A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Entocort Side Effects, and Drug Interactions - Budesonide
Entocort Side Effects, and Drug Interactions - Budesonide
SIDE EFFECTS
The safety of ENTOCORT EC was evaluated in 651 patients. They
ranged in age from 17 to 74 (mean 35), 40% were male and 97% were white, 2.6%
were ³ 65 years of age. Five hundred and twenty
patients were treated with ENTOCORT EC 9 mg (total daily dose). In general,
ENTOCORT EC was well tolerated in these trials. The most common adverse events
reported were headache, respiratory infection, nausea, and symptoms of hypercorticism.
Clinical studies have shown that the frequency of glucocorticosteroid-associated
adverse events was substantially reduced with ENTOCORT EC capsules compared
with prednisolone at therapeutically equivalent doses. Adverse events occurring
in ³ 5% of the patients are listed in Table
2:
Table 2: Adverse Events Occurring in ³
5% of the Patients in any Treated Group
|
|
ENTOCORT EC 9 mg n=520
|
Placebo n=107
|
Prednisolone 40 mg n=145
|
Comparator* n=88
|
|
Adverse Event
|
Number (%)
|
Number (%)
|
Number (%)
|
Number (%)
|
|
Headache
|
107(21)
|
19(18)
|
31(21)
|
11(13)
|
|
Respiratory Infection
|
55(11)
|
7(7)
|
20(14)
|
5(6)
|
|
Nausea
|
57(11)
|
10(9)
|
18(12)
|
7(8)
|
|
Back Pain
|
36(7)
|
10(9)
|
17(12)
|
5(6)
|
|
Dyspepsia
|
31(6)
|
4(4)
|
17(12)
|
3(3)
|
|
Dizziness
|
38(7)
|
5(5)
|
18(12)
|
5(6)
|
|
Abdominal Pain
|
32(6)
|
18(17)
|
6(4)
|
10(11)
|
|
Flatulence
|
30(6)
|
6(6)
|
12(8)
|
5(6)
|
|
Vomiting
|
29(6)
|
6(6)
|
6(4)
|
6(7)
|
|
Fatigue
|
25(5)
|
8(7)
|
11(8)
|
0(0)
|
|
Pain
|
24(5)
|
8(7)
|
17(12)
|
2(2)
|
*This drug is not approved for the treatment of Crohn’s disease
in the United States.
Adverse events occurring in 520 patients treated with ENTOCORT
EC 9 mg (total daily dose), with an incidence <5% and greater than placebo
(n=107), are listed below by body system:
Body as a Whole: asthenia, C-Reactive protein increased,
chest pain, dependent edema, face edema, flu-like disorder, malaise;
Cardiovascular: hypertension;
Central and Peripheral Nervous System: hyperkinesia,
paresthesia, tremor, vertigo;
Gastrointestinal: anus disorder, Crohn’s disease aggravated,
enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids,
intestinal obstruction, tongue edema, tooth disorder;
Hearing and Vestibular: Ear infection-not otherwise
specified;
Heart Rate and Rhythm: palpitation, tachycardia;
Metabolic and Nutritional: hypokalemia, weight increase;
Musculoskeletal: arthritis aggravated, cramps, myalgia;
Psychiatric: agitation, appetite increased, confusion,
insomnia, nervousness, sleep disorder, somnolence;
Resistance Mechanism: moniliasis;
Reproductive, Female: intermenstrual bleeding, menstrual
disorder;
Respiratory: bronchitis, dyspnea;
Skin and Appendages: acne, alopecia, dermatitis, eczema,
skin disorder, sweating increased;
Urinary: dysuria, micturition frequency, nocturia;
Vascular: flushing;
Vision: eye abnormality, vision abnormal;
White Blood Cell: leukocytosis
Glucocorticosteroid Adverse Reactions
Table 3 displays the frequency and incidence of symptoms of
hyper-corticism by active questioning of patients in clinical trials.
Table 3: Summary and Incidence of Symptoms of Hypercorticism
|
|
ENTOCORT EC 9 mg n=427
|
Placebo n=107
|
Prednisolone Taper 40 mg n=145
|
|
Symptom
|
Number (%)
|
Number (%)
|
Number (%)
|
|
Acne
|
63(15)
|
14(13)
|
33(23)*
|
|
Bruising Easily
|
63(15)
|
12(11)
|
13(9)
|
|
Moon Face
|
46(11)
|
4(4)
|
53(37)*
|
|
Swollen Ankles
|
32(7)
|
6(6)
|
13(9)
|
|
Hirsutisma
|
22(5)
|
2(2)
|
5(3)
|
|
Buffalo Hump
|
6(1)
|
2(2)
|
5(3)
|
|
Skin Striae
|
4(1)
|
2(2)
|
0(0)
|
a Adverse event dictionary included term hair growth
increased, local and hair growth increased, general.
*Statistically significantly different from ENTOCORT EC 9 mg
In addition to the symptoms in Table 3, three cases of benign
intracranial hypertension have been reported in patients treated with budes-onide
from post-marketing surveillance. A cause and effect relationship has not been
established.
CLINICAL LABORATORY TEST FINDINGS
The following potentially clinically significant laboratory
changes in clinical trials, irrespective of relationship to ENTOCORT EC, were
reported in ³ 1% of patients: hypokalemia, leukocytosis,
anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline
phosphatase increased, atypical neutrophils, C-reactive protein increased, and
adrenal insufficiency.
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 hepatocel-lular 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 hepatocycte 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 cortico-steroids, 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
Glucocorticosteroids are secreted in human milk. Because of the potential for adverse reactions in nursing infants from any cortico-steroid, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The amount of budesonide secreted in breast milk has not been determined.
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.
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