Uceris (Page 2 of 5)

6.2 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following adverse reactions have been identified during post-approval use of oral budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to UCERIS, or a combination of these factors.

Gastrointestinal Disorders: diarrhea, rectal bleeding

General Disorders and Administrative Site Conditions: peripheral edema

Immune System Disorders: anaphylactic reactions

Musculoskeletal and Connective Tissue Disorders: muscle cramps/spasms

Nervous System Disorders: benign intracranial hypertension, dizziness

Psychiatric Disorders: mood swings

Skin and Subcutaneous Tissue Disorders: rash

Vascular Disorders: increased blood pressure

7 DRUG INTERACTIONS

7.1 Interaction with CYP3A4 Inhibitors

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, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS 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. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

7.2 Inhibitors of Gastric Acid Secretion

Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., proton pump inhibitors (PPIs), H2 blockers and antacids).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform

a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical

Considerations). In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of

budesonide during organogenesis at doses 0.5 times and 0.05 times, respectively, the maximum recommended human

dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed

in both rats and rabbits at these dose levels (see Data). Based on animal data, advise pregnant women of the potential risk

to a fetus.

The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All

pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the

estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and

15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy

outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of

gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be

carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed

accordingly [see Warnings and Precautions (5.1)].

Data

Animal Data

Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats

dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on

fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times

the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant

rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and

effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in

rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal

toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits

(approximately 0.01 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).

In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post

coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth

and during lactation at exposures 0.02 times the MRHD (on a mg/m2 basis at maternal subcutaneous doses of 20

mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

8.2 Lactation

Risk Summary

Lactation studies have not been conducted with UCERIS or other oral budesonide products and no information is

available on the effects of budesonide on the breastfed infant or the effects of the drug on milk production. One published

study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data). The

developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for

UCERIS and any potential adverse effects on the breastfed infant from UCERIS, or from the underlying maternal

condition.

Data

One published study reports that budesonide is present in human milk following maternal inhalation of budesonide

which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio

ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected, and no adverse events were noted in

the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of UCERIS is higher

(9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described 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 to 10 nmol/L which is up to 10 times higher than the 1 to

2 nmol/L for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the

coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of

UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation.

8.4 Pediatric Use

Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS, may cause a reduction of growth velocity in pediatric patients.

8.5 Geriatric Use

Clinical studies of UCERIS 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, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients [see Warnings and Precautions (5.4)].

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