NDC 81749-004 Tarpeyo

Budesonide

NDC Product Code 81749-004

NDC CODE: 81749-004

Proprietary Name: Tarpeyo What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Budesonide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Budesonide is used to control and prevent symptoms (wheezing and shortness of breath) caused by asthma. This medication belongs to a class of drugs known as corticosteroids. It works directly in the lungs to make breathing easier by reducing the irritation and swelling of the airways. This medication must be used regularly to be effective. It does not work right away and should not be used to relieve sudden asthma attacks. If an asthma attack occurs, use your quick-relief inhaler as prescribed.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE)
Shape: CAPSULE (C48336)
Size(s):
19 MM
Imprint(s):
CAL10;4MG
Score: 1

NDC Code Structure

  • 81749 - Calliditas Therapeutics Ab

NDC 81749-004-01

Package Description: 120 CAPSULE, DELAYED RELEASE in 1 BOTTLE

NDC Product Information

Tarpeyo with NDC 81749-004 is a a human prescription drug product labeled by Calliditas Therapeutics Ab. The generic name of Tarpeyo is budesonide. The product's dosage form is capsule, delayed release and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 2587883 and 2587889.

Dosage Form: Capsule, Delayed Release - A solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) at a time other than promptly after administration. Enteric-coated articles are delayed release dosage forms.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Tarpeyo Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SUCROSE (UNII: C151H8M554)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)
  • ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62)
  • MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)
  • OLEIC ACID (UNII: 2UMI9U37CP)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • SHELLAC (UNII: 46N107B71O)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • TALC (UNII: 7SEV7J4R1U)
  • DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Corticosteroid - [EPC] (Established Pharmacologic Class)
  • Corticosteroid Hormone Receptor Agonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Calliditas Therapeutics Ab
Labeler Code: 81749
FDA Application Number: NDA215935 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-15-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Tarpeyo Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

TARPEYO is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g.
This indication is approved under accelerated approval based on a reduction in proteinuria. It has not been established whether TARPEYO slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

2 Dosage And Administration

The recommended duration of therapy is 9 months, with a dosage of 16 mg administered orally once daily [see Clinical Studies (14.1)]. When discontinuing therapy, reduce the dosage to 8 mg once daily for the last 2 weeks of therapy [see Warnings and Precautions (5.1)].
The delayed release capsules should be swallowed whole in the morning, at least 1 hour before a meal. Do not open, crush or chew.
If a dose is missed, take the prescribed dose at the next scheduled time. Do not double the next dose.
Safety and efficacy of treatment with subsequent courses of TARPEYO have not been established.

3 Dosage Forms And Strengths

Delayed release capsule containing 4 mg budesonide. White coated opaque capsules printed with “CAL10 4MG” in black ink.

4 Contraindications

TARPEYO is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of TARPEYO. Serious hypersensitivity reactions, including anaphylaxis have occurred with other budesonide formulations.

5.1 Hypercorticism And Adrenal Axis Suppression

When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Corticosteroids 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 corticosteroid is recommended. When discontinuing therapy [see Dosing and Administration (2)] or switching between corticosteroids, monitor for signs of adrenal axis suppression.
Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.2 Risks Of Immunosupression

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of corticosteroids. Avoid corticosteroid therapy in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. Avoid exposure to active, easily-transmitted infections (e.g., chicken pox, measles). Corticosteroid therapy may decrease the immune response to some vaccines.
How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, consider therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG). If exposed to measles, consider prophylaxis with pooled intramuscular immunoglobulin (IG). If chickenpox develops, consider treatment with antiviral agents.

5.3 Other Corticosteroid Effects

TARPEYO is a systemically available corticosteroid and is expected to cause related adverse reactions. Monitor patients with hypertension, prediabetes, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

6 Adverse Reactions

  • The following clinically significant adverse reactions are described elsewhere in the labeling:
  • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.1)]Risks of immunosuppression [see Warnings and Precautions (5.2)]Other corticosteroid effects [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TARPEYO has been evaluated in a randomized controlled study in 197 patients.
The most common adverse reactions reported in greater than or equal to 5% of TARPEYO-treated patients are listed in Table 1.
The majority of adverse reactions were mild or moderate in severity.
Table 1: Reported adverse reactions occurring in greater than or equal to 5% of TARPEYO treated patients, and greater than or equal to 2% higher than Placebo
Adverse ReactionTARPEYO 16 mg (N=97)Placebo (N=100)n (%)
n (%)
Patients with any Adverse Reaction
84 (87)
73 (73)
   Hypertension
15 (16)
2 (2)
   Peripheral edema
14 (14)
4 (4)
   Muscle spasms
13 (13)
4 (4)
   Acne
11 (11)
2 (2)
   Dermatitis
7 (7)
1 (1)
   Weight increased
7 (7)
3 (3)
   Dyspnea
6 (6)
0 (0)
   Face edema
6 (6)
1 (1)
   Dyspepsia
5 (5)
2 (2)
   Fatigue
5 (5)
2 (2)
   Hirsutism
5 (5)
0 (0)
Most adverse reactions that occurred at a greater incidence for TARPEYO compared to placebo were consistent with hypercortisolism.

7.1 Interaction With Cyp3a4 Inhibitors

Budesonide is a substrate for CYP3A4. Avoid use with potent CYP3A4 inhibitors; e.g. ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine [see Clinical Pharmacology (12.3)].
Avoid ingestion of grapefruit juice with TARPEYO. Intake of grapefruit juice, which inhibits CYP3A4 activity, can increase the systemic exposure to budesonide [see Clinical Pharmacology (12.3)].

Other

Risk SummaryThe 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 RiskIgA 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 ReactionsHypoadrenalism 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 DataBudesonide 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 SummaryBreastfeeding 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.

DataOne 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.

AbsorptionFollowing 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 EffectThere 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.

DistributionApproximately 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.

MetabolismBudesonide 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.

EliminationBudesonide 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.
ExcretionBudesonide 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 weightThe effect of age, race, and body weight on the pharmacokinetics of TARPEYO has not been established.

SexOf the 143 healthy volunteers included in the Phase 1 studies, 29% were female. Pharmacokinetics of budesonide was similar between males and females.

Hepatic ImpairmentSubjects 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 ImpairmentIntact budesonide is not excreted renally. The main metabolites of budesonide, which have negligible corticosteroid activity, are largely (60%) excreted in urine.

Drug Interaction StudiesBudesonide 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

KetoconazoleIn 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 JuiceIn 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 InhibitorsThe 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.

8.4 Pediatric Use

The safety and efficacy of TARPEYO in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of TARPEYO 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Avoid use in patients with severe hepatic impairments (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B).

10 Overdosage

Reports of acute toxicity and/or death following overdosage of corticoids are rare.
In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.

11 Description

TARPEYO (budesonide) delayed release capsules, for oral administration, contain budesonide, a synthetic corticosteroid, as the active ingredient. Budesonide is designated chemically as 16α, 17α-[(1RS)-Butylidenebis(oxy)]-11β, 21-dihydroxypregna-1,4-diene-3,20-dione.
Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is:
          Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform.
The beads in each capsule contain the following inactive ingredients: sugar spheres (sucrose and starch), hypromellose, polyethylene glycol, citric acid monohydrate, ethyl cellulose, medium chain triglycerides and oleic acid. The capsule shells contain hypromellose and titanium oxide (E171); and the printing ink on the capsules contain shellac, propylene glycol and black iron oxide (E172). The enteric coating on the capsules contain: methacrylic acid and methacrylate copolymer, talc and dibutyl sebacate.

12.1 Mechanism Of Action

Budesonide is a corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity that undergoes substantial first pass metabolism. Mucosal B-cells present in the ileum, including the Peyer's patches, express glucocorticoid receptors and are responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1) causing IgA nephropathy. Through their anti-inflammatory and immunosuppressive effects at the glucocorticoid receptor, corticosteroids can modulate B-cell numbers and activity. It has not been established to what extent TARPEYO's efficacy is mediated via local effects in the ileum vs systemic effects.

12.2 Pharmacodynamics

Treatment with corticosteroids, including TARPEYO, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function.

13.1 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 0.03 times the maximum recommended human dose (MRHD) on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.015 times the MRHD on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.03 times the MRHD 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 (approximately 0.03 times the MRHD 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 (approximately 0.03 times the MRHD of 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 0.06 times the MRHD on a body surface area basis).
Budesonide was not genotoxic in the Ames text, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethal test, the rat hepatocyte UDS test and the mouse micronucleus test.
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.05 times the MRHD 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 food consumption and body weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.012 times the MRHD on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.003 times the MRHD on a body surface area basis).

14.1 Treatment Of Igan

The effect of TARPEYO on proteinuria was assessed in a randomized, double-blind, multicenter study (Nef-301, NCT: 03643965) in patients with biopsy-proven IgAN, eGFR ≥35 mL/min/1.73 m2, and proteinuria (defined as either ≥1 g/day or UPCR ≥0.8 g/g) who were on a stable dose of maximally-tolerated RAS inhibitor therapy. Patients with other glomerulopathies, nephrotic syndrome, or those who had been treated with systemic immunosuppressive medications were excluded. Patients were randomized 1:1 to either TARPEYO 16 mg once daily or placebo and treated for nine months followed by a 2-week taper of either TARPEYO 8 mg once daily or placebo.
Of the 199 patients who completed the Month 9 visit, 68% were male, 86% were Caucasian, 12% were Asian, and 16% were from the US. The median age was 44 years (range 23 to 73 years). At baseline, the mean eGFR was approximately 58 mL/min/1.73 m2, with 62% of patients having an eGFR <60 mL/min/1.73 m2. The mean baseline UPCR was 1.6 g/g and 25% of patients had proteinuria >3.5 g/24 hours. Approximately 73% of patients had a history of hypertension and 5% had a history of type 2 diabetes mellitus. At baseline, 98% were treated with an ACE inhibitor or ARB and <1% of patients were on an SGLT2 inhibitor.
The primary endpoint was the percentage reduction in UPCR at 9 months compared to baseline.  The results are shown in Table 2.
Table 2: Analysis of the primary efficacy endpoint at 9 months in Phase 3 Study Nef-301
a
All patients with a UPCR reading regardless of use of prohibited medication at 9 months.bAdjusted geometric least squares mean ratio of UPCR relative to baseline were based on a longitudinal repeated measures model.c
The estimate of the ratio of geometric mean ratio of UPCR relative to baseline comparing TARPEYO 16 mg with placebo was reported as percentage reduction along with the respective 95% confidence interval from the longitudinal repeated measures model and p-values.CI: confidence interval; UPCR: urine protein creatinine ratio.Primary Endpoint: UPCR g/g
aTARPEYO 16 mg
(N=97)Placebo
(N=102)Percentage reduction from baseline (Adjusted for baseline) b34%
5%
TARPEYO 16 mg versus Placebo : Percentage reduction (95% CI) c; 2-sided p-value
31% (16% to 42%); p=0.0001
The treatment effect for the UPCR endpoint at 9 months were consistent across key subgroups, including key demographic (such as age, sex, race) and baseline disease (such as baseline proteinuria) characteristics.

16 How Supplied/Storage And Handling

TARPEYO (budesonide) delayed release capsules 4 mg, are white opaque- coated capsules marked with “CAL10 4 MG” in black ink on the body of the capsule. They are supplied as follows:
NDC 81749-004-01: Bottles of 120 capsules. Child-resistant cap.
Store at 20-25°C (68 - 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].
Keep container tightly closed. Protect from moisture.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advise patients that TARPEYO may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if discontinuing therapy [see Warnings and Precautions (5.1)].TARPEYO causes immunosuppression. Advise patients to avoid exposure to people with chicken pox or measles and, if exposed, to consult their healthcare provider immediately. There is an increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or ocular herpes simplex, and to contact their healthcare provider if they develop any symptoms of infection [see Warnings and Precautions (5.3)]. Provide advice regarding vaccination schedules for immunocompromised patients.
Advise patients that TARPEYO delayed release capsules should be swallowed whole and not chewed, crushed or broken and to take TARPEYO in the morning, at least 1 hour before a meal [See Dosage and Administration (2)].Advise patients to avoid the consumption of grapefruit juice for the duration of their TARPEYO therapy [See Drug Interactions (7.1)].TARPEYO is a trademark of Calliditas Therapeutics AB, or its affiliates.
© 2021 Calliditas Therapeutics AB (publ)
Manufactured for and distributed by:Calliditas Therapeutics AB
Stockholm, Sweden
Patent: http://www.calliditas.com/patents

Spl Patient Package Insert

  • This Patient Information has been approved by the U.S. Food and Drug Administration.
  • Issued: 12/2021
  • Patient InformationTARPEYO (tar-PAY-oh)(budesonide)delayed release capsulesWhat is TARPEYO?TARPEYO is a prescription medicine used to reduce levels of protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN), who are at high risk of disease progression.It is not known if TARPEYO is safe and effective in children.
  • Do not take TARPEYO if you are allergic to budesonide or any of the ingredients in TARPEYO. See the end of this leaflet for a complete list of ingredients in TARPEYO.
  • Before taking TARPEYO, tell your healthcare provider about all of your medical conditions, including if you:have liver problems.
  • Plan to have surgery.
  • Have chickenpox or measles or have recently been near anyone with chickenpox or measles.
  • Have an infection.
  • Have high blood sugar levels (prediabetes or diabetes).
  • Have glaucoma or cataracts.
  • Have a family history of diabetes or glaucoma.
  • Have or have had tuberculosis.
  • Have high blood pressure (hypertension).
  • Have decreased bone mineral density (osteoporosis).
  • Have stomach ulcers.
  • Are pregnant or plan to become pregnant. TARPEYO may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take TARPEYO when you are pregnant.
  • Are breastfeeding or plan to breastfeed. It is not known if TARPEYO passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with TARPEYO.
  • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TARPEYO and other medicines may affect each other causing side effects.
  • How should I take TARPEYO?Take TARPEYO exactly as your healthcare provider tells you.
  • Your healthcare provider will decide how long you should take TARPEYO. Do not stop taking TARPEYO without first talking with your healthcare provider.
  • Take your prescribed dose of TARPEYO 1 time each day in the morning, at least 1 hour before a meal.
  • Take TARPEYO capsules whole. Do not open, chew, crush, or break TARPEYO capsules before swallowing.
  • If you miss a dose of TARPEYO, take your prescribed dose at your next scheduled time. Do not take two doses of TARPEYO at the same time.
  • If you take too much TARPEYO, call your healthcare provider right away or go to the nearest hospital emergency room.
  • What should I avoid while taking TARPEYO?Do not eat grapefruit or drink grapefruit juice during your treatment with TARPEYO. Eating grapefruit or drinking grapefruit juice can increase the level of TARPEYO in your blood.
  • What are the possible side effects of TARPEYO?TARPEYO may cause serious side effects, including:Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of TARPEYO can cause you to have signs and symptoms of too much cortisol, a stress hormone in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism:
  • Acne
  • Bruise easily
  • Rounding of your face (moon face)
  • Ankle swelling
  • Thicker or more hair on your body and face
  • A fatty pad or hump between your shoulders (buffalo hump)
  • Pink or purple stretch marks on the skin of your abdomen, thighs, breasts, or arms
  • Adrenal suppression. When TARPEYO is taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include:tiredness
  • Weakness
  • Nausea and vomiting
  • Low blood pressure
  • Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with TARPEYO.Risk of immunosuppression. TARPEYO weakens your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases, such as chickenpox or measles, during treatment with TARPEYO. Tell your healthcare provider right away if you come in contact with anyone who has chickenpox or measles. Consult with your healthcare provider regarding appropriate vaccination scheduling.
  • Tell your healthcare provider if you develop any symptoms of infection during treatment with TARPEYO, including:
  • Fever
  • Feeling tired
  • Chills
  • Aches
  • Pain
  • Nausea and vomiting
  • The most common side effects of TARPEYO include:high blood pressure
  • Swelling of the lower legs, ankles, and feet
  • Muscle cramp
  • Acne
  • Irritation or inflammation of the skin
  • Weight increase
  • Shortness of breath
  • Swelling of the face
  • Indigestion
  • Tiredness
  • Thicker or more hair on your body and faceThese are not all the possible side effects of TARPEYO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
  • How should I store TARPEYO?Store TARPEYO at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep TARPEYO in a tightly closed container.
  • Protect from moisture.
  • Keep TARPEYO and all medicines out of the reach of children.General information about the safe and effective use of TARPEYO.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TARPEYO for a condition for which it was not prescribed. Do not give TARPEYO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TARPEYO that is written for health professionals.
  • What are the ingredients in TARPEYO?Active ingredient: budesonideInactive ingredients: sugar spheres (sucrose and starch), hypromellose, polyethylene glycol, citric acid monohydrate, ethyl cellulose, medium chain triglycerides and oleic acid.The capsules contain: hypromellose and titanium oxide (E171).The printing ink on the capsules contain: shellac, propylene glycol and black iron oxide (E172).The enteric coating on the capsules contain: methacrylic acid and methacrylate copolymer, talc and dibutyl sebacate.
  • Manufactured for and distributed by: Calliditas Therapeutics AB, Stockholm, SwedenTARPEYO is a trademark of Calliditas Therapeutics AB, or its affiliates.© 2021 Calliditas Therapeutics AB (publ)Patent: http://www.calliditas.com/patentsFor more information, go to www.TARPEYOTouchpoints.com or call 1-933-444-8277.

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