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Entocort EC (Budesonide) - Warnings and Precautions

 
 



WARNINGS

Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since ENTOCORT EC is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

Care is needed in patients who are transferred from glucocorticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of systemic steroid should be reduced cautiously.

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package insert for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

PRECAUTIONS

General

Caution should be taken in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Replacement of systemic glucocorticosteroids with ENTOCORT EC capsules may unmask allergies, eg, rhinitis and eczema, which were previously controlled by the systemic drug.

When ENTOCORT EC capsules are used chronically, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur.

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis.

Information for Patients

ENTOCORT EC capsules should be swallowed whole and NOT CHEWED OR BROKEN.

Patients should be advised to avoid the consumption of grapefruit juice for the duration of their ENTOCORT EC therapy.

Patients should be given the patient package insert for additional information.

Drug Interactions

Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, intraconazole, ritonavir, indinavir, saquinavir, erythromycin, etc.) is indicated, reduction of the budesonide dose should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. As with other drugs primarily being metabolized through CYP3A4, ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide administration.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis).

Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

Pregnancy

Teratogenic Effects: Pregnancy Category C: As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis).

There are no adequate and well-controlled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Nursing Mothers

The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum.1 Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant).

The recommended daily dose of ENTOCORT EC capsules is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 μg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for a 800 μg daily dose of inhaled budesonide at steady state in the above inhalation study.

Since there are no data from controlled trials on the use of ENTOCORT EC by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from ENTOCORT EC, a decision should be made whether to discontinue nursing or to discontinue ENTOCORT EC, taking into account the clinical importance of ENTOCORT EC to the mother.

Budesonide, like other corticosteroids, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of ENTOCORT EC, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of ENTOCORT EC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, 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.

CLINICAL LABORATORY TEST FINDINGS

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to ENTOCORT EC, were reported in ≥1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, C-reactive protein increased, and adrenal insufficiency.

Page last updated: 2009-06-24

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