Orion Meteorite - instructions for use, dose, side effects, contraindications

The drug is an injection form of methylprednisolone, a synthetic glucocorticosteroid (SCS), for intramuscular (IM) and intravenous (IV) administration.

Pharmacodynamics

Has anti-inflammatory, antiallergic, immunosuppressive action, increases the sensitivity of beta-adrenoreceptors to endogenous catecholamines. Interacts with specific cytoplasmic receptors (receptors for GCS are present in all tissues, especially in the liver), with the formation of a complex inducing the formation of proteins (including enzymes that regulate vital processes in cells).

Protein metabolism: reduces the number of globulins in plasma, increases the synthesis of albumin in the liver and kidneys (with increasing albumin / globulin ratio), reduces synthesis and enhances protein catabolism in muscle tissue.

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

Carbohydrate metabolism: increases the absorption of carbohydrates from the gastrointestinal tract: increasesactivity of glucose-6-phosphatase (increased intake of glucose from the liver into the blood); increases the activity of phosphoenolpyruvate carboxylase and the synthesis of aminotransferases (activation of gluconeogenesis); promotes the development of hyperglycemia.

Water-electrolyte exchange: retards sodium and water in the body, stimulates the excretion of potassium (mineralocorticoid activity), reduces the absorption of calcium from the gastrointestinal tract, reduces the mineralization of bone tissue.

Anti-inflammatory effect is associated with the suppression of the release of eosinophils and mast cells by inflammatory mediators; inducing the formation of lipocortins and reducing the number of mast cells that produce hyaluronic acid; with a decrease in the permeability of capillaries; stabilization of cell membranes (especially lysosomal) and membranes of organelles. It acts on all stages of the inflammatory process: it inhibits the synthesis of prostaglandins at the level of arachidonic acid (lipocortin depresses phospholipase A2, suppresses the liberation of arachidonic acid and inhibits the biosynthesis of endoperoxides, leukotrienes, which promote inflammation, allergies, etc.)synthesis of "pro-inflammatory cytokines" (interleukin 1, tumor necrosis factor alpha, etc.); increases the resistance of the cell membrane to the action of various damaging factors.

Immunodepressive effect is caused by involution of lymphoid tissue, suppression of lymphocyte proliferation (especially T-lymphocytes), suppression of B-cell migration and interaction of T and B lymphocytes, inhibition of release of cytokines (interleukin-1, 2, gamma-interferon) from lymphocytes and macrophages and a decrease the formation of antibodies.

Antiallergic effect develops as a result of a decrease in the synthesis and secretion of mediators of allergy, inhibition of release from sensitized mast cells and basophils of histamine and other biologically active substances, a decrease in the number of circulating basophils, T- and B-lymphocytes, mast cells; suppression of the development of lymphoid and connective tissue, reducing the sensitivity of effector cells to mediators of allergy, inhibition of antibody formation, changes in the immune response of the body.

In obstructive airway diseases, the effect is mainly due to the inhibition of inflammatory processes,prevention or reduction of the degree of edema of the mucous membranes, a decrease in the eosinophilic infiltration of the submucosal layer of the bronchial epithelium and the deposition of circulating immune complexes in the bronchial mucosa, as well as inhibition of erosion and desquamation of the mucosa. Increases the sensitivity of beta-adrenergic receptors of small and medium-sized bronchial tubes to endogenous catecholamines and exogenous sympathomimetics, reduces the viscosity of mucus by reducing its production.

Suppresses the synthesis and secretion of adrenocorticotropic hormone (ACTH) and again - the synthesis of endogenous GCS.

It inhibits connective tissue reactions during the inflammatory process and reduces the possibility of scar tissue formation.

Pharmacokinetics:

In any method of administration of methylprednisolone sodium, succinate is hydrolyzed to a considerable extent under the action of cholinesterases with the formation of an active form of free methylprednisolone. After intravenous infusion of 30 mg / kg for 20 minutes, or 1 g for 30-60 minutes after about 15 minutes, a peak concentration of methylprednisolone in the blood plasma (about 20 μg / ml) is reached. Approximately 25 minutes after iv bolus administration of 40 mg of methyl prednisolone, a peak in plasma concentration of 42-47 μg / 100 ml is achieved.With a / m introduction of 40 mg after 120 minutes, a concentration of methylprednisolone in the blood plasma reaches 34 μg / 100 ml. With the / m introduction, a lower peak value is achieved than with the / in the introduction. The mean maximum concentration in blood plasma (C_mOh) is achieved 1 hour after the / m introduction of 40 mg of methylprednisolone sodium succinate and is 454 ng / ml. After 12 hours, the concentration of methylprednisolone in the blood plasma is reduced to 31.9 ng / ml, and after 18 h methylprednisolone in the blood is not found. Comparison of the areas under the "concentration-time" curve indicates the same effectiveness of the action for iv and / m administration of equivalent doses of methylprednisolone sodium succinate.

After the / m administration, the drug is present in the blood plasma for a longer period than after intravenous administration, if an equivalent amount of methylprednisolone is administered. Taking into account the mechanism of action of methylprednisolone, it can be considered that these differences are of minimal clinical significance.

The clinical effect is usually observed after 4-6 hours after administration. In the treatment of bronchial asthma, the first positive results are detected within 1-2 hours.Pharmacotherapeutic action is maintained even when the concentration of methylprednisolone in the blood plasma is no longer determined. The duration of the anti-inflammatory activity of methylprednisolone is approximately equal to the duration of suppression of the hypothalamic-pituitary-adrenal (HHG) system.

Distribution. Methylprednisolone is actively distributed into the tissues of the body, passes through the blood-brain barrier and is excreted into breast milk. The volume of distribution is approximately 1.4 ml / kg. The connection of methylprednisolone with blood plasma proteins (albumin and corticosteroid-binding globulin) is approximately 40-90%.

Metabolism methylprednisolone is carried out in the liver, mainly with the help of isoenzyme CYP3A4, and this process is qualitatively similar to the metabolism of cortisol. The main metabolites are 20β-hydroxymethylprednisolone and 20β-hydroxy-6α-methylprednisolone.

Like many other isoenzyme substrates CYP3A4, methylprednisolone can also be a substrate of ATP-linked transport proteins of P-glycoprotein, affecting the distribution in tissues and interaction with other drugs.

Methylprednisolone is a substrate of isoenzyme CYP3A4. Isozyme CYP3A4 is the main isoenzyme in the most abundant subfamily of isoenzymes CYP in the liver of an adult. This isoenzyme catalyzes beta-hydroxylation of steroids - the main stage of the I phase of the metabolism of both endogenous and synthetic GCS. Many other compounds are also isoenzyme substrates CYP3A4, some of them (as well as other drugs) affect the metabolism of methylprednisolone by inducing or inhibiting the isoenzyme CYP3A4 (see section "Interaction with other drugs").

Excretion. Half-life (T_1/2) of methylprednisolone sodium succinate from plasma is 2.3-4 h and probably does not depend on the route of administration. The total clearance is 5-6 ml / min / kg. Methylprednisolone - SCS with an intermediate duration of action. Him T_1/2from the human body is 12-36 hours. Due to intracellular activity, a pronounced difference is revealed between T_1/2 methylprednisolone from plasma and T_1/2from the body as a whole. Metabolites are excreted mainly through the kidneys, both in unbound form and in the form of glucuronides and sulfates, which are formed mainly in the liver and partially in the kidneys.After intravenous administration of methylprednisolone labeled with carbon ¹⁴C, 75% of the total radioactivity is excreted by the kidneys during 96 hours, 9% is excreted through the intestine within 5 days and 20% is found in bile.

If the kidney function is not corrected, dose adjustment is not required.

Methylprednisolone is excreted in hemodialysis.

Indications:

Use strictly according to the doctor's prescription to avoid complications.

1. Endocrine diseases

Primary and secondary adrenal insufficiency (if necessary in combination with mineralocorticosteroids, especially in pediatric practice).
Acute adrenal insufficiency (there may be a need for addition of mineralocorticosteroids).
Shock, which is a consequence of adrenal insufficiency, or shock, at inefficiency of symptomatic therapy, when possible Availability adrenal insufficiency (if mineralocorticosteroid action is undesirable).
In the preoperative period, in the case of severe trauma or severe disease, in patients with established or suspected adrenal insufficiency.
Congenital hyperplasia of the adrenal glands.
Subacute thyroiditis.
Hypercalcemia on the background of cancer.

2. Rheumatic diseases (as an adjunctive therapy for short-term withdrawal from an acute condition or exacerbation)

Post-traumatic osteoarthritis.
Synovitis in osteoarthritis.
Rheumatoid arthritis, including juvenile rheumatoid arthritis (in In some cases, maintenance therapy may be required in low doses).
Acute and subacute bursitis.
Epicondylitis.
Acute nonspecific tenosynovitis.
Acute gouty arthritis.
Psoriatic arthritis.
Ankylosing spondylitis.

3. Systemic connective tissue diseases (during exacerbation or in some cases as maintenance therapy)

Systemic lupus erythematosus (and lupus nephritis).
Acute rheumatic heart disease.
Systemic dermatomyositis (polymyositis).
Inflammatory periarteritis.
Goodpasture Syndrome.

4. Skin diseases

Pemphigus.
Severe multiform erythema (Stevens-Johnson syndrome).
Exfoliative dermatitis.
Severe psoriasis.
Herpetiform bullous dermatitis.
Heavy seborrheic dermatitis.
Mushroomed mycosis.

5. Allergic conditions (in the case of severe or disabling conditions, at which conventional therapy is ineffective)

Bronchial asthma.
Contact dermatitis.
Atopic dermatitis.
Serum sickness.
Seasonal or all-the-year-round allergic rhinitis.
Reactions of hypersensitivity to medicines.
Posttransfusion reactions like urticaria.
Acute non-infectious edema of the larynx.

6. Eye diseases (severe acute and chronic allergic and inflammatory processes with eye damage)

Eye shape Herpes zoster.
Irit and iridocyclitis.
Chorioretinitis.
Diffusive posterior uveitis and choroiditis.
Optic neuritis.
Sympathetic ophthalmia.
Inflammation of the anterior segment.
Allergic conjunctivitis.
Allergic marginal ulcers of the cornea.
Keratitis.

7. Diseases of the gastrointestinal tract (to remove the patient from a critical condition)

Ulcerative colitis.
Regional enteritis.

8. Diseases of the respiratory tract

Symptomatic sarcoidosis.
Berylliosis.
Lightning and disseminated pulmonary tuberculosis in combination with appropriate anti-tuberculosis chemotherapy.
Leffler's syndrome, not amenable to therapy by other means.
Aspiration pneumonitis.

9. Hematological diseases

Acquired (autoimmune) hemolytic anemia.
Idiopathic thrombocytopenic purpura in adults (only in / in introduction; in / m administration is contraindicated).
Secondary thrombocytopenia in adults.
Erythroblastopenia (erythrocyte anemia).
Congenital (erythroid) hypoplastic anemia.

10. Oncological diseases (as a palliative therapy)

Leukemia and lymphomas in adults.
Acute leukemia in children.
To improve the quality of life of patients with oncological diseases in terminal stage.

11. Edema Syndrome

To stimulate diuresis and achieve remission of proteinuria in patients with nephrotic syndrome without uremia.

12. Nervous system

Cerebral edema due to a tumor - primary or metastatic, and / or associated with surgical or radiotherapy.
Exacerbation of multiple sclerosis.
Acute traumatic spinal cord injuries. Treatment should be start within the first 8 hours after the trauma.

13. Other indications for use

Tuberculous meningitis with subarachnoid block or in case of threat of block (in combination with appropriate anti-tuberculosis chemotherapy).
Trichinosis with damage to the nervous system or myocardium.
Organ transplantation.
Prevention of nausea and vomiting associated with chemotherapy for oncological diseases.

Contraindications:

Systemic fungal infections.
Hypersensitivity to any component of the drug in history.
Damage to the brain due to traumatic brain injury.
The drug is contraindicated for intrathecal and epidural administration.
Contraindicated simultaneous use of live or weakened vaccines in the treatment of immunosuppressive doses of the drug.
Idiopathic thrombocytopenic purpura (with intramuscular application of the drug).
Breastfeeding period.
It is not recommended to use the drug in patients with acute and subacute myocardial infarction, as the use of glucocorticosteroids in them can lead to the spread of necrosis, slow the formation of scar tissue and, consequently, to rupture of the heart muscle.
It is not recommended to use the drug in patients with Isenko-Cushing's disease.

Carefully:PIn the following diseases and conditions:

diseases of the gastrointestinal tract - peptic ulcer of the stomach and duodenum, esophagitis, gastritis, acute or latent peptic ulcer, newly created intestinal anastomosis, ulcerative colitis with perforation or abscessing, diverticulitis;
parasitic and infectious diseases of a viral, fungal or bacterial nature (currently or recently transferred, including recent contact with a patient) - herpes simplex, herpes zoster (viremic phase), chicken pox, measles; amebiasis, strongyloidiasis; active or latent tuberculosis. The use in severe infectious diseases is permissible only against the background of specific antimicrobial therapy;
pre- and post-vaccination period (8 weeks before and 2 weeks after vaccination), lymphadenitis after BCG vaccination;
immunodeficiency states (including AIDS or HIV infection);
diseases of the cardiovascular system (including the recently transferred myocardial infarction), severe chronic heart failure, hypertension, hyperlipidemia;
endocrine diseases - diabetes (including a violation of carbohydrate tolerance), thyrotoxicosis, hypothyroidism, obesity (III-IV century);
severe chronic renal and / or hepatic insufficiency, nephrourolythiasis;
hypoalbuminemia and conditions predisposing to its occurrence;
systemic osteoporosis;
myasthenia gravis;
acute psychosis;
poliomyelitis (with the exception of the form of bulbar encephalitis);
open and closed angle glaucoma;
pregnancy;
secondary adrenal insufficiency;
convulsive syndrome;
allergic reactions (bronchospasm) in the anamnesis for the introduction of methylprednisolone;
presence of thromboembolic complications or predisposition to such complications.

The use of the drug in chronic heart failure is possible only on absolute indications.

Methylprednisolone should be used with caution in elderly patients due to the increased risk of osteoporosis and hypertension.

In children during growth methylprednisolone It should be used only under absolute indications and under very careful supervision of the attending physician.

Pregnancy and lactation:

A number of studies in animals have shown that the administration of high doses of methylprednisolone to females can lead to developmental malformations in the fetus. There have been no relevant studies on the effect on reproductive function of humans.Since it is impossible to rule out the possible harm of using methylprednisolone, taking the drug during pregnancy and in women planning pregnancy is only indicated if the expected therapeutic effect of the mother exceeds the risk of adverse effects on the fetus. Methylprednisolone should be administered during pregnancy only by absolute indications. Methylprednisolone penetrates the placenta. There was an increase in the number of newborns with a delay in intrauterine development, born from mothers who received methylprednisolone, cases of cataract in newborns were also noted. The effect of methylprednisolone on the course and outcome of labor is unknown. Newborns born to mothers who received methylprednisolone during pregnancy, should be carefully screened to identify possible symptoms of adrenal insufficiency.

Because the methylprednisolone penetrates into breast milk; if necessary, use the drug during breastfeeding, breastfeeding should be discontinued.

Dosing and Administration:

Parenteral.The drug is administered in the form of slow intravenous jet injections or intravenous infusions, as well as intramuscular injections.

The dose of the drug and the duration of treatment is determined by the doctor individually, depending on the indications and severity of the disease. Children should be given lower doses (but not less than 0.5 mg / kg / day), but when choosing a dose, first of all, the severity of the condition and the patient's response to therapy, rather than age and body weight, are taken into account.

Preparation of the solution. A solution for injection is prepared by adding solvent (4 ml of water for injection) in a vial with lyophilized prior to use. The prepared solution contains 62.5 mg / ml methylprednisolone. The reconstituted solution should be used immediately after preparation.

As an additional therapy in life-threatening conditions inject a solution of 30 mg / kg body weight IV during at least 30 minutes. The administration of this dose can be repeated every 4-6 hours for no more than 48 hours.

Pulse therapy in the treatment of diseases in which GCS-therapy is effective, with exacerbations of the disease and / or when standard therapy is ineffective.

Recommended therapy regimens:
Rheumatic diseases:	1 g / day IV for 1 to 4 days or 1 g / month IV in
	within 6 months
Systemic lupus erythematosus:	1 g / day iv in 3 days
Multiple sclerosis:	1 g / day IV for 3 or 5 days
Edematous conditions, for example,	30 mg / kg IV every other day for 4 days or 1 g / day
glomerulonephritis, lupus	IV for 3, 5 or 7 days
nephritis:

The above doses should be administered for at least 30 minutes, the administration can be repeated if, within a week after the treatment, no improvement has been achieved, or if the patient's condition requires it.

Oncological diseases in the terminal stage - to improve the quality of life: Enter 125 mg / day intravenously daily for up to 8 weeks.

Prevention of nausea and vomiting associated with chemotherapy for cancer. In chemotherapy characterized by Mr.Significant or moderate vomiting, 250 mg IV is administered for at least 5 minutes 1 hour prior to administration of the chemotherapeutic drug, at the beginning of chemotherapy, and after its termination. In chemotherapy characterized by pronounced emetic action, 250 mg IV for at least 5 minutes in combination with appropriate doses of metoclopramide or butirofenone 1 hour prior to the administration of the chemotherapeutic drug, then 250 mg IV at the beginning of chemotherapy and after it.

Acute traumatic spinal cord injuries. Treatment should be started within the first 8 hours after the injury. It is recommended to use a bolus for 15 minutes at a dose of 30 mg / kg of body weight, then take a break for 45 minutes, and then continue a continuous infusion of 5.4 mg / kg / h for 23 hours (if treatment is started in the first 3 hours after injury) or 47 hours (if treatment is started in the first 3-8 hours after injury). The drug should be administered with the aid of an infusomat separate from other drugs.

With other indications the initial dose is 10-500 mg IV, depending on the nature of the disease. For a short course in severe acute conditions, higher doses may be required. The initial dose, not exceeding 250 mg, should be administered IV for at least 5 minutes, doses above 250 mg administered for at least 30 minutes. Subsequent doses are administered iv or I / m, and the duration of the intervals between administrations depends on the patient's response to therapy and on his clinical condition.

Side effects:

The frequency of development and severity of side effects depends on the duration of the application, the amount of dose used and the possibility of observing the circadian rhythm of prescribing the drug.

When Metired ® Orion is used, the following can be noted:

From the side of water-electrolyte exchange: sodium retention, fluid and salt retention in the body, increased excretion of potassium, hypokalemic alkalosis.

From the side of the cardiovascular system: increase or decrease in blood pressure pressure; disturbances in the rhythm of the heart (arrhythmias, bradycardia, tachycardia); chronic heart failure (in patients with predisposition); pulmonary edema, hypertrophic cardiomyopathy in premature infants; fainting; thromboembolism; vasculitis; thrombophlebitis; in patients with acute and subacute myocardial infarction - the spread of the focus of necrosis, slowing the formation of scar tissue, which can lead to rupture of the heart muscle. There are reports of cardiac arrhythmias and / or the development of circulatory collapse, and / or cardiac arrest after rapid IV injection of high doses of methylprednisolone (more than 0.5 g injected for less than 10 min).During and after intravenous administration of high doses of methylprednisolone, there were also cases of bradycardia, but they did not necessarily depend on the speed or duration of the infusion.

From the side of the musculoskeletal system: osteonecrosis, myopathy, muscle weakness, osteoporosis, pathological fractures, muscular atrophy, neuropathic atrophy, arthralgia, myalgia, compression fractures of the vertebrae, aseptic necrosis of the tubular bones epiphyses, tendon ruptures, especially Achilles tendon.

Acute myopathy most often develops when high doses of methylprednisolone are used in patients with impaired neuromuscular transmission (eg, with myasthenia gravis gravis), or in patients simultaneously receiving treatment with anticholinergic drugs, such as peripheral muscle relaxants (for example, pancuronium bromide). Such acute myopathy has a generalized character, it can affect the muscles of the eye and respiratory system, lead to the development of tetraparesis. It is possible to increase the content of creatine kinase. In this case, the improvement or recovery after methylprednisolone cancellation can occur only after many weeks or even several years.

From the digestive system: peptic ulcer with possible perforation and bleeding, gastric bleeding, pancreatitis, peritonitis, esophagitis (including ulcerative), intestinal wall perforation, abdominal pain, abdominal wall tension, diarrhea, dyspepsia, flatulence, nausea, vomiting, persistent hiccough.

After treatment with methylprednisolone, an increase in the activity of alanine aminotransferase (ALT) was observed. aspartate aminotransferase (ACT) and alkaline phosphatase in the blood plasma. Usually these changes are insignificant, not associated with any clinical syndromes, and reversible after discontinuation of treatment.

From the skin and subcutaneous tissue: angioedema, peripheral edema, skin atrophy, skin striae, petechiae and ecchymosis, decreased skin pigmentation, hirsutism, rash, erythema, pruritus, urticaria, acne, slow healing of wounds, reactions at the injection site, thinning of hair on the head, allergic dermatitis.

From the side of metabolism: negative nitrogen balance due to increased protein breakdown, slowing growth and ossification in children (premature closure of epiphyseal growth zones), increased appetite (may lead to increased body weight), increased sweating.

From the nervous system: epidural lipomatosis, increased intracranial pressure with edema of the optic nerve disk (benign intracranial hypertension), seizures, paresthesia, amnesia, thinking disorders, dizziness, headache, affective disorders (including mood lability, depressed mood, euphoria, psychological dependence, suicidal thinking ), psychotic disorders (including, mania, delusions, hallucinations, schizophrenia or exacerbation), confusion, mental disturbance, anxiety, change of the larvae rapid mood swings, unusual behavior, insomnia, irritability.

From the side of the psyche: drug dependence.

From the endocrine system: menstrual cycle disorders, Itenko-Cushing syndrome, hypopituitarism, the development of the withdrawal syndrome of steroid drugs, a decrease in glucose tolerance, an increase in the need for insulin or oral hypoglycemic drugs in patients with diabetes mellitus, growth retardation in children, lipomatosis, and latent diabetes mellitus.

From the side of the organ of sight and hearing: central serous chorioretinopathy.

Laboratory indicators: increased urea concentration in blood plasma, dyslipidemia, increased concentration of calcium in the urine, hypocalcemia.

From the sense organs: posterior subcapsular cataract, increased intraocular pressure, glaucoma, exophthalmos, vertigo, secondary fungal or viral ocular infection, perforation of the cornea (with ocular manifestations of herpes simplex).

From the immune system: infectious diseases, the emergence of infections caused by opportunistic pathogens, sensitivity reactions, including anaphylaxis with or without circulatory collapse, cardiac arrest, bronchospasm, suppression of reactions during skin tests.

Other: increased fatigue, weakness, burning and tingling (especially in the perineal region after intravenous administration), a "sterile abscess," an increase or decrease in motility and the number of spermatozoa.

AT case of intrathecal or epidural administration of the drug: arachnoiditis, meningitis, paresis / paraplegia, sensory disorders and disorders of the gastrointestinal tract and bladder.

It is reported that the patients receiving methylprednisolone therapy had a Kalosha sarcoma. If methylprednisolone is withdrawn, clinical remission may occur.

Overdose:

The clinical syndrome of acute overdose with methylprednisolone is not described. Reports of acute toxicity cases with methylprednisolone overdose are extremely rare. With a chronic overdose of methylprednisolone, symptoms of the Itenko-Cushing syndrome can be observed.

There is no specific antidote. Treatment is symptomatic. Methylprednisolone is displayed during dialysis.

Interaction:

The compatibility and stability of methylprednisolone solutions with IV administration with other drugs included in the mixtures for IV administration depend on pH, concentration, time, temperature, and also on the solubility of methylprednisolone itself. Methylprednisolone it is recommended, if possible, to be administered separately from other drugs, in the form of intravenous bolus injections, intravenous drip infusion, or via an additional dropper as a second solution.

Inhibitor inhibitors CYP3A4 - can suppress the metabolism of methylprednisolone, reduce its clearance and increase the concentration in the blood plasma. In this case, in order to avoid overdose phenomena, a dose of methylprednisolone should be titrated.

Inductors of isoenzyme CYP3A4 - can increase the clearance of methylprednisolone. This is manifested by a decrease in the concentration of methylprednisolone in the blood plasma, which may require increasing the dose of the drug to obtain the desired effect.

Substrates of the isoenzyme CYP3A4 - in the presence of another isoenzyme substrate CYP3A4, the methylprednisolone clearance may be delayed or induced, which may require appropriate dose adjustment of methylprednisolone. There is a chance that adverse reactions, manifested when using drugs in the form of monotherapy, can occur more often with the simultaneous use of drugs.

The following examples of drug interactions may have important clinical implications:

Class or type of medicinal product - drug or substance	Interaction / effect
Antibacterial drugs - isoniazid	Inhibitor of isoenzyme CYP3A4. In addition, there is the likelihood of the effect of methylprednisolone on the degree of acetylation and the clearance of isoniazid.
Antibiotic antituberculous - rifampicin	Inductor of isoenzyme CYP3A4.
Anticoagulants (for oral administration)	Methylprednisolone has a variety of effects on the effect of indirect anticoagulants. Both enhancement and reduction of the effect of anticoagulants taken simultaneously with methyl prednisolone are reported. To maintain the desired effect of the anticoagulant, constant monitoring of the coululogram is necessary.
Antiepileptic drugs - carbamazepine	Inductor and substrate of isoenzyme CYP3A4.
Antiepileptic drugs - phenobarbital - phenytoin	Inductors of isoenzyme CYP3A4.
N-cholinolytics (muscle relaxants) - neuromuscular blockers	Methylprednisolone may affect anticholinergic drugs. 1. reported cases of acute myopathy with simultaneous use of high doses of methylprednisolone and n-cholinolytics. 2. antagonism of the effect of blockade of pancuronium with simultaneous application with methylprednisolone was noted. This effect can be expected with any neuromuscular blocking blocker.
Hypoglycemic drugs	As methylprednisolone can increase the concentration of glucose in the blood plasma, should adjust the dose of hypoglycemic drugs.
Antiemetic drugs - aprepitant - fosaprepitant	Inhibitors and substrates of isoenzyme CYP3A4.
Antifungal drugs - itraconazole - ketoconazole	Inhibitors and substrates of isoenzyme CYP3A4.
Antiviral drugs - HIV protease inhibitors	Inhibitors and substrates of isoenzyme CYP3A4. HIV protease inhibitors, such as indinavir and ritonavir, can increase the concentration of methylprednisolone in the blood plasma. Methylprednisolone may enhance the metabolism of HIV protease inhibitors, which will lead to a decrease in their plasma concentration.
Aromatase inhibitors - aminoglutethimide	Suppression of adrenal function induced by aminoglutethimide can inhibit the endocrine changes caused by prolonged therapy with methylprednisolone.
Calcium channel blockers - diltiazem	Inhibitors and substrates of isoenzyme CYP3A4.
Oral contraceptive drugs - ethinyl estradiol / norethindrone	Inhibitors and substrates of isoenzyme CYP3A4.
Grapefruit juice	Inhibitor of isoenzyme CYP3A4.
Immunosuppressive drugs - cyclosporine	Inhibitors and substrates of isoenzyme CYP3A4. 1. The simultaneous use of methylprednisolone and cyclosporine causes mutual inhibition of metabolism, which can lead to an increase in the concentration in the blood plasma of one or both drugs.Therefore, it is likely that the side effects associated with the use of each of these drugs as monotherapy, with their joint application may occur more often. 2. When joint use of these drugs, cases of seizures were noted.
Immunosuppressive drugs: - cyclophosphamide - tacrolimus	Substrates of the isoenzyme CYP3A4.
Antibiotics-macrolides: - clarithromycin - erythromycin	Inhibitors and substrates of isoenzyme CYP3A4.
Non-steroidal anti-inflammatory drugs (NSAIDs): - high doses of aspirin (acetylsalicylic acid)	1. Probably increased incidence of gastrointestinal bleeding and ulceration with simultaneous use of methylprednisolone and NSAIDs. 2. Methylprednisolone may increase the clearance of acetylsalicylic acid taken in high doses for long periods, which can lead to reduced serum salicylate or salicylates increase the risk of toxicity when canceling methylprednisolone. Caution should be given to acetylsalicylic acid in combination with methylprednisolone.
Drugs that reduce the concentration of potassium in the blood plasma	With the simultaneous use of methylprednisolone and drugs that reduce the concentration of potassium in the blood plasma (eg, diuretics, amphotericin B), patients should be carefully monitored for the development of hypokalemia. It should also be noted that there is an increased risk of hypokalemia with simultaneous use of methylprednisolone and xanthines or beta2-agonists.
Cardiac glycosides	In patients with hypokalemia with the simultaneous use of methylprednisolone and cardiac glycosides, the risk of arrhythmias is increased.
Cholinesterase inhibitors	SCS can reduce the effect of cholinesterase inhibitors in patients with myasthenia gravis gravis.

Incompatibility

The following drugs are not compatible with methylprednisolone in solution: allopurinol sodium, doxapram hydrochloride, tigecycline, diltiazema hydrochloride, calcium gluconate, vecuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate, propofol. Methylprednisolone can suppress reactions during skin tests.

Special instructions:

- Since the complications of therapy with Metiredop® Orion depend on the dose and duration of treatment,in each case, based on the analysis of the risk / benefit ratio, a decision is made on the need for such treatment, and also determines the duration of treatment and the frequency of admission.

- In order to better control the patient's condition, the lowest dose of Metipred® Orion should be used. When the effect is achieved, if possible, gradually reduce the dose to a maintenance dose or discontinue treatment.

- In view of the risk of arrhythmia, the use of Metipred® Orion in high doses should be carried out in a hospital equipped with the necessary equipment (electrocardiograph, defibrillator).

- If long-term spontaneous remission occurs, treatment should be discontinued.

- With prolonged treatment, the patient should undergo a regular examination (radiography of the chest, blood glucose concentration in 2 hours after meals, general urine analysis, blood pressure, body weight control, it is desirable to conduct an x-ray or endoscopic examination if there is a history of gastric ulcer diseases, intestinal tract).

- It is necessary to carefully monitor the growth and development of children who are on long-term therapy with Metipred® Orion. Growth retardation can be observed in children receiving a long daily divided into several doses of therapy.

Long-term daily use of the drug in children is possible only in absolute terms. The use of the drug every other day may reduce the risk of developing this side effect or avoid it altogether.

- Children receiving long-term therapy with Metired ® Orion are at increased risk for developing intracranial hypertension.

- Metipred® Orion should also be administered with great care to patients with confirmed or suspected parasitic infections, such as strongyloidiasis. Methylprednisolone-induced immunosuppression, in such patients, leads to strongyloid hyperinfection and dissemination of the process with widespread migration of larvae, often with the development of severe forms of enterocolitis and Gram-negative septicemia with possible fatal outcome.

- Patients receiving drugs that suppress the immune system are more susceptible to infections than healthy individuals.For example, chicken pox and measles may have a more severe course, up to a lethal outcome in unimmunized children or in adults receiving Metipred® Orion.

- The efficacy of Metipred® Orion in septic shock is questionable. The results of a systematic review of the use of the drug in short courses in high doses do not support the possibility of their use in this mode.

- Patients who may be exposed to stress on the background of therapy with Metipred® Orion show an increase in the dose of the drug before, during and after a stressful situation.

- Due to the fact that there was an increase in lethality after 2 weeks or 6 months after head injury in patients treated with methylprednisolone sodium succinate, compared with placebo, Metipred® Orion should not be used for brain edema caused by head trauma. Causation of deaths with the use of methylprednisolone sodium succinate is not established.

- Against the background of therapy with Metipred® Orion, the susceptibility to infections may increase, some infections can occur in an erased form, and new infections can develop. In addition, the ability of the body to localize the infection process decreases.The development of infections caused by various pathogenic organisms, such as viruses, bacteria, fungi, protozoa or helminths that are localized in various human body systems, can be associated with the use of Metipred® Orion, both as monotherapy and in combination with other immunosuppressants , affecting cellular immunity, humoral immunity or neutrophil function. These infections can be mild, however, in some cases, a severe course and even a lethal outcome is possible.

Moreover, higher doses of the drug are used, the higher the probability of developing infectious complications.

- Patients treated with Metipred® Orion at doses that have immunosuppressive effects are not allowed to administer live or live attenuated vaccines, but dead or inactivated vaccines may be administered, but the response to administration of such vaccines may be reduced or even absent. Patients receiving treatment with Metired ® Orion in doses that do not have immunosuppressive action can be immunized according to the appropriate indications.

- The use of Metipred® Orion with active tuberculosis should be limited to cases of fulminant and disseminated tuberculosis, when methylprednisolone are used to treat the disease in combination with appropriate anti-tuberculosis chemotherapy.

- If Medetipen ® Orion is prescribed for patients with latent tuberculosis or positive tuberculin samples, treatment should be performed under strict medical supervision, as the disease can be reactivated. During prolonged therapy with the drug, such patients should receive appropriate preventive treatment.

- It is reported that in patients receiving methylprednisolone therapy, Kaposi's sarcoma was noted. With the withdrawal of the drug may come a clinical remission.

- Since patients who receive parenteral therapy with methylprednisolone rarely develop skin reactions and anaphylactic / anaphylactoid reactions, appropriate preventive measures should be taken before the administration of the drug, especially if the patient has had an allergic reaction to any medication in the history.Possible development of skin atrophy and subcutaneous fat at the injection site. It is necessary to avoid the introduction of the drug into the deltoid muscle.

- When methylprednisolone is administered intrathecally or epidurally, severe complications can develop. With prolonged therapy with high doses, the development of epidural lipomatosis is possible.

- When applying methylprednisolone in therapeutic doses for a long period, suppression of the hypothalamic-pituitary-adrenal system (secondary adrenocortical insufficiency) may develop. The degree and duration of insufficiency of the adrenal cortex are individual for each patient and depend on the dose, frequency of application, time of administration and duration of therapy. The severity of this effect can be reduced by using the drug every other day or by gradually reducing the dose. This type of relative insufficiency of the adrenal cortex can continue for several months after the end of treatment, therefore, under any stressful situations during this period, it is necessary to reassign methylprednisolone.

- The development of acute adrenal insufficiency, leading to a fatal outcome, is possible with a sharp abolition of methylprednisolone.

- The "cancellation" syndrome, apparently not related to adrenal insufficiency, can also occur due to the abrupt withdrawal of Metipred® Orion. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, skin peeling, myalgia, weight loss and lowering blood pressure. It is assumed that these effects arise due to a sharp fluctuation in the concentration of methylprednisolone in the blood plasma, and not because of a decrease in the concentration of methylprednisolone in the blood plasma. In patients with pheochromocytoma, it is possible to develop sympathetic adrenal crises (including fatal outcome).

- In patients with hypothyroidism or cirrhosis, the effect of methylprednisolone is enhanced. Pulse therapy with methylprednisolone may lead to the development of drug-induced liver damage.

- When high doses of methylprednisolone are used, it is possible to develop acute pancreatitis, including in children.

- The use of methylprednisolone can lead to an increase in the concentration of glucose in the blood plasma, worsening of the current diabetes.Patients receiving prolonged therapy with methylprednisolone may be predisposed to developing diabetes mellitus.

- Against the background of therapy with the drug Metired ® Orion, it is possible to develop various mental disorders: from euphoria, insomnia, mood instability, personality changes and severe depression to acute mental manifestations. In addition, the already existing emotional instability or propensities to psychotic reactions may increase.

- Potentially severe mental disorders may occur with the use of the drug Metiredop® Orion. Symptoms usually appear within a few days or weeks after the start of therapy. Most reactions disappear either after a dose reduction or after the drug is discontinued. Despite this, specific treatment may be required.

- Patients and / or their relatives should be warned that if there is a change in the patient's psychological status (especially with the development of a depressive state and suicidal attempts) it is necessary to seek medical help. Also, patients or their relatives should be warned about the possibility of developing mental disorders during or immediately after lowering the dose of the drug or completely canceling it.

- Prolonged use of Metired ® Orion can lead to the emergence of posterior subcapsular cataract and nuclear cataract (especially in children), exophthalmos or glaucoma with possible damage to the optic nerve and provoke attachment of secondary eye fungal or viral infection.

- When methylprednisolone is used, it is possible to develop central serous chorioretinopathy and retinal detachment.

- When using the drug Metired Orion, there is an increase in blood pressure, fluid and salt retention in the body, loss of potassium, hypokalemic alkalosis. These effects are less pronounced when using synthetic derivatives, except for cases when they are used in large doses. It may be necessary to limit the need for salt and products containing sodium.

- Therapy with Metipred® Orion can mask the symptoms of peptic ulceration and in this case perforation or bleeding can develop without a significant pain syndrome. With the simultaneous use of methylprednisolone with NSAIDs, the risk of ulceration in the gastrointestinal tract increases.

- Such adverse reactions of Metipred® Orion from the cardiovascular system, such as dyslipidemia, increased blood pressure, can provoke new reactions in predisposed patients in case of high doses of the drug and prolonged treatment. In this regard, the drug Metired ® Orion should be used with caution in patients with risk factors for cardiovascular disease. Regular monitoring of heart function is necessary. The use of low doses of Metipred® Orion in a day can reduce the severity of these side effects.

- Nessesary to use methylprednisolone with caution in patients with thromboembolic complications at the present time or having a predisposition to their development. cases of thrombosis development are possible.

Effect on the ability to drive transp. cf. and fur:

In connection with the possibility of developing dizziness, visual impairment and weakness in the use of Metipred® Orion, caution should be exercised by persons driving vehicles or engaged in activities requiring increased concentration of attention and rapidity of motor reactions.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous and intramuscular injection, 250 mg.

Packaging:

For 250 mg of methylprednisolone in a bottle of transparent neutral glass (type I), the bottle is sealed with a rubber stopper and an aluminum lid for running in.

For 1 or 10 bottles in a cardboard box together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003467

Date of registration:26.02.2016

Expiration Date:26.02.2021

The owner of the registration certificate:Orion CorporationOrion Corporation Finland

Manufacturer: & nbsp

ORION CORPORATION Finland

Representation: & nbspOrion Pharma LLCOrion Pharma LLC

Information update date: & nbsp26.07.2016

Illustrated instructions

Instructions

Metipred® Orion (Metypred® Orion)