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E4ocort EC
(budesonide) Capsu!es
BRIEF SUMMARY: Before prescribing, please see full Prescribing
Information.
CLINICAL • PHARMACOLOGY: Drug - Drug Interactions:
Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can
increase the plasma levels of budesonide severalfold. Co-administration of
ketoconazole results in an eight-fold increase in AUC of budesonide.
compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal
CYP3A, approximately doubles the systemic exposure of oral budesonide.
Conversely, induction of CYP3A4 can result in the lowering of budesonide
plasma levels. Oral contraceptives containing ethinyl estradiol, which are also
metabolized by CYP3A4, do not affect the pharmacokinetics of budesonide.
Budesonide does not affect the plasma levels of oral contraceptives (ie, ethinyl
estradiol).
Since the dissolution of the coating of ENTOCORT EC is pH dependent
(dissolves at pH >5.5). the release properties and uptake of the compound
may be altered after treatment with drugs that change the gastrointestinal pH.
However. the gastric acid inhibitory drug omeprazole, 20 mg rid does not
affect the absorption or pharmacokinetics of ENTOCORT EC. When an
uncoated oral formulation of budesonide is co-administered with a daily dose
of cimetidine 1 g. a slight increase in the budesonide peak plasma concen-
tration and rate of absorption occurs. resulting in significant cortisol
suppression.
Food Effects: A mean delay in time to peak concentration of 2.5 hours is
observed with the intake of a high-fat meal, with no significant differences in
AUC.
PHARMACODYNAMICS: Budesonide has a high glucocorticoid effect
and a weak mineralocorticoid effect. and the affinity of budesonide to GCS
receptors, which reflects the intrinsic potency of the drug. is about 200-fold
that of cortisol and 15-fold that of prednisolone.
Treatment with systemically active GCS is associated with a suppression of
endogenous cortisol concentrations and an impairment of the hypothalamus-
pituitary-adrenal (HPA) axis function. Markers. indirect and direct. of this are
cortisol levels in plasma or urine and response to ACTH stimulation.
Plasma cortisol suppression was compared following five days' adminis-
tration of ENTOCORT EC capsules and prednisolone in a crossover study in
healthy volunteers. The mean decrease in the integrated 0-24 hour plasma
cortisol concentration was greater (78%) with prednisolone 20 mg/day
compared to 45% with ENTOCORT EC 9 mg/day.
CONTRAINDICATIONS: ENTOCORT EC is contraindicated in patients
with known hypersensitivity to budesonide.
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 wamings concerning glucocorticoids should be
followed.
Care is needed in patients who are transferred from glucourticosteroid
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 hyper-
tension. 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 adminis-
tration 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 ushers 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 glucocorticos-
teroid effects such as hypercorticism and adrenal suppression may occur.
Enlocortra EC (budesonide) Capsules
Entocoe EC (budesonide) Capsules
Entocoe EC (budesonide) Capsules
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, intra-
conazole, 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 intes-
tinal 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 recom-
mended 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 (approx-
imately 0.05 Ames 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 (approxi-
mately 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 (approxi-
mately 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 (approxi-
mately 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 recom-
mended 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
corticosteroid, 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.
ADVERSE REACTIONS: 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 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 glucocor-
licosteroid-associated adverse events was substantially reduced with
ENTOCORT EC capsules compared with prednisolone at therapeutically equiv-
alent doses.
Adverse Events Occurring in 5% of the Patients in any Treated Group
leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate
increased. alkaline phosphatase increased. atypical neutrophils, C-reactive
protein increased, and adrenal insufficiency.
OVERDOSAGE: Reports of acute toxicity and/or death following
overdosage of glucocorticosteroids are rare. Treatment consists of immediate
gastric lavage or emesis followed by supportive and symptomatic therapy.
If glucocorticosteroids are used at excessive doses for prolonged periods,
systemic glucocorticosteroid effects such as hypercorticism and adrenal
suppression may occur. For chronic overdosage in the face of severe disease
requiring continuous steroid therapy, the dosage may be reduced temporarily.
Single oral doses of 200 and 400 mg/kg were lethal in female and male mice,
respectively. The signs of acute toxicity were decreased motor activity,
piloerection and generalized edema.
Prednisolone Comparator'
DOSAGE AND ADMINISTRATION: The recommended adult
Placebo
ENTOCORT EC
dosage for the treatment of mild to moderate active Crohn's disease involving
40 mg
9 mg
the ileum and/or the ascending colon is 9 mg taken once daily in the morning
n.88
n.145
n420
n.107
for up to 8 weeks. Safety and efficacy of ENTOCORT EC in the treatment of
Number (%)
Number (%)
Number (%)
Number (%)
Adverse Event
active Crohn's Disease have not been established beyond 8 weeks.
31(21)
11(13)
19(18)
107(21)
Headache
For recurring episodes of active Crohn's Disease. a repeat 8 week course of
20(14)
5(6)
ENTOCORT EC can be given.
7(7)
55(11)
Respiratory Infection
Treatment with ENTOCORT EC capsules can be tapered to 6 mg daily for 2
7(8)
18(12)
10(9)
57(11)
Nausea
weeks prior to complete cessation.
17(12)
5(6)
10(9)
36(7)
Back Pain
Patients with mild to moderate active Crohn's disease involving the ileum
4(4)
17(12)
3(3)
31(6)
Dyspepsia
and/or ascending colon have been switched from oral prednisolone to
ENTOCORT EC with no reported episodes of adrenal insufficiency. Since
5(6)
18(12)
38(7)
5(5)
Dizziness
prednisolone should not be stopped abruptly, tapering-should begin concomi-
10(11)
18(17)
6(4)
32(6)
Abdominal Pain
tantly with initiating ENTOCORT EC treatment.
12(8)
5(6)
30(6)
6(6)
Flatulence
Hepatic insufficiency: Patients with moderate to severe liver disease should be
_monitored for increased signs and/or symptoms of hypercorticism. Reducing
6(7)
6(4)
6(6)
Vomiting
29(6)
the
dose of ENTOCORT EC capsules should be considered in these patients.
0(0)
11(8)
8(7)
Fatigue
25(5)
CYP3A4 Inhibitors: If concomitant administration with ketoconazole, or any
8(7)
17(12)
I
2(2)
I
Pain
24(5)
other CYP3A4 inhibitor, is indicated, patients should be closely monitored for
This drug is not approved for the treatment of Crohn's disease in the United increased signs and/or symptoms of hypercorticism. Reduction in the dose of
ENTOCORT EC capsules should be considered.
States.
ENTOCORT EC capsules should be swallowed whole and not chewed or
Adverse events occurring in 520 patients treated with ENTOCORT EC 9 mg broken.
(total daily dose), with an incidence <5% and greater than placebo (5.107),
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, pares-
thesia, tremor, vertigo: Gastrointestinal: anus disorder, Crohn's disease
aggravated, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemor-
rhoids, 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:
Summary and Incidence of Symptoms of Hypercorticism
Prednisolone Taper
Placebo
ENTOCORT EC
40 mg
9 mg
nr145
n=107
n=427
Number (%)
Number (%)
Number(%)
Acne
63(15)
14(13)
33(23)*
Bruising Easity
63(15)
12(11)
13(9)
Moon Face
46(11)
4(4)
53(37)'
Swollen Ankles
32(7)
I
6(6)
13(9)
Hirsutisma
22(5)
I
2(2)
5(3)
Buffalo Hump
6(1)
I
2(2)
5(3)
Skin Striae
4(1)
I
2(2)
0(0)
Symptom
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 this table, three cases of benign intracranial
hypertension have been reported in patients treated with budesonide from
post-marketing surveillance. A cause and effect relationship has not been
established.
CLINICAL LABORATORY TEST FINDINGS: The following poten-
tially clinically significant laboratory changes in clinical trials. irrespective of
relationship to ENTOCORT EC. were reported in ?.1°/. of patients: hypokalemia.
ENTOCORT is a trademark of the AstraZeneca group of companies.
0AstraZeneca 2003
Manufactured for:
AstraZeneca LP. Wilmington, DE 19850
By: AstraZeneca AB
S-151 85 Sodertalje, Sweden
209180 Rev. 8/02
AstraZeneca
r
I
I
This coupon is part of AstraZeneca's FREE Starter Supply for ENTOCORT"" EC (budesonide) Capsules.
To the Physician:
• In order to use this coupon, your patients will require one prescription for
forty-two (42) free capsules of ENTOCORT EC (3 mg)
• For your patients to continue on ENTOCORT EC beyond the free 2-week trial
period, you must also provide a separate prescription to cover the remainder of
your recommended therapy: Continued therapy is not covered under this coupon
• Refills will not be authorized with this coupon
To the Pharmacist:
• Please dispense this AstraZeneca medication at no copay to the patient
• No purchase required
• This coupon must be accompanied by a prescription for forty-two (42)
capsules of ENTOCORT EC (3 mg). -No substitutions permitted
• This coupon is good for one fill only. Please process any additional fills for
ENTOCORT EC as a new prescription with a new Rx number
• Limit one free trial coupon redemption per person for the duration of the program
Pharmacists should follow these easy steps:
• Transmit the claim to AdvancePCS only
• Please remove this coupon identification number from the patient profile after
the claim is processed so that patient confidentiality is maintained
• This coupon must be attached to the original prescription and retained by
pharmacy for audit purposes for the period of 3 years from the date of receipt or
the usual period for which your pharmacy records are kept, whichever is longer
•
• For assistance with this claim, please call the AdvancePCS Help Desk at
1-800-345-5413
I certify that I have received this coupon from an eligible patient (as described in
the Eligibility Restrictions), have dispensed the ENTOCORT EC product as
indicated, and have not submitted, and will not submit, a claim for reimbursement
to the patient orany third-party payor. I certify that my participation in this program
is consistent with all applicable state laws and any obligation, contractual or
otherwise, that I have as a pharmacy provider.
Pharmacist's Signature
-
2003
16
III
Coupon expiration date on reverse side.
Eligibility Restrictions:
This offer is not valid for prescriptions purchased under Medicaid, Medicare.
similar federal or state programs, or where prohibited by law. It is a violation of
federal law to trade. sell, counterfeit, or dispense any products other than
ENTOCORT EC with this coupon. Not valid if reproduced or submitted to any other
payor. No mail orders accepted. Offer good in USA only. AstraZeneca reserves the
right to rescind, revoke. or amend this offer without notice.
PerforrnanceScript is a registered trademark of AdvancePCS.
ENTOCORT is a trademark of the AstraZeneca group of companies.
© 2003 AstraZeneca LP. All rights reserved.
209549
9/02