Nefecon

Budesonide.

The modified-release hard capsules are 19 mm, white coated, opaque, and printed with "CAL10 4MG" in black ink.
Each modified-release hard capsule contains budesonide 4 mg.
Excipient(s) with known effect: Each capsule contains 230 mg of sucrose.
Excipients/Inactive Ingredients: Capsule content: Sugar spheres (sucrose and corn starch), Hypromellose, Macrogol, Citric acid monohydrate, Ethylcellulose, Medium chain triglycerides, Oleic acid.
Capsule shell: Hypromellose, Macrogol, Titanium dioxide, Methacrylic acid and methyl methacrylate copolymers, Talc, Dibutyl sebacate.
Printing ink: Shellac, Iron oxide black.

Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, corticosteroids acting locally. ATC code: A07EA06.
Pharmacology: Pharmacodynamics: Mechanism of action: The intended action of Nefecon is the suppression of mucosal B-cells, located in the Peyer's patches in the ileum, and inhibition of their proliferation and differentiation into plasma cells that produce mucosal galactose-deficient IgA1 antibodies (Gd-IgA1). Consequently, it is expected that the occurrence of Gd-IgA1 antibodies and formation of immune complexes in the systemic circulation will be suppressed, therefore preventing the downstream effects of glomerular mesangial deposition of immune complexes containing Gd-IgA1, manifesting as glomerulonephritis and loss of renal function.
Pharmacodynamic effects: Nefecon is an oral, modified-release hard capsule formulation of budesonide which combines a delayed capsule disintegration with a prolonged release of the active substance budesonide in the ileum. By directing the release of budesonide to the ileum, where Peyer's patches reside in high density, a local pharmacological effect is anticipated.
Clinical efficacy: Primary IgA nephropathy: The efficacy of Nefecon has been evaluated in 2 randomised, double-blind, placebo-controlled studies of patients with primary IgAN, who were receiving Renin-Angiotensin System (RAS) inhibitor therapy. In both studies the primary endpoint evaluated proteinuria reduction by urine protein creatinine ratio (UPCR) at 9 months compared to baseline, with key secondary endpoint analyses of renal function based on estimated glomerular filtration rate (eGFR) at 9 and 12 months.
In 199 of the first 201 patients randomised who have completed part A of a phase 3 study, patients treated with Nefecon 16 mg once daily showed a statistically significant and clinically relevant 27% reduction in UPCR compared to placebo in the overall study population (p=0.0003) after 9 months of treatment. UPCR at 9 months was reduced from baseline by 31% in patients treated with Nefecon 16 mg once-daily compared with 5% in placebo-treated patients. After 3 months of observational follow up without treatment, the reduction in UPCR improved to 48% compared to placebo at 1 year (p<0.0001).
Consistent with the assessment of proteinuria reduction by UPCR, a 31% reduction in urine albumin creatinine ratio (UACR) compared to placebo was observed at 9 months (p=0.0005), and a 54% reduction in UACR at 12 months (p<0.0001).
After 9 months of treatment, Nefecon 16 mg once daily provided a statistically significant and clinically relevant 7% treatment benefit on eGFR CKD-EPI (serum creatinine) compared to placebo (p=0.0014). This 3.87 mL/min/1.73 m² treatment benefit at 9 months corresponded to a slight reduction from baseline of 0.17 mL/min/1.73 m² in patients who received Nefecon 16 mg once daily and a deterioration from baseline of 4.04 mL/min/1.73 m² in patients who received placebo.
The improvement in 1-year eGFR slope was 3.37 mL/min/1.73 m² per year with Nefecon 16 mg once daily compared to placebo (p=0.0111).
The effect of Nefecon treatment on stabilisation of the rate of loss of renal function was greater in patients with higher baseline proteinuria compared to the overall population. In patients with baseline UPCR ≥1.5 g/gram, the improvement in 1-year eGFR chronic slope (from 3 months onwards) was 7.62 mL/min/1.73 m² per year with Nefecon 16 mg once daily compared to placebo (p=0.0068), and the corresponding improvement in 1-year eGFR total slope was 9.31 mL/min/1.73 m² per year (p=0.0005).
A supportive phase 2b study with a similar study design was conducted in a total of 153 randomised patients who received Nefecon 16 mg, Nefecon 8 mg, or placebo, once daily for 9 months, while continuing to receive RAS inhibitor therapy.
The primary objective was met at an interim analysis that compared Nefecon to placebo, and showed a statistically significant reduction in UPCR at 9 months for the combined Nefecon 16 mg/day and 8 mg/day dose groups compared to placebo (p=0.0066).
Using the same statistical methodology as in the phase 3 study, a statistically significant 26% reduction in the primary endpoint UPCR was shown at 9 months for the 16 mg dose of Nefecon versus placebo (p=0.0100) and a 29% reduction at 12 months (p=0.0027).
The difference in eGFR CKD-EPI (serum creatinine) for the 16 mg dose of Nefecon versus placebo was 3.57 mL/min/1.73 m² at 9 months (p=0.0271), and 4.46 mL/min/1.73 m² at 12 months (p=0.0256). The improvement in 1-year eGFR slope was estimated to be 5.69 mL/min/1.73 m² per year with Nefecon 16 mg once daily compared to placebo (p=0.0007).
Paediatric population: Nefecon has not been studied in the paediatric population.
Pharmacokinetics: Absorption: The Nefecon formulation is designed to deliver budesonide topically in the ileum. Oral absorption of budesonide seems to be complete and is rapid, whereas systemic bioavailability due to high first-pass metabolism is low (approximately 10%).
Following single oral administration of Nefecon 16 mg to healthy subjects, the geometric mean C_max ranged between 3.2 and 4.4 ng/mL, and AUC_(0-24) ranged between 24.1 and 24.8 ng/mL×h.
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 dosing.
Distribution: Budesonide is rapidly and extensively distributed into tissues and organs. Approximately 85 to 90% of budesonide binds to plasma proteins in blood over the concentration range of 1 to 100 nmol/L. The volume of distribution at steady state is 3 to 4 L/kg.
Biotransformation: Budesonide is rapidly metabolised 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 glucocorticosteroid receptor affinity and anti-inflammatory activity of budesonide.
The metabolism of budesonide is 2- to 5-fold faster than that of hydrocortisone and 8- to 15-fold faster than that of prednisolone.
Elimination: Budesonide has a high clearance rate of approximately 72 to 80 L/h, which is close to the estimated liver blood flow, and, accordingly, suggests that budesonide is a high hepatic clearance medicinal product.
T_½ for budesonide after dosing with Nefecon ranged from 5 to 6.8 hours in healthy volunteer studies.
Budesonide is excreted in urine and feces in the form of metabolites. 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.
Hepatic impairment: Budesonide is predominantly metabolised by hepatic biotransformation.
In subjects with moderate hepatic impairment (Child-Pugh class B), systemic availability of orally administered budesonide was 3.5-fold higher (27%) compared with healthy volunteers (systemic availability 7.4%); there was no clinically relevant increase in systemic availability in patients with mild hepatic impairment (Child-Pugh class A).
Patients with severe hepatic impairment have not been studied.
Renal impairment: Intact budesonide is not excreted renally. The main metabolites of budesonide, which have negligible glucocorticosteroid activity, are largely (60%) excreted in urine.
Paediatric population: Nefecon was not studied in the paediatric population.
Toxicology: Preclinical safety data: The preclinical safety of budesonide has been documented in studies during the development of other formulations of this compound. No preclinical studies have been conducted with the Nefecon formulation itself.
Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex, are less severe or similar to those observed after administration of other glucocorticosteroids.
Budesonide, evaluated in six different test systems, did not show any signs of mutagenic or clastogenic effects.
An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control group.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect in this species.
Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in humans.
Budesonide had no effect on fertility in rats. In pregnant animals, budesonide, like other glucocorticoids, has been shown to cause foetal death and abnormalities of foetal development (smaller litter size, intrauterine growth retardation of foetuses and skeletal abnormalities). The clinical relevance of these findings to human has not been established (see Use in Pregnancy & Lactation).
The toxicity of budesonide modified-release hard capsules, with focus on the gastro-intestinal tract, has been studied in cynomolgus monkeys at doses of up to 5 mg/kg (approximately 15 times the recommended daily dose of Nefecon in humans on a dose per body weight basis) after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, either from gross pathology or histopathological examination.

Nefecon is indicated for the treatment of primary immunoglobulin A (IgA) nephropathy (IgAN) in adults at risk of rapid disease progression with a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/gram.

Posology: The recommended dose is 16 mg once daily in the morning, at least one hour before a meal, for 9 months. When treatment is to be discontinued, the dose should be reduced to 8 mg once daily for 2 weeks of therapy; the dose may be reduced to 4 mg once daily for an additional 2 weeks, at the discretion of the treating physician.
Re-treatment may be considered at the discretion of the treating physician. Safety and efficacy of treatment with subsequent courses of Nefecon have not been established.
If the patient forgets to take Nefecon, the patient should take Nefecon the next day, in the morning as usual. The patient should not double the daily dose to make up for a missed dose.
Special populations: Elderly: Experience of the use of Nefecon in the elderly is limited. However, from the clinical data available, the efficacy and safety of Nefecon are expected to be similar to that of other age groups studied.
Hepatic impairment: The safety and efficacy of Nefecon capsules in patients with hepatic impairment have not been studied.
Nefecon is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). See Contraindications, Precautions, and Pharmacology: Pharmacokinetics under Actions.
Renal impairment: The pharmacokinetics of budesonide are not expected to be altered in patients with renal impairment.
Paediatric population: The safety and efficacy of Nefecon capsules in children and adolescents below 18 years of age have not yet been established. No data are available.
Method of administration: Nefecon is for oral use. The modified-release hard capsules should be swallowed whole with water in the morning, at least 1 hour before a meal (see Pharmacology: Pharmacokinetics under Actions). The capsules must not be opened, crushed or chewed, as it could affect the release profile.

Reports of acute toxicity or death following overdose of glucocorticosteroids are rare. Acute overdose, even in excessive doses, is not expected to lead to clinically significant consequences. In the event of acute overdose, no specific antidote is available. Treatment consists supportive and symptomatic therapy.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Patients with severe hepatic impairment (Child-Pugh Class C).

Hypercorticism and adrenal axis suppression: When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids 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 glucocorticosteroid is recommended.
Since Nefecon contains a glucocorticosteroid, general warnings concerning glucocorticosteroids, as given as follows, should be followed.
Hepatic impairment: Patients with moderate or severe hepatic impairment (Child-Pugh Class B or C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Patients with moderate hepatic impairment (Child-Pugh Class B) should be monitored for increased signs and/or symptoms of hypercorticism.
Symptoms of steroid withdrawal in patients transferred from systemic corticosteroids: Patients who are transferred from glucocorticosteroid treatment with high systemic availability to glucocorticosteroids with lower systemic availability, such as budesonide, should be monitored since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.
Replacement of systemic glucocorticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic medicinal product.
Infections: Patients who are on medicinal products 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 glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.
How the dose, route, and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed to chickenpox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See Summaries of Product Characteristics for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered.
Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.
Caution with special diseases: Patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where use of glucocorticosteroids may be associated with an increased risk of adverse effects, should be monitored.
Visual disturbance: Visual disturbance may be reported with systemic and topical glucocorticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical glucocorticosteroids.
Concomitant treatment with potent CYP3A4 inhibitors: Concomitant treatment with potent CYP3A4 inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side effects attributable to budesonide. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticosteroid side effects. If this is not possible, the period between treatments should be as long as possible and a reduction of the budesonide dose to 8 mg budesonide daily could also be considered (see Interactions).
After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure to budesonide after oral administration increased approximately two-fold. As with other medicinal products primarily metabolised through CYP3A4, regular ingestion of grapefruit or its juice should be avoided in connection with Nefecon administration (other juices such as orange juice or apple juice do not inhibit CYP3A4). See also Interactions.
ACTH stimulation test: Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).
Sucrose: Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicinal product.
Effects on ability to drive and use machines: No studies on the effects of Nefecon on the ability to drive and use machines have been performed. It is expected that Nefecon has no or negligible influence on the ability to drive or use machinery.

Pregnancy: Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Nefecon. There are only few data of pregnancy outcomes after oral administration of budesonide in humans. Although data on the use of inhaled budesonide in a large number of exposed pregnancies indicate no adverse effect, the maximal concentration of budesonide in plasma is expected to be higher in association with treatment with Nefecon compared to inhaled budesonide. In pregnant animals budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). The relevance of this to man has not been established.
Therefore, Nefecon should not be used during pregnancy unless the clinical condition of the woman requires treatment with budesonide. The expected benefits for the pregnant woman have to be weighed against the potential risk for the fetus.
Budesonide was found to cross the placental barrier. The relevance of this observation to humans has not been established.
Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in utero; carefully observe neonates for signs and symptoms of hypoadrenalism.
Breast-feeding: Budesonide is excreted in breast milk.
Lactation studies have not been conducted with oral budesonide, including Nefecon, and no information is available on the effects of the medicinal product on the breast-fed infant or the effects of the medicinal product on milk production. A risk to the breast-fed infant cannot be excluded.
If Nefecon is used when a mother is breast-feeding, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from budesonide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: There are no data on the effect of budesonide on human fertility. There were no effects on fertility in rats after treatment with budesonide.

Summary of the safety profile: In the Nefecon phase 3 clinical study the most commonly reported adverse drug reactions were acne reported in approximately 10% of patients, hypertension, peripheral oedema, face oedema, and dyspepsia, each occurring in approximately 5% of patients; these were mainly of mild or moderate severity and reversible, reflecting the low systemic exposure to budesonide after oral administration.
Tabulated list of adverse reactions: Adverse drug reactions reported in the pivotal phase 3 clinical study with Nefecon are presented in the table. (See table.)
Adverse reactions reported are listed according to the following frequency: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Click on icon to see table/diagram/image

Description of selected adverse reactions: Potential class effects: Adverse drug reactions typical of systemic glucocorticosteroids may occur (e.g., cushingoid features, increased blood pressure, increased risk of infection, delayed wound healing, reduced glucose tolerance, sodium retention with oedema formation, muscle weakness, osteoporosis, glaucoma, mental disorders, peptic ulcer, increased risk of thrombosis). These adverse drug reactions are dependent on dose, treatment time, concomitant and previous glucocorticosteroid intake, and individual sensitivity. Not all of these adverse reactions were observed in the clinical study program of Nefecon.
Paediatric population: No data available.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Medicinal products/substances inhibiting CYP3A4: Budesonide is metabolised via CYP3A4. Potent inhibitors of CYP3A4 can increase plasma levels of budesonide. Co-administration of the potent CYP3A4 inhibitor ketoconazole or intake of grapefruit juice resulted in a 6.5-fold and 2-fold increase, respectively in the bioavailability of budesonide, compared to budesonide alone.
Thus, clinically relevant interactions with potent CYP3A inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice, are to be expected, and may increase systemic budesonide concentrations (see Precautions, and Pharmacology: Pharmacokinetics under Actions).
Medicinal products/substances inducing CYP3A4: Concomitant treatment with CYP3A4 inducers such as carbamazepine may reduce budesonide systemic exposure.
Medicinal products/substances metabolised by CYP3A4: Given its low affinity for CYP3A4 and P-gp, as well as the formulation, pharmacokinetic (PK) characteristics and low systemic exposure, Nefecon is unlikely to affect the systemic exposure of other medicinal products.
Oral contraceptives: Oral contraceptives containing ethinyl estradiol, which are also metabolised by CYP3A4, do not affect the pharmacokinetics of budesonide.
Proton pump inhibitors: The pharmacokinetics of budesonide have not been evaluated in combination with proton pump inhibitors (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 Nefecon. Beyond the duodenum, PPIs such as omeprazole are unlikely to affect pH.
Other interactions to be considered: Budesonide treatment may reduce serum potassium, which should be considered when Nefecon is co-administered with a medicinal product where the pharmacological effects may be potentiated by low serum potassium, such as cardiac glucosides, or when co-administered with diuretics that lower serum potassium.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Do not store above 30°C.
Shelf life: 3 years.

GIT Regulators, Antiflatulents & Anti-Inflammatories

A07EA06 - budesonide ; Belongs to the class of corticosteroids acting locally. Used in the treatment of intestinal inflammation.

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