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6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials for UCERIS rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of 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.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune system disorders: anaphylactic reactions

Nervous system disorders: dizziness, benign intracranial hypertension

Psychiatric disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculopapular rash, allergic dermatitis

7 DRUG INTERACTIONS

7.1 CYP3A4 Inhibitors

The active ingredient of UCERIS rectal foam, budesonide, is metabolized by CYP3A4. Inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine and grapefruit juice) can increase systemic budesonide concentrations. Avoid concomitant use of CYP3A4 inhibitors with UCERIS rectal foam [see Clinical Pharmacology (12.3)].

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 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, 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 of 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 wasteratogenic 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 1.2 times the recommended human intrarectal 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 0.12 times the recommended

human intrarectal dose of 4 mg/day 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 0.02 times the recommended human

intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human

intrarectal dose of 4 mg/day on a body surface area basis).

In a pre-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 0.05 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 rectal foam or other rectally administered 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 rectal foam and any potential adverse effects on the breastfed child from UCERIS

rectal foam or from the underlying maternal condition. Data

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

the milk/plasma ratio ranged 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 systemic exposure (AUC0-

12) following administration of 400 mcg twice a day of inhaled budesonide ranged from 1.27 to 2.26 ng*hr/mL. The

estimated budesonide AUC0-12 following rectal administration of 2 mg twice a day UCERIS was 4.31 ng*hr/mL [see

Clinical Pharmacology (12.3)]. Budesonide exposure to the nursing child may be higher with maternal rectal

administration of UCERIS than with maternal inhaled administration of budesonide.

8.4 Pediatric Use

The safety and effectiveness of UCERIS rectal foam has not been established in pediatric patients.

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This

negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitaryadrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

8.5 Geriatric Use

Clinical studies with UCERIS rectal foam did not include sufficient numbers of patients aged 65 and over to determine

whether they respond differently than younger patients. 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.

8.6 Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate

to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of

hypercorticism. Discontinuing the use of UCERIS rectal foam should be considered in these patients if signs of

hypercorticism are observed [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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