Dexamethasone solution for injection 4 mg ampoule 1 ml No. 25

Instructions Dexamethasone solution for injection 4 mg ampoule 1 ml No. 25

Composition

active ingredient: dexamethasone phosphate;

1 ml of solution for injection contains 4 mg of dexamethasone phosphate as dexamethasone sodium phosphate;

excipients: glycerin, disodium edetate, sodium hydrogen phosphate dihydrate, water for injection.

Dosage form

Solution for injection.

Main physicochemical properties: transparent, colorless to pale yellow solution, practically free of mechanical inclusions.

Pharmacotherapeutic group

Corticosteroids for systemic use. ATC code H02A B02.

Pharmacological properties

Pharmacodynamics.

Dexamethasone is a semisynthetic adrenal hormone (corticosteroid) with glucocorticoid activity. It has anti-inflammatory and immunosuppressive effects, and also affects energy metabolism, glucose metabolism, and (via negative feedback) the secretion of hypothalamic-activating factor and adenohypophyseal trophic hormone.

The mechanism of action of glucocorticoids is still not fully understood. There are now enough reports on the mechanism of action of glucocorticoids to confirm that they act at the cellular level. There are two well-defined receptor systems in the cytoplasm of cells. By binding to glucocorticoid receptors, corticosteroids exert anti-inflammatory and immunosuppressive effects and regulate glucose metabolism, and by binding to mineralocorticoid receptors, they regulate sodium, potassium metabolism and water-electrolyte balance.

Glucocorticoids are lipid-soluble and readily penetrate target cells through the cell membrane. Binding of the hormone to the receptor results in a conformational change in the receptor, which increases its affinity for DNA. The hormone/receptor complex enters the nucleus of the cell and binds to a regulatory center of the DNA molecule, also called the glucocorticoid response element (GRE). The activated receptor, bound to the GRE or to specific genes, regulates mRNA transcription, which can be increased or decreased. The newly formed mRNA is transported to the ribosome, after which new proteins are formed. Depending on the target cells and the processes occurring in the cells, protein synthesis can be increased (for example, the formation of tyrosine transaminase in liver cells) or decreased (for example, the formation of IL-2 in lymphocytes). Since glucocorticoid receptors are present in all types of tissues, it can be assumed that glucocorticoids act on most cells of the body.

Impact on energy metabolism and glucose homeostasis

Dexamethasone, together with insulin, glucagon and catecholamines, regulates energy storage and utilization. In the liver, glucose formation from pyruvate or amino acids and glycogen formation are increased. In peripheral tissues, especially in muscle, glucose consumption and mobilization of amino acids (from proteins), which are substrates for gluconeogenesis in the liver, are reduced. Direct effects on fat metabolism are the central distribution of adipose tissue and an increase in the lipolytic response to catecholamines.

Using receptors in the renal proximal tubules, dexamethasone increases renal blood flow and glomerular filtration, inhibits the formation and secretion of vasopressin, and improves the kidneys' ability to excrete acids from the body.

By increasing the number of β-adrenergic receptors and the affinity for β-adrenergic receptors that transmit the positive inotropic effect of catecholamines, dexamethasone directly increases cardiac contractile function and peripheral vascular tone.

At high doses, dexamethasone inhibits fibroblast production of type I and type III collagen and the formation of glycosaminoglycans. Thus, by inhibiting the formation of extracellular collagen and matrix, wound healing is delayed. Long-term administration of high doses causes progressive bone resorption by indirect action and reduces osteogenesis by direct action (increased secretion of parathyroid hormone and decreased secretion of calcitonin), and also causes a negative calcium balance by reducing calcium absorption in the intestine and increasing its excretion in the urine. This usually leads to secondary hyperparathyroidism and phosphaturia.

Effects on the pituitary gland and hypothalamus

The anti-inflammatory and immunosuppressive effects of glucocorticoids are based on their molecular and biochemical effects. The molecular anti-inflammatory effect occurs as a result of binding to glucocorticoid receptors and as a result of changes in the expression of a number of genes that regulate the formation of various information molecules, proteins and enzymes involved in the inflammatory reaction. The biochemical anti-inflammatory effect of glucocorticoids is the result of blocking the formation and functioning of humoral mediators of inflammation: prostaglandins, thromboxanes, cytokines and leukotrienes. Dexamethasone reduces the formation of leukotrienes by reducing the release of arachidonic acid from cellular phospholipids, caused by inhibition of the activity of phospholipase A2. The effect on phospholipases is achieved not by direct action, but as a result of an increase in the concentration of lipocortin (macrocortin), which is an inhibitor of phospholipase A2. Dexamethasone inhibits the formation of prostaglandins and thromboxane by reducing the formation of specific mRNA and thereby the amount of cyclooxygenase formed. Dexamethasone also reduces the production of platelet-activating factor (PAF) by increasing the concentration of lipocortin. Other biochemical anti-inflammatory effects include a decrease in the formation of tumor necrosis factor (TNF) and interleukin (IL-1).

In animal studies, cleft palate has been observed in rats, mice, hamsters, rabbits, dogs, and primates, but not in horses or sheep. In some cases, cleft palate has been associated with central nervous system and cardiac defects. In primates, brain abnormalities have been observed after irradiation. In addition, intrauterine growth retardation may occur. All of these effects have been observed with high doses of dexamethasone.

The RECOVERY (Randomized Evaluation of COVid-19 thERapY) trial is an investigator-initiated, individually randomized, controlled, open-label, adaptive platform study to evaluate the effects of a potential treatment in patients hospitalized with COVID-19.

The trial was conducted in 176 hospital organizations in the UK.

A total of 6425 patients were randomized to receive either dexamethasone (2104 patients) or usual care alone (4321 patients). 89% of patients had laboratory-confirmed infection

SARS-CoV-2.

At randomization, 16% of patients received invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% received oxygen alone (with or without noninvasive ventilation), and 24% received neither.

The mean age of the patients was 66.1 +/- 15.7 years. 36% of the patients were female. 24% of the patients had a history of diabetes mellitus, 27% had heart disease, and 21% had chronic lung disease.

Primary endpoint

Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with mortality reported in 482 of 2104 patients (22.9%) and 1110 of 4321 patients (22.9%).

(25.7%), respectively (odds ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P < 0.001).

In the dexamethasone group, the mortality rate was lower than in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving supplemental oxygen without invasive ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94).

There was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91-1.55).

Secondary endpoints

Patients in the dexamethasone group had a shorter length of hospital stay than those in the usual care group (median, 12 days vs. 13 days) and were more likely to be discharged alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17).

According to the primary endpoint, the greatest effect on discharge within 28 days was observed in patients receiving invasive mechanical ventilation at randomization (rate ratio, 1.48; 95% CI, 1.16, 1.90), followed by oxygen alone (rate ratio, 1.15; 95% CI, 1.06-1.24), with no beneficial effect in patients not receiving oxygen (rate ratio, 0.96; 95% CI, 0.85-1.08).

*Ratios were adjusted for age for 28-day mortality and hospital discharge outcomes. Hazard ratios were adjusted for age for invasive mechanical ventilation or death and its components;

† This category excludes patients who received invasive mechanical ventilation at randomization.

During the study, 4 serious adverse events related to the study treatment were recorded, namely: 2 cases of hyperglycemia, 1 case of steroid-induced psychosis, and 1 case of upper gastrointestinal bleeding. All cases resolved.

Subgroup analysis

Effects of dexamethasone administration on 28-day mortality, depending on age and method of respiratory support, obtained by randomization2

Effects of dexamethasone administration on 28-day mortality, by respiratory support method, obtained at randomization, and by the presence of any chronic disease3

1 www.recoverytrial.net

2, 3 (source: Horby P. et al., 2020; https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1;

doi: https://doi.org/10.1101/2020.06.22.20137273).

Pharmacokinetics.

Absorption

Dexamethasone reaches peak plasma concentrations within the first 5 minutes after intravenous administration and within 1 hour after intramuscular administration. After local administration into a joint or soft tissue (inflammation site), absorption is slower than after intramuscular administration. With intravenous administration, the onset of action is immediate; after intramuscular administration, the clinical effect occurs after 8 hours. The effect lasts 17-28 days after intramuscular administration and from 3 days to 3 weeks after local administration.

Distribution

In blood plasma and synovial fluid, the conversion of dexamethasone phosphate to dexamethasone occurs very rapidly. In blood plasma, approximately 77% of dexamethasone is bound to plasma proteins, mainly albumin. Only a small amount of dexamethasone is bound to other proteins. Dexamethasone is fat-soluble, so it freely penetrates cells and the intercellular space. In the central nervous system (hypothalamus, pituitary gland) it binds and acts through membrane receptors. In peripheral tissues it binds and acts through cytoplasmic receptors.

Biotransformation

Dexamethasone is broken down at the site of action, i.e. within the cell itself. Dexamethasone is primarily metabolized in the liver, but also possibly in the kidneys and other tissues.

Breeding

The biological half-life of dexamethasone is 24-72 hours. It is mainly excreted in the urine.

Indication

Dexamethasone should be administered intravenously or intramuscularly in emergency cases and if oral administration is not possible.

Diseases of the endocrine system:

replacement therapy for primary or secondary (pituitary) adrenal insufficiency (except for acute adrenal insufficiency, in which hydrocortisone or cortisone are more suitable, given their more pronounced hormonal effect);

acute adrenal insufficiency (hydrocortisone or cortisone are the drugs of choice; concomitant use with mineralocorticoids may be necessary, especially when using synthetic analogues);

before operations and in cases of serious injuries or illnesses in patients with established adrenal insufficiency or with uncertain adrenocortical reserve;

shock resistant to conventional therapy, with existing or suspected adrenal insufficiency;

congenital adrenal hyperplasia;

non-purulent inflammation of the thyroid gland and severe forms of radiation thyroiditis.

Rheumatological diseases:

(as adjunctive therapy during the period when basic therapy was ineffective, i.e. in patients in whom the analgesic and anti-inflammatory effects of NSAIDs were unsatisfactory);

rheumatoid arthritis, including juvenile rheumatoid arthritis and extra-articular manifestations of rheumatoid arthritis (rheumatic lung, changes in the heart, eyes, cutaneous vasculitis);

synovitis in osteoarthritis; post-traumatic osteoarthritis; epicondylitis; acute nonspecific tendosynovitis; acute gouty arthritis; psoriatic arthritis; ankylosing spondylitis; systemic connective tissue diseases; vasculitis.

Skin diseases:

pemphigus; severe erythema multiforme (Stevens-Johnson syndrome); exfoliative dermatitis; bullous dermatitis herpetiformis; severe forms of exudative erythema; erythema nodosum; severe forms of seborrheic dermatitis; severe forms of psoriasis; urticaria that does not respond to standard treatment; mycosis fungoides; dermatomyositis.

Allergic diseases:

(that are not amenable to traditional treatment)

bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness; chronic or seasonal allergic rhinitis; drug allergy; urticaria after blood transfusion.

Diseases of the organs of vision:

inflammatory eye diseases (acute central choroiditis, optic neuritis); allergic diseases (conjunctivitis, uveitis, scleritis, keratitis, iritis); systemic immune diseases (sarcoidosis, temporal arteritis); proliferative changes in the orbit (endocrine ophthalmopathy, pseudotumor); immunosuppressive therapy during corneal transplantation.

The solution can be administered systemically or locally (subconjunctival injection and retrobulbar or parabulbar injection)

Gastrointestinal diseases:

to remove the patient from the critical period when:

ulcerative colitis (severe development); Crohn's disease (severe development); chronic autoimmune hepatitis; liver transplant rejection.

Respiratory tract diseases:

symptomatic sarcoidosis (symptomatically); acute toxic bronchiolitis; chronic bronchitis and asthma (during exacerbation); focal or disseminated pulmonary tuberculosis (along with appropriate anti-tuberculosis therapy); berylliosis (granulomatous inflammation); radiation or aspiration pneumonitis.

Hematological diseases:

acquired or congenital chronic aplastic anemia; autoimmune hemolytic anemia;

secondary thrombocytopenia in adults; erythroblastopenia; acute lymphoblastic leukemia (induction therapy); idiopathic thrombocytopenic purpura in adults (intravenous administration only, intramuscular administration is contraindicated).

Kidney diseases:

immunosuppressive therapy in kidney transplantation; stimulation of diuresis or reduction of proteinuria in idiopathic nephrotic syndrome (without uremia) and renal dysfunction in systemic lupus erythematosus.

Malignant oncological diseases:

palliative treatment of leukemia and lymphoma in adults; acute leukemia in children; hypercalcemia in malignant diseases.

Brain edema:

cerebral edema due to primary or metastatic brain tumor, craniotomy, and traumatic brain injury.

Shock:

shock that is not amenable to classical treatment; shock in patients with adrenal insufficiency; anaphylactic shock (intravenously after administration of adrenaline); before surgery to prevent shock in suspected or established adrenal insufficiency.

Other indications:

tuberculous meningitis with subarachnoid block (along with appropriate anti-tuberculosis therapy); trichinellosis with neurological symptoms or myocardial trichinellosis; cystic tumor of the aponeurosis or tendon (ganglion).

Dexamethasone KRKA is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and over with a body weight of at least 40 kg) who require supplemental oxygen therapy.

rheumatoid arthritis (severe inflammation of a single joint); ankylosing spondylitis (when inflamed joints do not respond to traditional treatment); psoriatic arthritis (oligoarticular form and tendovaginitis); monoarthritis (after evacuation of synovial fluid); osteoarthritis of the joints (only in the case of synovitis and exudation); extra-articular rheumatism (epicondylitis, tendovaginitis, bursitis); acute and gouty arthritis.

Local administration (administration to the lesion site):

keloid lesions; hypertrophic, inflammatory and infiltrated lesions in lichen, psoriasis, granuloma annulare, sclerosing folliculitis, discoid lupus and cutaneous sarcoidosis; discoid lupus erythematosus; Urbach-Oppenheim disease; localized alopecia.

Contraindication

Hypersensitivity to the active substance or to any other ingredient of the drug.

Acute viral, bacterial or systemic fungal infections (if not treated appropriately).

Cushing's syndrome.

Vaccination with a live vaccine.

Breastfeeding period (except in emergency cases).

Intramuscular administration is contraindicated in patients with severe blood clotting disorders.

Topical administration is contraindicated in bacteremia, systemic fungal infections, patients with unstable joints, and infections at the application site, including septic arthritis due to gonorrhea or tuberculosis.

Interaction with other medicinal products and other types of interactions

Concomitant use of dexamethasone and nonsteroidal anti-inflammatory drugs increases the risk of gastrointestinal bleeding and ulceration.

The effect of dexamethasone is reduced by concomitant use of drugs that activate the CYP 3A4 enzyme (phenytoin, phenobarbital, carbamazepine, primidone, rifabutin, rifampicin) or increase the metabolic clearance of glucocorticoids (ephedrine and aminoglutethimide). In these cases, the dose of dexamethasone should be increased. The interaction between dexamethasone and all of the above-mentioned drugs can distort the dexamethasone suppression test. This should be taken into account when evaluating the test results.

Concomitant use of dexamethasone and drugs that inhibit CYP 3A4 enzyme activity (ketoconazole, macrolides) may result in increased serum concentrations of dexamethasone. Dexamethasone is a moderate inducer of CYP 3A4. Concomitant use with drugs that are metabolized by CYP 3A4 (indinavir, erythromycin) may increase their clearance, resulting in decreased serum concentrations.

By inhibiting the enzyme CYP 3A4, ketoconazole may increase serum dexamethasone concentrations. On the other hand, ketoconazole may inhibit adrenal glucocorticoid synthesis, thus adrenal insufficiency may develop due to decreased dexamethasone concentrations.

Dexamethasone reduces the therapeutic effect of antidiabetic drugs, hypertension, praziquantel and natriuretics (therefore, the dose of these drugs should be increased), but increases the activity of heparin, albendazole and kaliuretics (the dose of these drugs should be reduced if necessary).

Dexamethasone may alter the effect of coumarin anticoagulants, so when using this combination of drugs, prothrombin time should be checked more frequently.

Concomitant use of high doses of glucocorticoids and b2-adrenergic agonists increases the risk of hypokalemia. In patients with hypokalemia, cardiac glycosides are more likely to cause arrhythmias and are more toxic.

Dexamethasone reduces the therapeutic effect of anticholinesterase agents used for myasthenia gravis.

Antacids reduce the absorption of dexamethasone in the stomach. The effect of dexamethasone when taken with food and alcohol has not been studied, but simultaneous use of the drug and food with a high sodium content is not recommended. Smoking does not affect the pharmacokinetics of dexamethasone.

Glucocorticoids increase the renal clearance of salicylates, so it is sometimes difficult to obtain therapeutic serum concentrations. Caution should be exercised in patients who are gradually reducing the dose of corticosteroids, as this may result in increased serum salicylate concentrations and intoxication.

If oral contraceptives are used concurrently, the half-life of glucocorticoids may be prolonged, which enhances their biological effects and may increase the risk of side effects.

Concomitant use of ritordin and dexamethasone is contraindicated during labor because it may result in maternal death due to pulmonary edema. Death from this condition has been reported.

Concomitant use of dexamethasone and thalidomide may cause toxic epidermal necrolysis.

Concomitant treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic adverse reactions. This combination should be avoided unless the benefit outweighs the risk, in which case the patient should be monitored for systemic corticosteroid effects.

Application features

Hypersensitivity reactions may rarely occur during parenteral corticosteroid treatment, therefore appropriate precautions should be taken before starting treatment with dexamethasone, taking into account the possibility of allergic reactions (especially in patients with a history of allergic reactions to any other drugs).

Severe psychiatric reactions may accompany systemic corticosteroid use. Symptoms usually appear within a few days or weeks of initiating therapy. The risk of these symptoms increases with higher doses. Most reactions resolve with dose reduction or discontinuation of therapy. Changes in mental status, especially depressed mood, suicidal ideation, and suicidal ideation, should be monitored and promptly identified. Corticosteroids should be used with caution in patients with a history of affective disorders, especially in patients with a history of allergic reactions to any other drug, and in close relatives. Undesirable effects can be avoided by using the lowest effective dose for the shortest duration possible or by taking the required daily dose once a day in the morning.

In patients treated with dexamethasone for a long time, withdrawal syndrome (without visible signs of adrenal insufficiency) may occur upon discontinuation of treatment with symptoms such as fever, runny nose, conjunctival redness, headache, dizziness, drowsiness or irritability, muscle and joint pain, vomiting, weight loss, general weakness, and often convulsions. Therefore, the dose of dexamethasone should be reduced gradually. Abrupt discontinuation may be fatal. If the patient is under severe stress (due to trauma, surgery, or serious illness) during therapy, the dose of dexamethasone should be increased, and if this occurs during discontinuation of treatment, hydrocortisone or cortisone should be used.

Patients who have been given dexamethasone for a long time and who experience severe stress after stopping therapy should resume dexamethasone, as the adrenal insufficiency caused by it may persist for several months after stopping treatment.

Treatment with dexamethasone or natural glucocorticoids may mask symptoms of existing or new infection, as well as symptoms of intestinal perforation.

Dexamethasone may exacerbate systemic fungal infection, latent amebiasis, and pulmonary tuberculosis.

Patients with active pulmonary tuberculosis should receive dexamethasone (along with anti-tuberculosis drugs) only in cases of rapid or highly disseminated pulmonary tuberculosis. Patients with inactive pulmonary tuberculosis treated with dexamethasone or patients who respond to tuberculin should receive chemical prophylactic agents.

Caution and medical supervision are recommended in patients with osteoporosis, arterial hypertension, heart failure, tuberculosis, glaucoma, hepatic or renal failure, diabetes, active peptic ulcer, recent intestinal anastomosis, ulcerative colitis and epilepsy. Special care is required in patients during the first weeks after myocardial infarction, patients with thromboembolism, myasthenia gravis, glaucoma, hypothyroidism, psychosis or psychoneurosis, and elderly patients.

During treatment, exacerbation of diabetes or transition from the latent phase to clinical manifestations of diabetes may occur.

During long-term treatment, serum potassium levels should be monitored.

Vaccination with live vaccines is contraindicated during treatment with dexamethasone. Vaccination with inactivated viral or bacterial vaccines does not induce the expected antibody response and does not have the expected protective effect. Dexamethasone should not usually be administered for 8 weeks prior to vaccination and should not be initiated for 2 weeks after vaccination.

Patients who are treated with high doses of dexamethasone for a long time and have never had measles should avoid contact with infected individuals; in case of accidental contact, prophylactic treatment with immunoglobulin is recommended.

Caution is advised in patients recovering from surgery or bone fractures, as dexamethasone may slow wound healing and bone formation.

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

Intra-articular administration of corticosteroids can lead to local and systemic effects. Frequent use can cause cartilage damage or bone necrosis.

Before intra-articular injection, synovial fluid should be removed from the joint and examined (checked for infection). Corticosteroids should be avoided in infected joints. If a joint infection develops after injection, appropriate antibiotic therapy should be initiated.

Patients should be advised to avoid physical exertion on the affected joints until the inflammation has resolved.

Corticosteroids may distort the results of skin allergy tests.

When treating coronavirus disease 2019 (COVID-19), systemic corticosteroids should not be discontinued in patients who are already being treated with systemic (oral) corticosteroids for other reasons (e.g., patients with chronic obstructive pulmonary disease) but do not require supplemental oxygen.

Visual disturbances may occur with systemic and topical corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, which may include cataracts, glaucoma, or rare conditions such as central serous chorioretinopathy (CSR), which have been reported following the use of systemic and topical corticosteroids.

Premature infants: Long-term neurodevelopmental impairment has been reported following early treatment (< 96 hours) of premature infants with chronic lung disease with initial doses of dexamethasone

0.25 mg/kg twice daily.

Special precautions for excipients

This medicine contains less than 1 mmol (23 mg) sodium per dose, which is essentially sodium.

Use during pregnancy or breastfeeding

Pregnancy.

Harmful effects on the fetus and newborn cannot be excluded. The drug inhibits intrauterine development of the child. Dexamethasone should be administered to pregnant women only in exceptional cases of emergency, when the expected benefit to the mother outweighs the potential risk to the fetus. Particular caution is recommended in preeclampsia. In accordance with general recommendations for treatment with glucocorticoids during pregnancy, the lowest effective dose should be used to control the underlying disease. Children born to mothers who were prescribed glucocorticoids during pregnancy should be carefully monitored for adrenal insufficiency.

Glucocorticoids cross the placenta and reach high concentrations in the fetus. Dexamethasone is less extensively metabolized in the placenta than, for example, prednisone. Accordingly, high concentrations of dexamethasone may be observed in the fetal serum. According to some data, even pharmacological doses of glucocorticoids may increase the risk of placental insufficiency, oligohydramnios, fetal growth retardation or intrauterine death, increased fetal leukocyte (neutrophil) count, and adrenal insufficiency. There is no evidence to support the teratogenic effect of glucocorticosteroids.

Administration of corticosteroids to pregnant animals may cause fetal malformations, including cleft palate, intrauterine growth retardation, and effects on brain growth and development. There is no evidence that corticosteroids increase the incidence of congenital malformations such as cleft palate/lip in humans (see Pharmacological Properties).

It is recommended to use additional doses of glucocorticosteroids during labor for women who took glucocorticosteroids during pregnancy. In cases of prolonged labor or planned cesarean section, intravenous administration of 100 mg of hydrocortisone every 8 hours is recommended.

Breast-feeding.

Use during breastfeeding is contraindicated (except in emergency cases).

Small amounts of glucocorticoids are excreted in breast milk, so breastfeeding is not recommended for mothers treated with dexamethasone, especially when used in excess of physiological doses (about 1 mg). This may lead to growth retardation in the infant and decreased secretion of endogenous corticosteroids.