Estilsona 7 mg инструкция на русском

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<‘Undesirable effects’).

Raised intracranial pressure Raised intracranial pressure with papilloedema (pseudotumour cerebri) associated with corticosteroid treatment has been reported in both children and adults.’Undesirable effects’).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Use in the elderly

Treatment of elderly patients, particularly if long term, should be undertaken with caution bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life threatening reactions.

Paediatric population

Corticosteroids cause growth retardation in infancy, childhood and adolescence, which may be irreversible, and therefore long-term administration of pharmacological doses should be avoided. If prolonged therapy is necessary, treatment should be limited to the minimum suppression of the hypothalamo-pituitary adrenal axis and growth retardation. The growth and development of infants and children should be closely monitored. Treatment should be administered where possible as a single dose on alternate days.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Alterations in Endocrine Function

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving corticosteroids already, dosage may have to be increased.

Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Mineralocorticoid supplementation is of particular importance in infancy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Increased Risks Related to Infection

Corticosteroids may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. The degree to which the dose, route and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized, however, with increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Corticosteroids may mask some signs of infection and may reduce resistance to new infections.

Corticosteroids may exacerbate infections and increase risk of disseminated infections.

The use of prednisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate anti-tuberculous regimen.

Chickenpox and measles can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions.

Corticosteroids may increase risk of reactivation or exacerbation of latent infection.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Corticosteroids should not be used in cerebral malaria.

Alterations in Cardiovascular/Renal Function

Corticosteroids can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. These agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Use in Patients with Gastrointestinal Disorders

There is an increased risk of gastrointestinal perforation in patients with certain GI disorders. Signs of GI perforation, such as peritoneal irritation may be masked in patients receiving corticosteroids.

Corticosteroids should be used with caution if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; and active or latent peptic ulcer.

Behavioral and Mood Disturbances

Corticosteroids use may be associated with central nervous system effects ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Decrease in Bone Density

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy and bone density should be monitored in patients on long term corticosteroid therapy.

Ophthalmic Effects

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Intraocular pressure may become elevated in some individuals. If corticosteroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered; however, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.

Effect on Growth and Development

Long-term use of corticosteroids can have negative effects on growth and development in children.

Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully monitored.

Use in Pregnancy

Prednisone can cause fetal harm when administered to a pregnant woman. Human and animal studies suggest that use of corticosteroids during the first trimester of pregnancy is associated with an increased risk of orofacial clefts, intrauterine growth restriction, and decreased birth weight. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

Neuromuscular Effects

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect.

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Kaposi’s Sarcoma

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Prednisone was not formally evaluated in carcinogenicity studies. Review of the published literature identified carcinogenicity studies of prednisolone, the active metabolite of prednisone, at doses which were less than the typical clinical doses. In a 2-year study, male Sprague-Dawley rats administered prednisolone in drinking water at a dose of 368 mcg/kg/day (equivalent to 3.5 mg/day in a 60-kg individual based on a mg/m² body surface area comparison) developed increased incidences of hepatic adenomas. Lower doses were not studied, and therefore, a no effect level could not be identified. In an 18-month study, intermittent oral gavage administration of prednisolone did not induce tumors in female Sprague-Dawley rats when given 1, 2, 4.5, or 9 times per month at 3 mg/kg prednisone (equivalent to 29 mg in a 60-kg individual based on a mg/m² body surface area comparison).

Prednisone was not formally evaluated for genotoxicity. However, in published studies prednisolone was not mutagenic with or without metabolic activation in the Ames bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli, or in a mammalian cell gene mutation assay using mouse lymphoma L5178Y cells, according to current evaluation standards. In a published chromosomal aberration study in Chinese Hamster Lung (CHL) cells, a slight increase was seen in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested, however, the effect appears to be equivocal. Prednisolone was not genotoxic in an in vivo micronucleaus assay in the mouse, though the study design did not meet current criteria.

Prednisone was not formally evaluated in fertility studies. However, menstrual irregularities have been described with clinical use.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D : Multiple cohort and case controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip with or without cleft palate from about 1/1000 infants to 3-5/1000 infants. Two prospective case control studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.

RAYOS was not formally evaluated for effects on reproduction. Published literature indicates prednisolone, the active metabolite of prednisone, has been shown to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring. In teratogenicity studies, cleft palate along with elevation of fetal lethality (or increase in resorptions) and reductions in fetal body weight were seen in rats at maternal doses of 30 mg/kg (equivalent to 290 mg in a 60 kg individual based on mg/m² body surface comparison) and higher. Cleft palate was observed in mice at a maternal dose of 20 mg/kg (equivalent to 100 mg in a 60 kg individual based on mg/m² comparison). Additionally, constriction of the ductus arteriosus has been observed in fetuses of pregnant rats exposed to prednisolone.

In humans, the risk of decreased birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses. It is likely that underlying maternal conditions contribute to intrauterine growth restriction and decreased birth weight, but it is unclear to what extent these maternal conditions contribute to the increased risk of orofacial clefts.

Prednisolone can cause fetal harm when used in pregnancy. RAYOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Prednisolone, the active metabolite of prednisone, is secreted in human milk. Reports suggest that prednisolone concentrations in human milk are 5 to 25% of maternal serum levels, and that total infant daily doses are small, about 0.14% of the maternal daily dose. The risk of infant exposure to prednisolone through breast milk should be weighed against the known benefits of breastfeeding for both the mother and baby.

Caution should be exercised when RAYOS is administered to a nursing woman. If RAYOS must be prescribed to a breastfeeding mother, the lowest dose should be prescribed to achieve the desired clinical effect. High doses of corticosteroids for long periods could potentially produce problems in infant growth and development and interfere with endogenous corticosteroid production.

Pediatric Use

The efficacy and safety of prednisone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome ( > 2 years of age), and aggressive lymphomas and leukemias ( > 1 month of age). However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of prednisone in pediatric patients are similar to those in adults. Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience with prednisone has not identified differences in responses between the elderly and younger patients. However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and are dose-related. Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls. Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e., ≥ 5 mg/day). Prednisone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involution osteoporosis. Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level. Co­administration of certain bisphosphonates have been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment of corticosteroid-induced osteoporosis.

It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Care should be taken to ensure that the eye is not infected before Minims Prednisolone is used.

Systemic absorption may be reduced by compressing the lacrimal sac at the medial canthus for a minute during and following the instillation of the drops. (This blocks the passage of drops via the naso-lacrimal duct to the wide absorptive area of the nasal and pharyngeal mucosa. It is especially advisable in children.).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Alterations in Endocrine Function

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving corticosteroids already, dosage may have to be increased.

Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Mineralocorticoid supplementation is of particular importance in infancy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Increased Risks Related to Infection

Corticosteroids may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. The degree to which the dose, route and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized, however, with increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Corticosteroids may mask some signs of infection and may reduce resistance to new infections.

Corticosteroids may exacerbate infections and increase risk of disseminated infections.

The use of prednisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate anti-tuberculous regimen.

Chickenpox and measles can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions.

Corticosteroids may increase risk of reactivation or exacerbation of latent infection.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Corticosteroids should not be used in cerebral malaria.

Alterations in Cardiovascular/Renal Function

Corticosteroids can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. These agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Use in Patients with Gastrointestinal Disorders

There is an increased risk of gastrointestinal perforation in patients with certain GI disorders. Signs of GI perforation, such as peritoneal irritation may be masked in patients receiving corticosteroids.

Corticosteroids should be used with caution if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; and active or latent peptic ulcer.

Behavioral and Mood Disturbances

Corticosteroids use may be associated with central nervous system effects ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Decrease in Bone Density

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy and bone density should be monitored in patients on long term corticosteroid therapy.

Ophthalmic Effects

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Intraocular pressure may become elevated in some individuals. If corticosteroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered; however, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.

Effect on Growth and Development

Long-term use of corticosteroids can have negative effects on growth and development in children.

Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully monitored.

Use in Pregnancy

Prednisone can cause fetal harm when administered to a pregnant woman. Human and animal studies suggest that use of corticosteroids during the first trimester of pregnancy is associated with an increased risk of orofacial clefts, intrauterine growth restriction, and decreased birth weight. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

Neuromuscular Effects

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect.

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Kaposi’s Sarcoma

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Prednisone was not formally evaluated in carcinogenicity studies. Review of the published literature identified carcinogenicity studies of prednisolone, the active metabolite of prednisone, at doses which were less than the typical clinical doses. In a 2-year study, male Sprague-Dawley rats administered prednisolone in drinking water at a dose of 368 mcg/kg/day (equivalent to 3.5 mg/day in a 60-kg individual based on a mg/m² body surface area comparison) developed increased incidences of hepatic adenomas. Lower doses were not studied, and therefore, a no effect level could not be identified. In an 18-month study, intermittent oral gavage administration of prednisolone did not induce tumors in female Sprague-Dawley rats when given 1, 2, 4.5, or 9 times per month at 3 mg/kg prednisone (equivalent to 29 mg in a 60-kg individual based on a mg/m² body surface area comparison).

Prednisone was not formally evaluated for genotoxicity. However, in published studies prednisolone was not mutagenic with or without metabolic activation in the Ames bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli, or in a mammalian cell gene mutation assay using mouse lymphoma L5178Y cells, according to current evaluation standards. In a published chromosomal aberration study in Chinese Hamster Lung (CHL) cells, a slight increase was seen in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested, however, the effect appears to be equivocal. Prednisolone was not genotoxic in an in vivo micronucleaus assay in the mouse, though the study design did not meet current criteria.

Prednisone was not formally evaluated in fertility studies. However, menstrual irregularities have been described with clinical use.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D : Multiple cohort and case controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip with or without cleft palate from about 1/1000 infants to 3-5/1000 infants. Two prospective case control studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.

Estilsona was not formally evaluated for effects on reproduction. Published literature indicates prednisolone, the active metabolite of prednisone, has been shown to be teratogenic in rats, rabbits, hamsters, and mice with increased incidence of cleft palate in offspring. In teratogenicity studies, cleft palate along with elevation of fetal lethality (or increase in resorptions) and reductions in fetal body weight were seen in rats at maternal doses of 30 mg/kg (equivalent to 290 mg in a 60 kg individual based on mg/m² body surface comparison) and higher. Cleft palate was observed in mice at a maternal dose of 20 mg/kg (equivalent to 100 mg in a 60 kg individual based on mg/m² comparison). Additionally, constriction of the ductus arteriosus has been observed in fetuses of pregnant rats exposed to prednisolone.

In humans, the risk of decreased birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses. It is likely that underlying maternal conditions contribute to intrauterine growth restriction and decreased birth weight, but it is unclear to what extent these maternal conditions contribute to the increased risk of orofacial clefts.

Prednisolone can cause fetal harm when used in pregnancy. Estilsona should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Prednisolone, the active metabolite of prednisone, is secreted in human milk. Reports suggest that prednisolone concentrations in human milk are 5 to 25% of maternal serum levels, and that total infant daily doses are small, about 0.14% of the maternal daily dose. The risk of infant exposure to prednisolone through breast milk should be weighed against the known benefits of breastfeeding for both the mother and baby.

Caution should be exercised when Estilsona is administered to a nursing woman. If Estilsona must be prescribed to a breastfeeding mother, the lowest dose should be prescribed to achieve the desired clinical effect. High doses of corticosteroids for long periods could potentially produce problems in infant growth and development and interfere with endogenous corticosteroid production.

Pediatric Use

The efficacy and safety of prednisone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome ( > 2 years of age), and aggressive lymphomas and leukemias ( > 1 month of age). However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of prednisone in pediatric patients are similar to those in adults. Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience with prednisone has not identified differences in responses between the elderly and younger patients. However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and are dose-related. Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls. Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e., ≥ 5 mg/day). Prednisone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involution osteoporosis. Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level. Co­administration of certain bisphosphonates have been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment of corticosteroid-induced osteoporosis.

It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

A prednisone-based pharmacotherapy should only be given when absolutely necessary and should be accompanied by appropriate anti-infectious therapy in the presence of the following conditions:

— Acute viral infections (herpes zoster, herpes simplex, varicella, herpetic keratitis),

— HBsAg-positive chronic active hepatitis,

— Approximately 8 weeks before and 2 weeks after immunisation with live vaccines,

— Systemic mycoses and parasitoses (e.g. nematodes),

— Poliomyelitis,

— Lymphadenitis following BCG inoculation,

— Acute and chronic bacterial infections,

— History of tuberculosis (caution: reactivation!) Due to their immunosuppressive properties glucocorticoids can induce or aggravate infections. Such patients should be monitored carefully e.g. by performing a tuberculin test. Patients at special risk should receive a tuberculostatic treatment.

In addition, a prednisone-based pharmacotherapy should only be given when necessary and should be accompanied if required by appropriate therapy in the presence of the following conditions:

— Gastrointestinal ulcers,

— Severe osteoporosis and osteomalacia

— Hypertension that is difficult to control,

— Severe diabetes mellitus,

— Psychiatric disorders (also if in patient’s history),

— Narrow- and wide-angle glaucoma,

— Corneal ulcers and corneal injuries.

Because of the risk of intestinal perforation, prednisone may only be used if absolutely necessary and with adequate monitoring in cases of:

— Severe ulcerative colitis with imminent perforation,

— Diverticulitis,

— Entero-anastomoses (immediately postoperative).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Scleroderma renal crisis

Caution is required in patients with systemic sclerosis because of an increased incidence of (possibly fatal) scleroderma renal crisis with hypertension and decreased urinary output observed with a daily dose of 15 mg or more prednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.

Lodotra cannot achieve the desired blood concentration of prednisone if taken under fasting conditions. Therefore, Lodotra should always be taken with or after the evening meal in order to ensure sufficient efficacy. In addition, low plasma concentrations may occur in 6% -7% of Lodotra doses as observed across all pharmacokinetic studies and 11% in a single pharmacokinetic study when taken according to the recommendations. This should be considered if Lodotra is not sufficiently effective. In these situations a switch to a conventional immediate-release formulation may be considered.

Lodotra should not be substituted by prednisone immediate-release tablets in the same administration regime because of Lodotra‘s delayed release mechanism.

In case of substitution, termination, or discontinuing prolonged treatment, the following risks must be considered: Recurrence of the rheumatoid arthritis disease activity, acute adrenal failure (especially in stressful situations, e. g. during infections, after accidents, with increased physical strain), cortisone withdrawal syndrome.

Lodotra should not be given as for acute indications instead of prednisone immediate-release tablets due to its pharmacological properties.

During the use of Lodotra, a possibly increased need for insulin or oral anti-diabetics should be considered. Patients with diabetes mellitus should therefore be treated under close monitoring.

During the treatment with Lodotra, regular blood pressure checks are required in patients with hypertension that is difficult to control.

Patients with severe cardiac insufficiency have to be closely monitored because of the risk of deterioration of the condition.

Caution is necessary when corticosteroids, including prednisone, are prescribed to a patient with recent myocardial infarction due to a risk of myocardial rupture.

Caution is necessary when corticosteroids, including prednisone, are prescribed to patients with renal insufficiency.

Sleep disorder is documented to occur more frequently with Lodotra than with conventional immediate release formulations which are taken in the morning. If insomnia occurs and does not improve, a switch to a conventional immediate release formulation may be advisable.

The treatment with Lodotra can also mask signs and symptoms of an existing or developing infection and thus may render diagnostic efforts more difficult.

Even with low doses, long-term use of Lodotra results in an increased risk of infection. These possible infections may also be brought about by microorganisms that rarely cause infection under normal circumstances (so-called opportunistic infections).

Certain viral diseases (varicella, measles) may take a more severe course in patients treated with glucocorticoids. Immunosuppressed individuals without prior varicella or measles infection are at particular risk. If such individuals, while being treated with Lodotra, have contact with persons infected with varicella or measles, a preventive treatment should be initiated, if required.

In patients with known or suspected Strongyloids (threadworm) infestation glucocorticoids may lead to Strongyloides hyperinfection and dissemination with widespread larval migration.

Vaccinations with inactivated vaccines are generally possible. However, it has to be taken into account that the immune response and consequently the success of the vaccination may be impaired with higher doses of glucocorticoids.

In case of long-term therapy with Lodotra, regular medical follow-ups (including ophthalmologic examinations at three month intervals) are indicated; if comparatively high doses are given, sufficient supply of potassium supplements and restriction of sodium have to be ensured and serum potassium levels have to be monitored.

If during the treatment with Lodotra high levels of physical stress are caused by certain events (accidents, surgical procedure etc.), a temporary dose increase may become necessary.

Depending on the duration of the treatment and the dosage used, a negative impact on calcium metabolism must be expected. Osteoporosis prophylaxis is therefore recommended and is particularly important if other risk factors are present (including familial predisposition, advanced age, postmenopausal status, insufficient intake of protein and calcium, excessive smoking, excessive alcohol consumption, as well as reduced physical activity). The prophylaxis is based on a sufficient supply of calcium and vitamin D, as well as on physical activity. In case of pre-existing osteoporosis, an additional therapy should be considered.

The medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

When using high doses of prednisolone for an extended period of time (30 mg/day for a minimum of 4 weeks), reversible disturbances of spermatogenesis were observed that persisted for several months after discontinuation of the medicinal product.

WARNINGS

Prolonged use of corticosteroids may result in posterior subcapsular cataract formation and may increase intraocular pressure in susceptible individuals, resulting in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections.

If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently. Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation.

Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication.

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended.

Estilsona^® suspension contains sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

PRECAUTIONS

General

The initial prescription and renewal of the medication order beyond 20 milliliters of PRED FORTE^® suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy, and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.

As fungal infections of the cornea are particularly prone to develop coincidentally with longterm local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been conducted in animals or in humans to evaluate the potential of these effects.

Pregnancy

Prednisolone has been shown to be teratogenic in mice when given in doses 1-10 times the human dose. Dexamethasone, hydrocortisone, and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice. There are no adequate well-controlled studies in pregnant women. Prednisolone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from prednisolone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness in pediatric patients have been established. Use in pediatric patients is supported by evidence from adequate and well-controlled studies of prednisolone acetate ophthalmic suspension in adults with additional data in pediatric patients.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

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Ответ опубликован 4 ноября 2015