Pulmicort turbuhaler

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PULMICORT TURBUHALER (Pulmicort® Turbuhaler®)

Composition:

Active substance: budesonide;

1 dose (inhalation) contains 100 mcg or 200 mcg of budesonide.

Pharmaceutical form. Powder for inhalation.

Main physicochemical properties:

100 mcg/dose:

A specially designed powder inhaler made of plastic materials. The rotating dose indicator is light-brown in color. On the base of the rotating dose indicator, "Budesonide 100" is embossed. Contents: round granules from white to almost white, which disintegrate into fine powder under slight pressure. Powder fraction may be present.

200 mcg/dose:

A specially designed powder inhaler made of plastic materials. The rotating dose indicator is brown in color. On the base of the rotating dose indicator, "Budesonide 200" is embossed. Contents: round granules from white to almost white, which disintegrate into fine powder under slight pressure. Powder fraction may be present.

Pharmacotherapeutic group. Inhalation preparations used in the treatment of obstructive airway diseases. Glucocorticoids. ATC code: R03BA02.

Pharmacological properties.

Pharmacodynamics.

Budesonide is a glucocorticosteroid with potent local anti-inflammatory activity.

The precise mechanism of action of glucocorticosteroids in the treatment of asthma has not been fully elucidated. The primary effects are anti-inflammatory, including suppression of inflammatory mediator release and inhibition of cytokine-mediated immune responses. Budesonide exhibits activity due to its affinity for glucocorticosteroid receptors, which is approximately 15 times greater than that of prednisolone.

Budesonide exerts anti-inflammatory effects that reduce bronchial obstruction during both the early and late phases of the allergic reaction. Budesonide reduces the responsiveness to histamine and methacholine in patients with airway hyperresponsiveness.

Studies have demonstrated that the earlier budesonide treatment is initiated following the onset of asthma symptoms, the greater the improvement in lung function that can be expected.

In patients with mild to moderate COPD, Pulmicort Turbuhaler at a dose of 400 mcg twice daily led to an increase in forced expiratory volume in one second (FEV1) after 3–6 months of treatment compared to placebo. This effect was maintained over three years of therapy.

Studies using Pulmicort Turbuhaler in healthy volunteers showed a dose-dependent effect on plasma and urinary cortisol. When administered at recommended doses, Pulmicort Turbuhaler has significantly less impact on adrenal function than 10 mg of prednisone, as demonstrated by ACTH stimulation tests.

In children aged 5 years and older, no systemic effects were observed with doses up to 400 mcg daily. At doses of 400–800 mcg daily, biochemical signs of systemic effects may occur, while such signs are common at daily doses exceeding 800 mcg.

Bronchial asthma, as well as the use of inhaled corticosteroids, may lead to growth suppression. However, long-term studies in children treated with budesonide (up to 13 years) have shown that patients reach their expected adult height. In most cases, a minor growth delay (approximately 1 cm) was observed during the first year of treatment. Inhaled budesonide therapy is effective in preventing exercise-induced asthma.

Pharmacokinetics.

Absorption

Inhaled budesonide is rapidly absorbed. Peak plasma concentrations are reached within 30 minutes after inhalation. In studies, the average lung deposition of budesonide after inhalation via Turbuhaler was 25–35% of the administered dose. Systemic bioavailability is approximately 38%.

Distribution and metabolism

Plasma protein binding is approximately 90%. The volume of distribution is approximately 3 L/kg.

Budesonide undergoes extensive (approximately 90%) first-pass metabolism in the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites, 6-beta-hydroxybudesonide and 16-alpha-hydroxyprednisolone, is less than 1% of that of budesonide.

Elimination

Budesonide is eliminated via metabolism, primarily catalyzed by the CYP3A4 enzyme. Metabolites are excreted in urine, either unchanged or in conjugated form. Only a negligible amount of unchanged budesonide is detected in urine. Budesonide has a high systemic clearance (approximately 1.2 L/min), and its plasma half-life after intravenous administration averages 4 hours. Budesonide pharmacokinetics are dose-proportional within the therapeutic dose range.

The pharmacokinetics of budesonide in children and in patients with renal impairment are not known. The effect of budesonide may be increased in patients with hepatic disease.

Clinical characteristics.

Indications.

• Persistent bronchial asthma requiring treatment with inhaled glucocorticoids.
• Treatment of moderate to severe chronic obstructive pulmonary disease (COPD).

Contraindications.

Hypersensitivity to budesonide.

Interaction with other medicinal products and other forms of interaction.

Pulmicort Turbuhaler may enhance the effect of inhaled beta-2-adrenergic agonists. Budesonide metabolism is primarily mediated by the CYP3A4 enzyme of the cytochrome P450 subfamily. Therefore, concomitant use of inhibitors of this enzyme—such as ketoconazole, itraconazole, clotrimazole, ritonavir, cyclosporine, ethinylestradiol, troleandomycin, and HIV protease inhibitors—may result in several-fold increases in systemic exposure to budesonide (see section "Special warnings and precautions for use"). Due to lack of dosing recommendations, such combinations should be avoided. If avoidance is not possible, the interval between administration of the drugs should be as long as possible. Alternatively, consideration may be given to reducing the dose of budesonide.

Limited data on these interactions with high-dose inhaled budesonide suggest that plasma levels may increase significantly (on average fourfold) when itraconazole 200 mg once daily is co-administered with inhaled budesonide (single dose 1000 µg). In vivo studies have shown that oral administration of ketoconazole and itraconazole may increase systemic concentrations of budesonide. This has minimal clinical significance for short-term treatment (1–2 weeks), but should be considered during long-term therapy.

Concomitant administration of cimetidine and budesonide may lead to a slight increase in plasma budesonide levels; however, this is not considered clinically significant.

Increased plasma concentrations and enhanced corticosteroid effects have been observed in women concurrently receiving estrogens or oral contraceptives. However, no clinically relevant changes have been noted with concomitant use of budesonide and low-dose combined oral contraceptives.

Since adrenal function may be suppressed, an ACTH stimulation test performed to diagnose pituitary insufficiency may yield false-negative results (low values).

Special precautions for use.

Exacerbations of COPD should be treated with additional medications as determined by the responsible physician.

Budesonide is not intended for the relief of acute asthma attacks when rapid-acting inhaled bronchodilators are required.

Transition from oral corticosteroids

Patients receiving systemic corticosteroid therapy should be switched to Pulmicort Turbuhaler once control of symptoms has been achieved. In patients with impaired adrenal cortex function, systemic corticosteroids should be withdrawn gradually rather than stopped abruptly. During the initial transition to Pulmicort Turbuhaler, systemic corticosteroids should be continued for approximately 1 week. Thereafter, the daily dose of systemic corticosteroids may be reduced by an amount equivalent to 2.5 mg of prednisone weekly, depending on the patient's response, over a period of 1–2 weeks.

Special caution is required when treating patients transitioning from oral corticosteroids, as they may remain at risk of adrenal insufficiency for a prolonged period. Patients requiring emergency high-dose corticosteroid therapy or long-term treatment with inhaled corticosteroids at the highest recommended dose may also be at risk. Such patients may develop symptoms of adrenal insufficiency during periods of significant stress. During stressful periods or prior to elective surgical procedures, consideration should be given to additional systemic corticosteroid therapy.

If stressful or emergency situations (e.g., severe infections, trauma, surgical procedures) occur within the first few months after switching from systemic corticosteroids to inhaled therapy, re-institution of systemic corticosteroids may be necessary.

Systemic effects of inhaled corticosteroids

Systemic effects of inhaled corticosteroids may occur, particularly with prolonged use of high doses. These effects are considerably less likely than with oral corticosteroids. Potential systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma, and, less commonly, a range of psychological and behavioral effects such as psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (particularly in children). Therefore, it is important that the dose of inhaled corticosteroid be reduced to the lowest effective dose that maintains adequate control of asthma.

Effect on growth

Regular monitoring of growth is recommended in children and adolescents receiving long-term corticosteroid therapy, regardless of the formulation used. The benefits of corticosteroid treatment should be weighed against the potential risk of growth retardation. In addition, referral to a pediatric pulmonologist should be considered.

In the event of growth retardation, and to minimize potential systemic effects, therapy should be re-evaluated to ensure that the dose of inhaled corticosteroid is adjusted to the lowest effective dose for maintaining disease control.

Use in patients with hepatic impairment

Impaired liver function affects the ability to eliminate corticosteroids, resulting in reduced clearance and increased systemic exposure. The potential for systemic adverse effects should be considered.

Concomitant use with other medicinal products

Concomitant use of the drug with ketoconazole, itraconazole, HIV protease inhibitors, or other potent CYP3A4 inhibitors should be avoided. If avoidance is not possible, the interval between administration of the drugs should be as long as possible (see section "Interaction with other medicinal products and other forms of interaction***").

Respiratory tract infections

Particular caution is required in patients with active pulmonary tuberculosis or latent pulmonary tuberculosis, as well as in patients with fungal or viral respiratory tract infections.

Oropharyngeal candidiasis

Oropharyngeal candidiasis may develop during treatment with inhaled corticosteroids. To reduce the risk of developing candidiasis of the mouth and throat, Pulmicort Turbuhaler should be used before meals or the patient should rinse the mouth with water after each inhalation. If necessary, appropriate antifungal agents may be used, and in some patients, temporary discontinuation of Pulmicort Turbuhaler may be required (see section "Dosage and administration").

Bronchospasm

As with other inhaled medications, paradoxical bronchospasm with wheezing may occur immediately after administration of the drug. In such cases, inhaled budesonide therapy should be discontinued immediately, the patient's condition assessed, and alternative therapy initiated if necessary.

Patients should be advised to seek medical attention if overall effectiveness of treatment decreases, as repeated inhalations during severe asthma attacks should not delay initiation of other essential therapy. In case of sudden worsening of symptoms, treatment should be supplemented with short-term oral corticosteroids.

During transition from systemic corticosteroid therapy to Pulmicort Turbuhaler, patients may experience previous symptoms such as muscle and joint pain. In such cases, temporary increase in the dose of oral corticosteroids may be required. If (in individual cases) symptoms such as increased fatigue, headache, nausea, vomiting, or similar occur, inadequate steroid effect should be suspected in most cases.

When replacing systemic corticosteroid therapy with Pulmicort Turbuhaler, allergies previously controlled by systemic therapy (e.g., rhinitis, eczema) may occasionally reappear.

Pneumonia in patients with COPD

An increased incidence of pneumonia, including pneumonia requiring hospitalization, has been observed in patients with chronic obstructive pulmonary disease (COPD) receiving inhaled corticosteroids. There is some evidence of increased pneumonia risk with higher corticosteroid doses, although this has not been definitively demonstrated in any study.

There are no comprehensive clinical data demonstrating intra-class differences in pneumonia risk among inhaled corticosteroids.

Physicians should remain vigilant for possible pneumonia in COPD patients, as clinical signs of such infections overlap with symptoms of COPD exacerbations.

Risk factors for pneumonia in COPD patients include smoking, advanced age, low body mass index (BMI), and severe COPD.

Visual disturbances

Visual disturbances have been reported with both systemic and topical corticosteroid use. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which have been reported after systemic and topical corticosteroid use.

Note.

Pulmicort Turbuhaler is not suitable for the treatment of acute asthma attacks.

Information for patients not previously treated with corticosteroids.

In patients who have not previously received corticosteroid therapy or who have only received short-term intermittent treatment, improvement in breathing may be observed approximately 1 week after starting regular use of Pulmicort Turbuhaler as prescribed by a physician. However, severe edema and inflammatory changes may cause such bronchial obstruction that budesonide cannot be fully effective with local administration.

In such cases, therapy should begin with the addition of systemic corticosteroids (initially at a dose equivalent to 40–60 mg of prednisone per day). Inhalations should be continued during gradual tapering of systemic corticosteroids.

Exacerbation of symptoms during acute respiratory infections.

In case of symptom exacerbation during acute respiratory infections, appropriate antibiotics should be considered. If necessary, the dose of Pulmicort Turbuhaler may be adjusted, and systemic glucocorticoid administration may be indicated under certain circumstances.

Use of Pulmicort Turbuhaler may result in positive doping test results.

Use during pregnancy or breastfeeding.

Pregnancy

Most prospective epidemiological studies and post-marketing data worldwide have not shown an increased risk of adverse effects on the fetus or newborn associated with inhaled budesonide use during pregnancy. It is important for both the fetus and the mother that asthma is adequately controlled during pregnancy. As with other medicinal products used during pregnancy, the benefit of budesonide use for the mother should be weighed against potential risks to the fetus.

Animal studies have demonstrated that glucocorticoids may cause developmental abnormalities; however, these findings are not considered relevant to humans when used at recommended doses.

Animal studies have also shown that excess prenatal glucocorticoids may affect intrauterine growth retardation, adult cardiovascular disease, and permanent changes in glucocorticoid receptor density, neurotransmitter metabolism, and behavior at doses below teratogenic levels.

During pregnancy, the lowest effective dose of budesonide should be used, taking into account the risk of worsening asthma.

Lactation

Budesonide is excreted in human breast milk.

However, when therapeutic doses of Pulmicort Turbuhaler are used, no effect on the breastfed infant is expected, as systemic exposure to the infant is negligible. Pulmicort Turbuhaler can be used during breastfeeding.

Maintenance therapy with inhaled budesonide (200 or 400 mcg twice daily) in breastfeeding women with asthma results in only minimal systemic exposure to budesonide in breastfed infants. In a pharmacokinetic study, the calculated daily infant dose was 0.3% of the maternal daily dose for both doses.

The average plasma concentration in infants was estimated to be one six-hundredth of the concentration observed in maternal plasma, assuming complete bioavailability in the infant. Budesonide concentrations in all infant plasma samples were below the limit of quantification.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of Administration and Dosage

Bronchial Asthma

The dosage of Pulmicort Turbuhaler should be individually adjusted.

At the beginning of inhaled corticosteroid therapy for treatment of severe asthma exacerbations, or during dose reduction, or when discontinuing oral corticosteroids, the dosage should be as follows:

Children aged 5–7 years: 100–400 mcg per day, divided into 2–4 inhalations. The total daily dose may be administered as a single dose.

Children aged 7 years and older: 100–800 mcg per day, divided into 2–4 inhalations. When daily doses up to 400 mcg are used, the entire dose may be administered as a single dose.

Adults: the usual dose is 200–800 mcg per day, divided into 2–4 inhalations. In more severe cases, daily doses up to 1600 mcg may be required. When daily doses up to 400 mcg are used, the entire dose may be administered as a single dose.

The maintenance dose should be as low as possible.

When using the Turbuhaler inhaler, an inspiratory flow rate of approximately 35–60 L/min, which is observed in most patients (including children), ensures adequate delivery of the drug and provides therapeutic efficacy. An inspiratory flow rate below 35 L/min still has proven therapeutic effect. The efficacy of Pulmicort Turbuhaler is at least equivalent to that of conventional glucocorticoids administered via pressurized metered-dose inhalers.

It is possible that when using Pulmicort Turbuhaler, the patient may not feel any taste or sensation of the medication; this is due to the very small particle size of the substance released during use.

After administration of a single dose, the effect is expected within several hours. Full therapeutic effect is achieved only after several weeks of treatment. Treatment with Pulmicort Turbuhaler is a preventive therapy and has no proven effect on acute symptoms.

Clinical studies have shown that when Pulmicort Turbuhaler is used, a greater amount of budesonide is deposited in the lungs compared to the use of Pulmicort in a pressurized metered-dose inhaler (pMDI). Switching a stable patient from Pulmicort metered-dose inhaler to Pulmicort Turbuhaler may require a reduction in dose.

In patients requiring enhanced therapeutic effect, increasing the dose of Pulmicort Turbuhaler is generally preferred over combination therapy with oral corticosteroids, as the risk of systemic side effects is lower with Pulmicort Turbuhaler.

Patients on Oral Steroids

Pulmicort may allow replacement or substantial reduction of oral corticosteroid dosage while maintaining asthma control.

When switching from oral steroids to Pulmicort Turbuhaler, the patient should be in a relatively stable condition. For 10 days, administer a high dose of Pulmicort Turbuhaler in combination with the previously used dose of oral steroid. After this period, the oral steroid dose should be gradually reduced, for example, by 2.5 mg/month of prednisolone or equivalent per month, to the lowest possible level. Often, oral steroid therapy can be completely discontinued.

Chronic Obstructive Pulmonary Disease (COPD)

The recommended dose of Pulmicort Turbuhaler is 400 mcg twice daily.

For patients who respond positively during the first 3–6 months of Pulmicort Turbuhaler therapy, the drug should be continued long-term.

When prescribing Pulmicort Turbuhaler to COPD patients who are using oral glucocorticosteroids, dose reduction of the oral steroid should follow the recommendations for bronchial asthma therapy.

Hepatic or Renal Impairment

There is no clinical experience in treating patients with hepatic or renal impairment. Since budesonide is primarily eliminated via hepatic metabolism, an enhanced effect may be expected in patients with severe liver cirrhosis.

Instructions for Correct Use of Pulmicort Turbuhaler

The active substance enters the body through inhaled air, i.e., when the patient inhales through the mouthpiece, the substance is delivered to the airways along with the inhaled air.

It is important to instruct the patient to:

• follow the instructions for use;
• inhale strongly and deeply through the mouthpiece to ensure optimal delivery to the lungs;
• never exhale through the mouthpiece;
• close the Pulmicort Turbuhaler with the cap immediately after use;
• rinse the mouth with water after each maintenance dose to minimize the risk of oral candidiasis.

Instructions for Correct Use of Pulmicort Turbuhaler

Pulmicort Turbuhaler is a multi-dose inhaler delivering a very fine powder (Fig. 1). The powder reaches the lungs when inhaled through the mouthpiece. Therefore, it is essential to inhale strongly and deeply through the mouthpiece.

Fig. 1.

How to Use the Inhaler

1. Unscrew and remove the protective cap.
2. Hold the inhaler vertically with the dose counter at the bottom. Do not hold the inhaler by the mouthpiece when turning the dose disk.
3. Turn the dose disk fully in one direction, then back fully in the opposite direction until it stops. (Fig. 2). The initial direction of rotation does not matter. A clicking sound may be heard during this process. (For first-time use, repeat this step twice. For second and subsequent uses, perform once only.)

Fig. 2.

Overdosing is not possible, even if the dose disk is accidentally activated several times.

1. First, exhale fully without using the device. Then place the mouthpiece between the lips and inhale strongly and deeply through the device (Fig. 3). Do not chew or bite the mouthpiece, as it may become loose or detached!

Do not use the device if it is damaged or if the mouthpiece has become detached.

Fig. 3.

1. Remove the device from the mouth and hold the breath for a few seconds.

Do not exhale through the device!

If more than one inhalation is prescribed, repeat steps 2–5.

1. Immediately after use, replace the protective cap and screw it tightly back onto the device.

Notes

Never exhale through the mouthpiece.

Always replace the protective cap immediately after using the device.

Since each dose contains only the pure active substance and no inactive excipients, in most cases the patient may not feel the medication particles depositing on the oral mucosa. In rare cases, a bitter taste may be noticed. Even if the medication cannot be tasted or felt after inhalation, the patient can be confident that the dose was delivered if the instructions were followed correctly. To reduce the risk of Candida fungal infection, the patient should use Pulmicort Turbuhaler before meals or rinse the mouth after inhalation.

Cleaning the Mouthpiece

It is recommended to clean the outer surface of the mouthpiece weekly using a dry cloth. Do not use water or other liquids to clean the mouthpiece.

When the Device is Empty

When a red marker appears in the dose indicator window located below the mouthpiece, approximately 20 inhalations remain (Fig. 4).

Approximately 20 doses remaining

Fig. 4.

When the red marker reaches the bottom edge of the window, the remaining 20 doses have been used (Fig. 5). Although a small amount of active substance may still remain, the device should not be used further for technical reasons.

Mouthpiece

empty empty

Fig. 5.

The sound heard when shaking the Turbuhaler inhaler is caused by movement of the desiccant residue, which protects the active substance from excess moisture. The active substance itself does not produce sound.

Other Information

The rotating dosing mechanism features a Braille code for identification of Pulmicort Turbuhaler (the code for Pulmicort Turbuhaler is the number 2, distinguishing it from other AstraZeneca products).

Children

Do not use in children under 5 years of age.

Overdose

Acute overdose of Pulmicort Turbuhaler, even at high doses, is not expected to cause any clinical problems. Chronic use of high doses may lead to systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression.

Adverse reactions.

Adverse reactions are categorized by their frequency of occurrence:

Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Adverse reactions by organ systems and frequency of occurrence during the use of the medicinal product

Systemic organs	Frequency	Adverse reactions to the drug
Infections and infestations	Common	Candida infections of the mouth and throat, pneumonia (in COPD patients)
Immune system disorders	Uncommon	Immediate and delayed hypersensitivity reactions, including rash, pruritus, contact dermatitis, urticaria, angioedema, and anaphylactic reaction.
Endocrine system disorders	Uncommon	Symptoms indicating systemic corticosteroid effects, including adrenal suppression and growth retardation*, increased susceptibility to infections
Eye disorders	Frequency unknown	Glaucoma.
	Uncommon	Cataract**, Blurred vision (see also section "Special precautions")
Psychiatric disorders	Uncommon	Restlessness, nervousness, behavioral changes (mainly in children).
	Frequency unknown	Sleep disturbances, psychomotor hyperactivity, aggression.
	Uncommon	Anxiety, depression.
Nervous system disorders	Uncommon	Tremor
Respiratory, thoracic and mediastinal disorders	Common	Cough, throat irritation.
	Uncommon	Bronchospasm, dysphonia, hoarseness
Skin and subcutaneous tissue disorders	Uncommon	Contusion formation.
Musculoskeletal and connective tissue disorders	Uncommon	Osteoporosis (with long-term use), muscle spasm.

* See below "Children".

** See below "Eye disorders".

Systemic corticosteroid side effects may occasionally occur during inhaled glucocorticosteroid therapy, likely depending on dose, duration of exposure, concomitant and prior corticosteroid exposure, as well as individual sensitivity.

Infections and infestations

Due to the risk of developing candidiasis of the mouth and throat, patients should rinse their mouth with water after each dose administration.

Eye disorders

Cataract was also reported as an uncommon adverse event in the placebo group in placebo-controlled studies.

Psychiatric disorders

In pooled clinical trials, 13,119 patients received inhaled budesonide and 7,278 patients received placebo. 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.

Children

Due to the risk of growth suppression in children, growth parameters should be monitored regularly (see section "Special precautions for use").

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing period. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 30 °C. Close the inhaler with the protective cap after use.

Packaging. 200 doses (for 100 mcg/dose) or 100 doses (for 200 mcg/dose) in a plastic inhaler. One inhaler per cardboard box.

Prescription status. Prescription only.

Manufacturer. AstraZeneca AB.

Manufacturer's address and place of business.
Forskargatan 18, Sodertalje, 151 36, Sweden / Forskargatan 18, Sodertalje, 151 36, Sweden.