Risk Summary
The available data from published case series, epidemiological studies and reviews with oral budesonide use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with IgA Nephropathy. Infants exposed to in-utero corticosteroids, including budesonide, are at risk for hypoadrenalism (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.3 times or 0.03 times, respectively, the maximum recommended human dose (MRHD), 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).
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
IgA nephropathy in pregnancy is associated with adverse maternal outcomes, including increased rates of cesarean section, pregnancy-induced hypertension, pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including stillbirth and low birth weight.
Fetal/Neonatal Adverse Reactions
Hypoadrenalism may occur in infants born to 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 embryo-lethal in rabbits and rats.
In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis on gestation days 6 to 15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.3 times the maximum recommended human dose (MRHD) on a body surface area basis).
In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis on gestation days 6 to 18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses from approximately 25 mcg/kg (approximately 0.03 times the MRHD 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 0.006 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.3 times the maximum recommended human dose on a body surface area basis).
In a peri- and post-natal development study, subcutaneous treatment of pregnant rats with budesonide during the period from Day 15 post coitum to Day 21 post partum, 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 ≥ 0.012 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.
Risk Summary
Breastfeeding is not expected to result in significant exposure of the infant to TARPEYO. Lactation studies have not been conducted with oral budesonide, including TARPEYO, and no information is available on the effects of the drug on the breastfed infant or the effects on the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data). Routine monitoring of linear growth in infants is recommended with chronic use of budesonide in the nursing mother. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TARPEYO and any potential adverse effects on the breastfed infant from TARPEYO, 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 to plasma ratio was approximately 0.5. Budesonide was not detected in plasma, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide.
Assuming a daily average milk intake of about 150 mL/kg/day and a milk to plasma ratio of 0.5, the estimated oral dose of budesonide for a 5 kg infant is expected to be less than 2 mcg/day for a maternal dose of 16 mg TARPEYO. Assuming 100% bio-availability in the infant this is about 0.1% of the maternal dose and about 3% of the highest inhaled dose used clinically for asthma in infants.
Absorption
Following single oral administration of TARPEYO 16 mg to healthy subjects, the average geometric mean Cmax (CV%) was 4.4 ng/mL (58.3), and AUC0-24 was 24.1 h*ng/mL (49.7). Median Tlag (min, max) was 3.1 h (0, 6) while median Tmax (min, max) was 5.1 h (4.5, 10).
Food Effect
There was no clinically relevant food effect observed on the overall systemic exposure of budesonide when either a moderate or high fat meal was consumed 1 hour after administration of TARPEYO.
Distribution
Approximately 85 to 90% of budesonide binds to plasma proteins in blood over the concentration range of 0.43 to 99 ng/mL. The volume of distribution at steady state reported in the literature is 3 to 4 L/kg.
Metabolism
Budesonide is metabolized by the liver (and to lesser extent the gut), primarily by oxidative pathways via CYP3A4 to two main metabolites, 16α-hydroxyprednisolone and 6β-hydroxybudesonide, which have less than 1% of the corticosteroid activity of budesonide.
Elimination
Budesonide had a high plasma clearance, 0.9 to 1.8 L/min in healthy adults, which is close to the estimated liver blood flow, and, accordingly, suggests that budesonide is a high hepatic clearance drug.
Following single oral administration of TARPEYO 16 mg to healthy subjects, the elimination half-life (t½) for TARPEYO ranged from 5.0 to 6.8 hours.
Excretion
Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 16α-hydroxyprednisolone and 6β-hydroxybudesonide, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.
Specific Populations
Age, race, and body weight
The effect of age, race, and body weight on the pharmacokinetics of TARPEYO has not been established.
Sex
Of the 143 healthy volunteers included in the Phase 1 studies, 29% were female. Pharmacokinetics of budesonide was similar between males and females.
Hepatic Impairment
Subjects with moderate hepatic impairment (Child-Pugh class B) had 3.5 times the budesonide AUC compared with healthy volunteers while subjects with mild hepatic impairment (Child-Pugh class A) had approximately 40% higher budesonide AUC compared with healthy volunteers.
Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.
Renal Impairment
Intact budesonide is not excreted renally. The main metabolites of budesonide, which have negligible corticosteroid activity, are largely (60%) excreted in urine.
Drug Interaction Studies
Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase plasma levels of budesonide.
Thus, clinically relevant drug interactions with potent CYP3A inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice, are to be expected. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations.
Effects of Other Drugs on Budesonide
Ketoconazole
In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in 8-fold the AUC of budesonide, compared to budesonide alone.
In an open, randomized, cross-over study 8 healthy subjects were given Entocort EC 3 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 4 days treatment with ketoconazole 200 mg once daily. Co-administration of ketoconazole resulted in 6.5-fold the AUC of budesonide, compared to budesonide alone.
Grapefruit Juice
In an open, randomized, cross-over study, 8 healthy subjects were given Entocort EC 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in doubling the bioavailability of budesonide compared to budesonide alone.
Proton Pump Inhibitors
The pharmacokinetics of TARPEYO have not been evaluated in combination with proton pump inhibitors (PPIs). Since the disintegration of TARPEYO is pH dependent, the release properties and uptake of budesonide may be altered when TARPEYO is taken after treatment with PPIs. In a study assessing intragastric and intraduodenal pH in healthy volunteers after repeated dosing with the PPI omeprazole 40 mg once daily, intragastric and intraduodenal pH did not exceed that required for disintegration of TARPEYO. Beyond the duodenum, PPIs such as omeprazole are unlikely to affect pH.
Oral Contraceptives (CYP3A4 Substrates)
In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 μg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate. The effect of budesonide 16 mg once daily on the plasma concentrations of desogestrel and ethinyl estradiol was not studied.
