

The GCS cross the placental barrier and may reach high concentrations in the fetus. Newborns whose mothers received therapeutic doses of GCS during pregnancy should be medically monitored (for early detection of signs of adrenal insufficiency).

The use of GCS in pregnant animals can cause fetal malformations including cleft palate, fetal retardation and can affect brain growth and development. There are no data on an increase in human cases of congenital malformations such as cleft palate/mouth against the background of GCS use. However, with long-term or repeated use during pregnancy, GCS may increase the risk of fetal growth retardation. Theoretically, newborns may develop adrenal hypofunction after prenatal use of GCS, which usually subsides spontaneously after birth and is rarely clinically significant. Cases of myocardial hypertrophy and gastroesophageal reflux have been reported in neonates when betamethasone has been used during pregnancy.

When used systemically in pregnant women, betamethasone may result in a transient decrease in heart rate (HR) and inhibition of fetal biophysical activity, which are commonly used to assess fetal status. These characteristics may include decreased respiratory movements, fetal motor activity, and fetal heart rate.

Breastfeeding period

Breastfeeding should be discontinued if betamethasone must be used during breastfeeding, given the importance of GCS therapy to the mother and the potential for adverse effects in the baby.

Similarities