< 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