Senticort^® (Suspension) Instructions for Use

Marketing Authorization Holder

Sentiss Pharma, Pvt. Ltd. (India)

Contact Information

SENTISS RUS LLC (Russia)

ATC Code

R03BA02 (Budesonide)

Active Substance

Budesonide (Rec.INN registered by WHO)

Dosage Forms

	Senticort®	Metered dose inhalation suspension 0.5 mg/1 ml: amp. 2 ml 20 pcs.
		Metered dose inhalation suspension 0.25 mg/1 ml: amp. 2 ml 20 pcs.

Dosage Form, Packaging, and Composition

Metered dose inhalation suspension white, opalescent.

Excipients: sodium citrate dihydrate, citric acid monohydrate, disodium edetate, sodium chloride, polysorbate 80, water for injections.

2 ml – polyethylene ampoules (1) – laminated foil envelopes (20) – cardboard packs.
2 ml – polyethylene ampoules (5) – laminated foil envelopes (4) – cardboard packs.

Metered dose inhalation suspension white, opalescent.

Excipients: sodium citrate dihydrate, citric acid monohydrate, disodium edetate, sodium chloride, polysorbate 80, water for injections.

2 ml – polyethylene ampoules (1) – laminated foil envelopes (20) – cardboard packs.
2 ml – polyethylene ampoules (5) – laminated foil envelopes (4) – cardboard packs.

Clinical-Pharmacological Group

Inhaled corticosteroids

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; other agents for inhalation administration used for the treatment of obstructive airway diseases; glucocorticoids

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Budesonide, an inhaled glucocorticosteroid (GCS), at recommended doses has an anti-inflammatory effect in the bronchi, reducing the severity of symptoms and the frequency of exacerbations of bronchial asthma with a lower frequency of adverse reactions than with the use of systemic GCS.

It reduces the severity of bronchial mucosal edema, mucus production, sputum formation, and airway hyperreactivity. It is well tolerated during long-term treatment and does not possess mineralocorticosteroid activity.

A dose-dependent effect on plasma and urine cortisol levels has been shown with budesonide administration. At recommended doses, Budesonide has a significantly lesser effect on adrenal function than prednisolone at a dose of 10 mg, as shown in ACTH tests.

Children

In bronchial asthma and with the use of inhaled GCS, growth retardation may be observed. Studies involving children and adolescents receiving long-term budesonide therapy (up to 13 years) have shown that patients achieved their expected adult height.

Inhaled budesonide therapy is effective in preventing exercise-induced bronchial asthma.

Clinical efficacy and safety

Clinical studies – exacerbations of chronic obstructive pulmonary disease (COPD)

Several studies on the use of nebulized budesonide at a dose of 4-8 mg/day have shown efficacy in the treatment of COPD exacerbations.

Clinical studies – bronchial asthma

The efficacy of budesonide has been evaluated in numerous studies. It has been shown that the drug is effective in the treatment of persistent bronchial asthma in both adults and children when used once or twice daily. It has also been shown that inhaled Budesonide is effective in treating and preventing exacerbations of bronchial asthma in children and adults.

Children

Clinical studies – croup

A number of studies in children with croup compared budesonide with placebo. Below are examples of representative studies evaluating the use of budesonide for the treatment of children with croup.

Efficacy in children with mild to moderate croup

A randomized, double-blind, placebo-controlled study involving 87 children aged from 7 months to 9 years, hospitalized with a clinical diagnosis of croup, was conducted to determine whether Budesonide suspension improves the croup symptom score or reduces the duration of hospital stay. Patients received Budesonide suspension at an initial dose of 2 mg or placebo followed by budesonide 1 mg or placebo every 12 hours.

Budesonide suspension led to a statistically significant reduction in the severity of croup symptoms at 12 hours and 24 hours, as well as at 2 hours after administration in a subgroup of patients with a baseline symptom score above 3. The duration of hospital stay was also reduced by 33%.

Efficacy in children with moderate to severe croup

A randomized, double-blind, placebo-controlled study compared the efficacy of budesonide and placebo in the treatment of croup in 83 infants and children (aged from 6 months to 8 years) hospitalized for croup. Patients received Budesonide suspension 2 mg or placebo every 12 hours for up to 36 hours or until discharge from the hospital. The overall croup symptom score was assessed at 0, 2, 6, 12, 24, 36, and 48 hours after the initial dose administration. At 2 hours, a similar reduction in the severity of croup symptoms was observed in both the budesonide and placebo groups, with no statistically significant difference between the groups. At 6 hours after the initial dose, a statistically significant reduction in the severity of croup symptoms was observed in the Budesonide suspension group compared to the placebo group, and this improvement was similar at 12 and 24 hours.

Pharmacokinetics

Absorption

Inhaled Budesonide is rapidly absorbed. In adults, the systemic bioavailability of budesonide after inhalation of Senticort^® via a nebulizer is approximately 15% of the total prescribed dose and about 40-70% of the delivered dose. C_max in plasma is reached within 30 minutes after the start of inhalation.

Distribution

Plasma protein binding averages 90%. The V_d of budesonide is approximately 3 L/kg.

Metabolism

After absorption, Budesonide undergoes intensive (more than 90%) biotransformation in the liver to form metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of the glucocorticosteroid activity of budesonide. Budesonide is metabolized mainly by the CYP3A4 enzyme.

Excretion

Metabolites are excreted unchanged in the urine or in conjugated form. Budesonide has a high systemic clearance (about 1.2 L/min). The pharmacokinetics of budesonide are proportional to the administered dose of the drug.

Pharmacokinetics in special patient groups

Renal impairment

The pharmacokinetics of budesonide in patients with impaired renal function have not been studied.

Hepatic impairment

In patients with liver disease, exposure to budesonide may be increased.

Preclinical safety data

Budesonide has low acute toxicity of the same order and type as the reference GCS studied (beclometasone dipropionate, fluocinolone acetonide).

Results from subacute and chronic toxicity studies indicate that the systemic effects of budesonide are less pronounced or similar to those observed after administration of other GCS, for example, reduced weight gain, atrophy of lymphoid tissue and adrenal cortex.

An increased incidence of brain gliomas in male rats in a carcinogenicity study was not confirmed in a repeat study, which found no significant differences in the incidence of gliomas between the active drug treatment groups (Budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the primary carcinogenicity study were again found in the repeat budesonide study, as well as with reference GCS. These effects are most likely related to receptor-mediated effects and are thus class effects.

Available clinical experience indicates that there is no evidence that the use of budesonide or other GCS leads to the occurrence of brain glioma or primary hepatocellular neoplasms in humans.

In animal reproduction studies, corticosteroids such as Budesonide have been shown to cause malformations (cleft palate, skeletal malformations). However, these experimental animal results do not appear to be applicable to humans at recommended doses.

Animal studies have also identified an association between excessive prenatal intake of GCS and an increased risk of intrauterine growth retardation, cardiovascular disease in adulthood, and irreversible changes in glucocorticoid receptor density, neurotransmitter metabolism, and behavior at exposure levels below the dose range causing teratogenic effects.

Indications

Bronchial asthma requiring glucocorticosteroid therapy for

• Maintenance therapy;
• Exacerbations when the use of budesonide inhalation suspension is justified.

Chronic obstructive pulmonary disease (COPD) for

• Maintenance therapy;
• Exacerbations when the use of budesonide inhalation suspension is justified as an alternative to systemic glucocorticosteroids.

Stenosing laryngotracheitis (croup).

ICD codes

Dosage Regimen

Bronchial asthma

The dose of the drug is selected individually. If the recommended dose does not exceed 1 mg/day, the entire dose of the drug can be taken at one time (as a single dose). If a higher dose is taken, it is recommended to divide it into 2 doses. For all patients, it is desirable to determine the minimum effective maintenance dose.

Recommended initial dose

Adults/elderly patients 1-2 mg/day.

Maintenance treatment dose

Adults/elderly patients 0.5-4 mg/day.

In case of severe exacerbations, the dose may be increased.

If an additional therapeutic effect is needed, an increase in the daily dose of Senticort^® can be recommended instead of combining the drug with oral GCS, due to the lower risk of systemic effects.

Onset of effect in maintenance treatment

Improvement in asthma control during maintenance therapy with Senticort^® may occur within 3 days after the start of treatment, although the maximum effect may not be achieved for 2-4 weeks.

Patients receiving oral GCS

Discontinuation of oral GCS should be started when the patient’s condition is stable. A high dose of Senticort^® should be taken for 10 days while continuing oral GCS at the usual dose. Subsequently, over the course of a month, the dose of oral GCS should be gradually reduced (for example, by 2.5 mg of prednisolone or its equivalent) to the minimum effective dose. In many cases, it is possible to completely discontinue oral glucocorticosteroids.

COPD

COPD maintenance therapy

The dose of the drug is selected individually. If the recommended dose does not exceed 1 mg/day, the entire dose of the drug can be taken at one time (as a single dose). If a higher dose is taken, it is recommended to divide it into 2 doses. For all patients, it is desirable to determine the minimum effective maintenance dose.

Recommended initial dose

Adults/elderly patients 1-2 mg/day.

Maintenance treatment dose

Adults/elderly patients 0.5-4 mg/day.

COPD exacerbations

Adults/elderly patients: 4-8 mg/day.

The dose should be divided into 2-4 doses. Treatment should be continued until clinical improvement is achieved, but for no more than 10 days.

Onset of effect

After inhalation of Senticort^® for the treatment of COPD exacerbations, the time to symptom improvement is comparable to that with systemic corticosteroids.

Special patient groups

Patients with impaired liver or kidney function

There are no data on the use of budesonide in patients with impaired liver or kidney function. Considering the fact that Budesonide is eliminated by biotransformation in the liver, increased exposure to the drug can be expected in patients with severe liver cirrhosis.

Children

Bronchial asthma

Recommended initial dose

Children from 6 months and older 0.25-0.5 mg/day. If necessary, the dose can be increased to 1 mg/day.

Maintenance treatment dose

Children from 6 months and older 0.25-2 mg/day.

Children under 6 months of age

Senticort^® is contraindicated in children under 6 months of age (see section “Contraindications”).

COPD

Children and adolescents under 18 years of age

The safety and efficacy of Senticort^® in children and adolescents under 18 years of age have not been established.

Stenosing laryngotracheitis (croup)

Children from 6 months and older 2 mg/day. The drug dose can be taken as a single dose or divided into 2 doses of 1 mg with a 30-minute interval.

Children under 6 months of age

Senticort^® is contraindicated in children under 6 months of age (see section “Contraindications”).

Method of administration

By inhalation.

Senticort^® is used for inhalation using an appropriate nebulizer equipped with a mouthpiece and a special mask. The nebulizer is connected to a compressor to create the required air flow (5-8 L/min), the filling volume of the nebulizer should be 2-4 ml.

Dosing table

* should be diluted with 0.9% sodium chloride solution to a volume of 2 ml

Since Senticort^®, used as a suspension via a nebulizer, enters the lungs during inhalation, it is important to instruct the patient to inhale the drug through the nebulizer mouthpiece calmly and evenly.

It is important to inform the patient

• Ultrasonic nebulizers are not suitable for the use of Senticort^® suspension;
• Senticort^® suspension can be mixed with 0.9% sodium chloride solution or with solutions of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate, and ipratropium bromide; the diluted suspension should be used within 30 minutes;
• After inhalation, the mouth should be rinsed with water to reduce the development of oropharyngeal candidiasis;
• To prevent skin irritation, the face should be washed with water after using the mask;
• It is recommended to regularly clean the nebulizer according to the manufacturer’s instructions.

In cases where a child cannot independently inhale through a nebulizer, a special mask is used.

Use of Senticort^® with a nebulizer

Before use, gently shake the ampoule with a light rotating motion.

Hold the ampoule straight upright and open it by twisting.

Carefully place the ampoule with the open end into the nebulizer and slowly squeeze out the contents.

The ampoule containing a single dose is marked with a line. If the ampoule is turned over, this line will indicate a volume equal to 1 ml.

If only 1 ml of suspension needs to be used, the contents of the ampoule are squeezed out until the liquid surface reaches the level marked by the line, and the remaining suspension is not sterile and must be disposed of immediately.

Before using the remaining liquid, the contents of the ampoule are gently shaken with a rotating motion.

After each inhalation, it is necessary to rinse the mouth with water and wash the face.

When using a mask, it is necessary to ensure that the mask fits tightly to the face during inhalation.

Cleaning

The nebulizer chamber, mouthpiece, or mask should be cleaned after each use. The nebulizer chamber, mouthpiece, or mask should be washed with warm water using a mild detergent or according to the manufacturer’s instructions. Rinse thoroughly and dry the nebulizer by connecting the chamber to the compressor or inlet air valve.

Adverse Reactions

Tabulated summary of adverse reactions

The frequency of adverse reactions is presented as follows: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data). Up to 10% of patients taking the drug may experience the following adverse reactions

* see Description of selected adverse drug reactions; facial skin irritation, see below

** refer to pediatric patients, see below

*** based on frequency reported in clinical studies

**** rarely observed in children

Sometimes signs or symptoms of systemic adverse reactions of corticosteroids may develop with the use of inhaled corticosteroids, probably depending on the dose, duration of exposure, concomitant and prior corticosteroid exposure, and individual sensitivity (see section “Special Precautions”).

Description of selected adverse reactions

Given the risk of oropharyngeal candidiasis, the patient should thoroughly rinse the mouth with water after each inhalation of the drug.

In rare cases, symptoms caused by the systemic action of corticosteroids may occur, including adrenal hypofunction and growth retardation in children. The severity of these symptoms likely depends on the drug dose, duration of therapy, concomitant or previous glucocorticosteroid therapy, as well as individual sensitivity.

Cases of facial skin irritation have been reported when using a nebulizer with a mask. To prevent irritation, the face should be washed with water after using the mask.

As with other inhalation therapy, paradoxical bronchospasm may occur very rarely (see section “Special Precautions”). Data from clinical studies involving 13,119 patients receiving inhaled Budesonide and 7,278 patients receiving placebo were combined. The incidence of anxiety was 0.52% with inhaled budesonide and 0.63% with placebo; the incidence of depression was 0.67% with inhaled budesonide and 1.15% with placebo. In placebo-controlled studies, reports of cataract development in the placebo group were also infrequent.

Children

Due to the risk of growth retardation in pediatric patients, growth monitoring should be performed as described in the “Special Precautions” section.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to budesonide or to any of the excipients included in the drug;
• Children under 6 months of age.

With caution pulmonary tuberculosis (active or inactive form); fungal, viral, or bacterial respiratory infections; liver cirrhosis; pregnancy; breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

Most results from prospective epidemiological studies and global post-marketing data do not indicate an increased risk of adverse effects on the fetus and newborn when using inhaled budesonide during pregnancy. In animal studies, corticosteroids have been shown to cause malformations (see subsection “Preclinical safety data”). This effect is unlikely to be observed in humans at recommended doses, but therapy with inhaled budesonide should be regularly reviewed and the minimum effective dose should be used. Maintaining adequate asthma control during pregnancy is important for both the fetus and the mother. As with other drugs prescribed during pregnancy, the benefit of budesonide for the mother should be weighed against the risk to the fetus.

Inhaled corticosteroids should be preferred over oral corticosteroids because they have less pronounced systemic effects at doses required to achieve a similar pulmonary response to therapy.

Breastfeeding period

Budesonide is excreted in breast milk. However, no effects on breastfed infants are observed at therapeutic doses of budesonide. The drug Senticort^® can be used during breastfeeding.

Maintenance therapy with inhaled budesonide (200 or 400 mcg twice daily) in breastfeeding women with asthma results in minimal systemic exposure to budesonide in breastfed infants.

In a pharmacokinetic study, the estimated infant daily dose was 0.3% of the mother’s daily dose for both doses, and the average plasma concentration in infants was estimated to be 1/600 of the concentration observed in the mother’s plasma, assuming complete oral bioavailability in infants. All budesonide concentrations in infant plasma samples were below the limit of quantification.

Based on data on inhaled budesonide and the fact that Budesonide exhibits linearity of pharmacokinetic properties within therapeutic dosing intervals after nasal, inhalation, oral, and rectal administration, it is assumed that exposure to the breastfed infant will be low at therapeutic doses of budesonide.

Use in Hepatic Impairment

Since Budesonide is eliminated by biotransformation in the liver, increased drug exposure can be expected in patients with severe liver cirrhosis.

Use in Renal Impairment

There are no data on the use of budesonide in patients with renal impairment.

Pediatric Use

Use in children under 6 months of age is contraindicated.

Special Precautions

Budesonide is not intended for the rapid relief of acute asthma attacks, which require the use of short-acting inhaled bronchodilators.

In case of exacerbation, the dose of Senticort^® can be increased or short-term additional therapy can be prescribed.

As with other inhalation therapy, paradoxical bronchospasm with immediate worsening of wheezing after using Senticort^® may occur. In such a case, inhaled budesonide therapy should be discontinued immediately, the patient’s condition should be assessed, and, if necessary, alternative therapy should be prescribed.

Fungal infections of the oral cavity may occur with the use of inhaled corticosteroids. If such an infection develops, appropriate antifungal treatment may be required, and in some patients, discontinuation of inhaled corticosteroids may be necessary. To reduce the risk of oropharyngeal fungal infection, the patient should be instructed to thoroughly rinse the mouth with water after each inhalation of the drug.

Concomitant administration of budesonide with ketoconazole, itraconazole, or other potent CYP3A4 inhibitors should be avoided. If Budesonide and ketoconazole or other potent CYP3A4 inhibitors are prescribed, the time between drug administrations should be increased as much as possible.

Due to the possible risk of adrenal function impairment, special attention is required for patients who are switched from oral corticosteroids to Senticort^®. Special attention should also be paid to patients who have taken high doses of corticosteroids or have received the maximum recommended doses of inhaled corticosteroids for a long time. In stressful situations, such patients may show signs and symptoms of adrenal insufficiency. During stress or in cases of surgery, additional therapy with systemic corticosteroids is recommended.

Special attention is required for patients who are switched from systemic to inhaled corticosteroids (Senticort^®) or when impairment of pituitary-adrenal function can be expected. In such patients, the dose of systemic corticosteroids should be reduced with particular caution and hypothalamic-pituitary-adrenal function should be monitored. Patients may also require supplementation with oral corticosteroids during stressful situations such as trauma, surgery, etc.

When switching from oral corticosteroids to Senticort^®, patients may experience previously observed symptoms, such as muscle pain or joint pain. In such cases, a temporary increase in the dose of oral corticosteroids may be needed. In rare cases, symptoms such as fatigue, headache, nausea, and vomiting, indicating systemic corticosteroid insufficiency, may be observed.

Replacing oral corticosteroids with inhaled ones sometimes leads to the manifestation of concomitant allergies, such as rhinitis and eczema, which were previously controlled by systemic drugs.

Systemic effects may occur with the use of any inhaled corticosteroids, especially when used in high doses for long periods. The likelihood of developing such symptoms is significantly lower with inhaled glucocorticosteroid therapy than with oral corticosteroids.

Possible systemic effects include Cushing’s syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma, psychological symptoms and behavioral disorders, including psychomotor hyperactivity, sleep disorders, anxiety, depression, and aggression, especially in children (see section “Adverse Reactions”). The dose of the inhaled glucocorticosteroid should be the lowest at which effective disease control is maintained.

Impaired liver function may affect the elimination of corticosteroids, causing a decrease in elimination rate and an increase in systemic exposure. Patients should be warned about possible systemic adverse reactions.

Clinical studies and meta-analyses have shown that the use of inhaled corticosteroids in maintenance therapy for COPD may lead to an increased risk of pneumonia. Physicians should be aware of the possibility of pneumonia development in COPD patients, as the clinical signs of pneumonia and disease exacerbation often overlap.

Visual impairment may occur with systemic and local use of corticosteroids. If a patient develops symptoms such as blurred vision or other visual disturbances, the need for referral to an ophthalmologist should be considered to assess possible causes, which may include cataract, glaucoma, or rare conditions such as central serous retinopathy, reported after systemic and local use of glucocorticosteroids.

Children

In children and adolescents receiving glucocorticosteroid treatment (regardless of the delivery method) for prolonged periods, it is recommended to regularly monitor growth parameters. In case of growth retardation, therapy should be reviewed to reduce the dose of the inhaled corticosteroid, if possible, to the lowest dose that maintains effective control of bronchial asthma. The benefit of glucocorticosteroid therapy and the potential risk of growth retardation should be carefully evaluated. Additionally, it is recommended to refer the patient to a pediatric pulmonologist.

The use of budesonide in doses up to 400 mcg/day in children over 3 years of age did not lead to systemic effects. Biochemical signs of the drug’s systemic effect may occur when taking the drug in doses from 400 to 800 mcg/day. At doses exceeding 800 mcg/day, systemic effects of the drug occur frequently.

Effect on ability to drive vehicles and machinery

Senticort^® does not affect the ability to drive a car or operate machinery.

Overdose

Acute overdose does not produce clinical manifestations. With long-term use of the drug in doses significantly exceeding the recommended ones, a systemic glucocorticosteroid effect in the form of hypercortisolism and adrenal suppression may develop.

Drug Interactions

No interaction of budesonide with other drugs used in the treatment of bronchial asthma has been observed.

Ketoconazole (200 mg once daily) increases the plasma concentration of oral budesonide (3 mg once daily) by an average of 6 times when taken concomitantly. When ketoconazole was taken 12 hours after budesonide intake, the plasma concentration of the latter increased by an average of 3 times. Information on such interaction with inhaled budesonide is lacking, but it is assumed that an increase in budesonide plasma concentration should also be expected in this case. If it is necessary to take ketoconazole and budesonide, the time between drug administrations should be increased as much as possible. The possibility of reducing the budesonide dose should also be considered. Another potential CYP3A4 inhibitor, such as itraconazole, also significantly increases the plasma concentration of budesonide.

Preliminary inhalation of beta-agonists dilates the bronchi, improves the delivery of budesonide to the airways, and enhances its therapeutic effect.

Phenobarbital, phenytoin, rifampicin reduce the effectiveness (induction of microsomal oxidation enzymes) of budesonide.

Methandrostenolone, estrogens enhance the effect of budesonide.

Storage Conditions

The drug should be stored at a temperature below 30°C (86°F) in a laminated foil envelope to protect from light, in an upright position. Do not freeze.

Unopened envelope – shelf life 2 years.

After first opening the envelope – the ampoules must be used within 3 months.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.