布地奈德缓释胶囊(Tarpeyo)的中文说明书

The company developing budesonide sustained-release capsules (Tarpeyo) is Swedish Calliditas. On December 17, 2021, the US FDA approved the marketing of budesonide sustained-release capsules.

Indications for Budesonide Extended-Release Capsules (Tarpeyo)

It is suitable for reducing the loss of renal function in adult patients with primary immunoglobulin A nephropathy (IgAN) who are at risk of disease progression.

Usage and dosage of Budesonide sustained-release capsules (Tarpeyo)

1. Recommended treatment course

The recommended course of treatment is 9 months.

2. Dosage

Take 16 mg orally once a day. When treatment is discontinued, reduce the dose to 8 mg once daily during the last 2 weeks of treatment.

3. How to take the medicine

Sustained-release capsules should be swallowed whole in the morning, at least 1 hour before meals. Do not open, crush or chew.

4. Treatment of missed doses

If you miss a dose, please take the prescribed dose at the next scheduled time. Do not double your next dose.

5. Dosage forms and specifications

Sustained-release capsules, each containing 4 mg of budesonide. White-coated opaque capsules with black "CAL104MG" printed on the capsule body.

6. Overdose

There are few reports of acute toxicity and/or death following corticosteroid overdose. If acute overdose occurs and there is no specific antidote, treatment includes supportive and symptomatic care.

The pictures come from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

Contraindications of Budesonide Extended-Release Capsules (Tarpeyo)

It is contraindicated in patients who are allergic to budesonide or any component of budesonide, and who have experienced severe hypersensitivity reactions, including anaphylaxis, with other budesonide formulations.

Precautions for Budesonide extended-release capsules (Tarpeyo)

1. Cortical hyperfunction and adrenal axis suppression

When corticosteroids are used for a long time, systemic effects, such as cortical hyperfunction and adrenal suppression, may occur. Corticosteroids decrease the ability of the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress.

Supplementation with systemic corticosteroids is recommended when patients face surgery or other stressful situations. Monitor for signs of adrenal axis suppression when treatment is discontinued or when switching between different corticosteroids.

Patients with moderate to severe hepatic impairment (Child-Pugh class B and C, respectively) may be at higher risk for hypercortical hyperfunction and adrenal axis suppression due to increased systemic exposure to oral budesonide.

Avoid use in patients with severe hepatic impairment (Child-Pugh Class C).

Monitor patients with moderate hepatic impairment (Child-Pugh class B) for signs and/or increased symptoms of hypercortical hyperfunction.

2. Immunosuppression and increased risk of infection

Corticosteroids, including budesonide, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoal, or helminthic pathogens. Corticosteroids can decrease resistance to new infections, aggravate existing infections, increase the risk of disseminated infection, increase the risk of reactivation or exacerbation of latent infection, and mask certain signs of infection.

Corticosteroid-related infections can be mild, but they can also be serious and sometimes fatal. The incidence of infectious complications increases with corticosteroid dose.

Monitor the development of infection and consider discontinuing budesonide if necessary.

3. Tuberculosis

Reactivation of tuberculosis may occur if budesonide is used to treat patients with latent tuberculosis or tuberculin reactivity. Budesonide should be discontinued in patients with latent tuberculosis or tuberculin reactivity.

4. Varicella zoster and measles virus infection

Varicella and measles can have a serious or even fatal course in unimmunized patients who are taking corticosteroids (including budesonide). For patients receiving corticosteroids who have not had these diseases or are not immunized, special attention should be paid to avoid exposure to chickenpox and measles:

(1) If a patient receiving budesonide is exposed to chickenpox, varicella zoster immune globulin prophylaxis may be required. If chickenpox occurs, treatment with antiviral medications may be considered.

(2) If patients receiving budesonide are exposed to measles, immune globulin prophylaxis may be required.

5. Hepatitis B virus reactivation

Hepatitis B virus reactivation may occur in hepatitis B carrier patients who receive immunosuppressive doses of corticosteroids (including budesonide). Reactivation may also occur occasionally in patients receiving corticosteroids from seemingly resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive therapy with budesonide. For patients who show evidence of hepatitis B infection, consultation with a physician with expertise in hepatitis B management is recommended for monitoring and consideration of hepatitis B antiviral therapy.

6. Fungal infections

Corticosteroids, including budesonide, may aggravate systemic fungal infections; therefore, avoid using budesonide in the presence of such infections.

7. Amebiasis

Corticosteroids, including budesonide, may activate latent amebiasis. Therefore, it is recommended that latent or active amoebiasis be ruled out before initiating budesonide therapy in patients who have spent time in tropical areas or who have unexplained diarrhea.

8. Strongyloides infection

Corticosteroids, including budesonide, should be discontinued in patients known or suspected to be infected with Strongyloides (nematode).

In such patients, corticosteroid-induced immunosuppression may result in hyperinfection and dissemination of Strongyloides with extensive larval migration, often with severe enterocolitis and potentially fatal gram-negative sepsis.

9. Cerebral malaria

Avoid the use of corticosteroids, including budesonide, in patients with cerebral malaria.

10. Ocular Herpes Simplex Virus Infection

Corticosteroids, including budesonide, may aggravate ocular herpes simplex virus infection; therefore, avoid using budesonide in the presence of such infection.

11. Kaposi's sarcoma

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy (most commonly for chronic diseases). Discontinuation of corticosteroids may result in clinical improvement in Kaposi's sarcoma.

12. Immunization

Corticosteroid treatment, including budesonide, may reduce the immune response to some vaccines.

13. Other corticosteroid effects

Budesonide is a corticosteroid with systemic bioavailability and is expected to cause related adverse reactions. Monitor patients with hypertension, prediabetes, diabetes, osteoporosis, peptic ulcers, glaucoma, or cataracts, or a family history of diabetes or glaucoma, or any other condition in which corticosteroids may have adverse effects.

Adverse reactions of budesonide extended-release capsules (Tarpeyo)

The most common adverse reactions (incidence ≥5% and ≥2% higher than the placebo group) are as follows: hypertension (incidence 11% vs 5%), muscle spasm (incidence 9% vs 3%), acne (incidence 7% vs <1%), dermatitis (7% vs 2%), weight gain (7% vs 0%), dyspnea (6% vs 3%), facial edema (6% vs 0%), indigestion (5% vs 1%) and fatigue (5% vs 3%).

Drug interactions with Budesonide extended-release capsules (Tarpeyo)

1. Budesonide is a substrate of CYP3A4. Avoid coadministration with strong CYP3A4 inhibitors; such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine.

2. Avoid ingesting grapefruit juice while taking budesonide sustained-release capsules. Ingestion of grapefruit juice, which inhibits CYP3A4 activity, may increase systemic exposure of budesonide.

Special Population Use of Budesonide Extended-Release Capsules (Tarpeyo)

1. Pregnancy

Existing data on oral budesonide in pregnant women from published case series, epidemiological studies, and reviews have not identified significant drug-related risks of birth defects, miscarriage, or other adverse maternal or fetal outcomes. IgA nephropathy poses risks to the mother and fetus. Infants exposed to corticosteroids in utero, including budesonide, are at risk for developing adrenal insufficiency.

2. Lactation

Breastfeeding is not expected to result in significant infant exposure to budesonide, lactation studies have not been conducted with oral budesonide, and there is no information on the effects of this drug on breastfed infants or on milk production.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for budesonide and any potential adverse effects on the breastfed infant from budesonide extended-release capsules or underlying maternal disease.

3. Use in children

The safety and effectiveness of budesonide in pediatric patients have not been established.

4. Use in the Elderly

Clinical studies of budesonide did not include a sufficient number of subjects aged 65 and over to determine whether their responses were different from those of younger subjects.

Other reported clinical experience has not found differences in response between older and younger patients. In general, dose selection in elderly patients should be cautious, reflecting a greater frequency of decreased hepatic, renal, or cardiac function as well as concurrent illness or other drug therapy.

5. Hepatic insufficiency

Patients with moderate to severe hepatic impairment (Child-Pugh class B and C, respectively) may be at higher risk for cortical hyperfunction and adrenal axis suppression due to increased systemic exposure of budesonide.

Avoid use in patients with severe hepatic impairment (Child-Pugh Class C).

Monitor patients with moderate hepatic impairment (Child-Pugh class B) for signs and/or increased symptoms of hypercortical hyperfunction.

Mechanism of action of Budesonide extended-release capsules (Tarpeyo)

Budesonide is a corticosteroid with strong glucocorticoid activity and weak mineralocorticoid activity. Mucosal B cells in the ileum (including Peyer's patches) express glucocorticoid receptors and are responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1) that cause IgA nephropathy.

Through their anti-inflammatory and immunosuppressive effects on the glucocorticoid receptor, corticosteroids can regulate the number and activity of B cells. The extent to which budesonide's efficacy is mediated through local effects in the ileum or through systemic effects has not been determined.

Pharmacokinetics of Budesonide extended-release capsules (Tarpeyo)

1. Absorption

After a single oral administration of 16 mg of budesonide to healthy subjects, the average geometric mean Cmax (CV%) was 4.4ng/mL (58.3), and the AUC0-24 was 24.1h*ng/mL (49.7). The median Tlag (minimum, maximum) is 3.1 hours (0,6), while the median Tmax (minimum, maximum) is 5.1 hours (4.5,10).

Food Effects: No clinically relevant food effects on overall systemic exposure to budesonide were observed when a moderate or high-fat meal was consumed 1 hour after taking TARPEYO.

2. Distribution

In the concentration range of 0.43-99ng/mL, budesonide is approximately 85%-90% bound to plasma proteins in the blood, and the steady-state distribution volume reported in the literature is 3-4L/kg.

3. Metabolism

Budesonide is metabolized primarily in the liver (and to a lesser extent in the intestine) via the CYP3A4 oxidation pathway to two major metabolites: 16α-hydroxyprednisolone and 6β-hydroxybudesonide, which have less than 1% of the corticosteroid activity of budesonide.

4. Elimination

Budesonide has a high plasma clearance rate, ranging from 0.9 to 1.8L/min in healthy adults, which is close to the estimated liver blood flow, thus indicating that budesonide is a drug with high hepatic clearance.

After a single oral administration of 16 mg of TARPEYO to healthy subjects, the elimination half-life (t½) of TARPEYO ranged from 5.0 to 6.8 hours.

5. Excretion

Budesonide is excreted in urine and feces in the form of metabolites. Approximately 60% of the recovered radioactivity is found in urine after oral and intravenous administration of micronized [3H]-budesonide. The major metabolites, including 16α-hydroxyprednisolone and 6β-hydroxybudesonide, are primarily excreted by the kidneys in unchanged or conjugated forms. Unaltered budesonide was not detected in the urine.

Population-specific pharmacokinetics of budesonide extended-release capsules (Tarpeyo)

1. Age, race and weight

The effects of age, race and body weight on the pharmacokinetics of budesonide have not been determined.

2. Gender

Among the 143 healthy volunteers included in the Phase 1 study, 29% were women. Budesonide pharmacokinetics are similar between men and women.

3. Hepatic insufficiency

The AUC of budesonide in subjects with moderate hepatic impairment (Child-Pugh Class B) is 3.5 times that of healthy volunteers, while the AUC of budesonide in subjects with mild hepatic impairment (Child-Pugh Class A) is approximately 1.4 times that of healthy volunteers.

Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

4. Renal insufficiency

Intact budesonide is not excreted by the kidneys. The major metabolite of budesonide has negligible corticosteroid activity and is mostly (60%) excreted in the urine.

Storage of Budesonide extended-release capsules (Tarpeyo)

Store at 20°C-25°C (68°F-77°F); excursions allowed between 15°C-30°C (59°F-86°F). Keep container tightly closed to prevent moisture.