Pulmicort Turbuhaler (Budesonide)

PULMICORT® TURBUHALER®

Astra

Budesonide

Glucocorticosteroid for the Treatment of Bronchial Asthma

Action And Clinical Pharmacology: Budesonide is a potent nonhalogenated synthetic glucocorticosteroid with strong topical and weak systemic effects.

Budesonide has a high topical anti-inflammatory potency and it is rapidly biotransformed in the liver. This favorable separation between topical anti-inflammatory activity and systemic effect is due to strong glucocorticosteroid receptor affinity and an effective first pass metabolism with a short half-life.

The late reaction can be significantly inhibited if budesonide is given at least 2 hours before a bronchial challenge. Pretreatment for 1 to 4 weeks with inhaled budesonide may inhibit the immediate bronchial reaction.

After initiation of therapeutic use of orally inhaled budesonide, several weeks may pass before the full effect is obtained.

Indications And Clinical Uses: Patients with bronchial asthma: in patients who require inhaled steroids and in patients for whom a reduction of systemic glucocorticoids is desirable.

Contra-Indications: Status asthmaticus; not to be used in primary treatment of acute episodes of asthma or in patients with moderate to severe bronchiectasis. Hypersensitivity to budesonide. Active or quiescent pulmonary tuberculosis. Untreated fungal, bacterial or viral infections of the respiratory system.

Manufacturers’ Warnings In Clinical States: Budesonide is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required. If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for increased anti-inflammatory therapy, e.g., higher doses of inhaled budesonide or a course of oral corticosteroid.

Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to inhaled corticosteroids; therefore particular care is needed in patients who are transferred from systemically active corticosteroids to budesonide. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis, or other conditions associated with severe electrolyte loss.

Although budesonide may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies.

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large dosages) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level.

Patients previously on high doses of systemic steroids may regain earlier symptoms not related to asthma such as rhinitis and eczema when transferred from oral therapy to budesonide. These symptoms are a result of the generally lower systemic steroid action which will be experienced. Patients may also suffer from tiredness, headache, pain in muscles and joints and, occasionally, nausea and vomiting. Temporary resumption of systemic steroids may be necessary to treat these conditions.

The development of pharyngeal and laryngeal candidiasis is cause for concern because the extent of its penetration of the respiratory tract is unknown. If oral pharyngeal candidiasis develops, appropriate antifungal therapy should be implemented to eradicate the infection. The incidence of candidiasis can generally be held to a minimum by having patients rinse their mouths out with water after each inhalation (see Dosage).

Glucocorticosteroids may mask some signs of infection and new infections may appear during their use.

There is no evidence that control of asthma can be achieved by administration of budesonide in doses higher than those recommended. During such episodes, patients may require therapy with systemic corticosteroids.

Precautions: In transferring patients from a systemic steroid to budesonide, the reduction of the systemic steroid must be very gradual and carefully supervised by the physician since systemic withdrawal symptoms (e.g., joint and/or muscular pain, lassitude, depression), may occur in spite of maintenance or improvement of respiratory functions (see Dosage).

It is essential that the patient be instructed that budesonide is a preventative agent which must be taken at regular intervals and is not to be used to relieve an acute asthmatic attack.

The long-term effects of budesonide on developmental or immunologic processes in the mouth, pharynx, trachea, eyes and lungs are unknown. With the recommended therapeutic doses of budesonide, there is little risk of adverse systemic effects.

In children, treated for 2 to 6 years, with budesonide via Turbuhaler at daily doses up to 400 µg, no effect was demonstrated on statural growth compared with nonsteroidal therapy. However, to allow for individuals that are excessively sensitive, it is recommended that height is monitored in growing children.

Treatment with budesonide should not be stopped abruptly, but tapered off gradually.

Pulmonary infiltrates with eosinophilia may occur in patients on budesonide therapy. Although this is possible in some patients who are administered inhalational steroids, their causative role cannot be ruled out.

Pregnancy: Administration during pregnancy should be avoided unless there are compelling reasons. In experimental animal studies, budesonide was found to cross the placental barrier. Like other glucocorticosteroids, budesonide is teratogenic to rodent species. High doses of budesonide administered s.c. produced fetal malformations, primarily skeletal defects, in rabbits, rats, and in mice. The relevance of these findings to humans has not yet been established. In the absence of further studies in humans, budesonide should be used during pregnancy only if the potential benefits clearly outweigh the risk to the fetus. Infants born of mothers who have received substantial doses of corticosteroids, especially oral steroids, during pregnancy should be carefully observed for hypoadrenalism.

Lactation: Glucocorticoids are secreted in human milk. It is not known whether budesonide would be secreted in human milk, but it is suspected to be likely. The use of budesonide in nursing mothers, requires that the possible benefits of the drug be weighed against the potential hazards to the mother, or infant.

Children under 6 years of age: Budesonide via Turbuhaler is not presently recommended for children younger than 6 years of age due to limited clinical data in this age group.

Corticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy. During long-term therapy, pituitary-adrenal function and height (in children) should be periodically assessed.

Patients should be advised to inform subsequent physicians of the prior use of corticosteroids.

There may be enhanced systemic effects of budesonide in patients with an advanced liver cirrhosis, and in those with hypothyroidism. Reduced liver function may affect the elimination of corticosteroids. The i.v. pharmacokinetics of budesonide however, are similar in cirrhotic patients and in healthy subjects. The pharmacokinetics after oral ingestion of budesonide were affected by compromised liver function as evidenced by increased systemic availability. This is however, of little importance for budesonide, as after inhalation the oral contribution to the systemic availability is very small.

ASA should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Special care is needed in patients with lung tuberculosis and fungal and viral infections. Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chickenpox and measles, for example, can have a more serious or fatal course in children on immunosuppressant corticosteroids. In such children, or in adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled i.v. immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops treatment with antiviral agents may be considered.

If, however, a viral upper respiratory infection is present, the patient should adhere to the regular asthma medication. In patients who are known to deteriorate rapidly when they have a viral respiratory infection, a short course of oral corticosteroid therapy should be considered.

Clinical studies have shown that viral upper respiratory infections cause significantly fewer problems in patients who are on regular treatment with topical glucocorticosteroids.

To ensure the proper dosage and administration of the drug, the patient should be instructed by a physician or other health professional in the use of Pulmicort Turbuhaler.

Adequate oral hygiene is of primary importance in minimizing overgrowth of microorganisms such as C. albicans (see Dosage).

Drug Interactions: Budesonide has not been observed to interact with any drug used for the treatment of asthma.

Cimetidine: The kinetics of budesonide were investigated in a study of healthy subjects without and with cimetidine, 1 000 mg daily. After a 4 mg oral dose the values for Cmax (nmol/L) and systemic availability (%) of budesonide without and with cimetidine (3.3 vs 5.1 nmol/L and 10 vs 12%, respectively) indicated a slight inhibitory effect on hepatic metabolism of budesonide, caused by cimetidine. This should be of little clinical importance.

Ketoconazole: Ketoconazole, a potent inhibitor of cytochrome P450 3A, the main metabolic enzyme for corticosteroids, increases plasma levels of orally ingested budesonide.

Omeprazole: At recommended doses, omeprazole has no effect on the pharmacokinetics of oral budesonide.

Adverse Reactions: No major side effects attributable to the use of budesonide, in all dosage forms, have been reported. During clinical trials, the frequency of subjectively reported side effects was low.

The most common side effects were cough, throat irritation, and hoarseness (2 to 4%). Bad taste, headache, nausea and dryness of the throat were reported less frequently. Other side effects reported on occasion during budesonide treatment were tiredness, thirst and diarrhea. Skin reactions (urticaria, rash, dermatitis, angioedema, etc.) may, in rare cases, occur in association with local corticosteroid therapy. In rare cases, skin bruising has been reported following treatment with inhaled glucocorticosteroids.

Psychiatric symptoms such as nervousness, restlessness and depression, as well as behavioral disturbances in children, have been observed.

As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted.

In rare cases, signs or symptoms of systemic glucocorticosteroid effect including hypofunction of the adrenal gland and oropharyngeal complications may occur, depending on dose, exposure time, concomitant and previous steroid exposure, and individual sensitivity. Candidiasis has been reported by some patients and may occur at therapeutic doses.

In patients in whom systemic steroids are reduced or stopped, withdrawal symptoms due to decreased systemic activity occur frequently (see Dosage, Clinical Management).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Occasional overdosing will not give any obvious symptoms in most cases but it will decrease the plasma cortisol level. Other pharmacological effects are an increase in the number and percentage of circulating neutrophils, where the number and percentage of eosinophils will decrease concurrently. Stopping the treatment or decreasing the dose will abolish the induced effects.

Habitual overdosing may cause hypercorticism and hypothalamic-pituitary-adrenal suppression. Decreasing the dose or stopping the therapy will abolish these effects, although the restitution of the HPA-axis may be a slow process and during periods with pronounced physical stress (severe infections, trauma, surgical operations, etc.) it may be advisable to supplement with systemic steroids.

Dosage And Administration: Adults and Children over 12 years of age: When treatment with inhaled glucocorticosteroids is started, during periods of severe asthma, and while reducing or discontinuing oral glucocorticosteroids the dosage should be 400 to 2 400 g daily divided into 2 to 4 administrations.

The maintenance dose is usually 200 to 400 g twice daily but higher doses may be necessary for longer or shorter periods of time in some patients. The dose should be individualized to the patient’s need and should be the lowest possible dose that fills the therapeutic objective.

Once daily dosing may be considered in patients who require a dosage of 400 g budesonide per day. The dose may then be given in the morning or in the evening. If deterioration of asthma occurs, the frequency of dosing and the daily dose should be increased.

Treatment with budesonide should not be stopped abruptly, but tapered off gradually.

Children 6 to 12 years: When starting therapy with budesonide in children, during periods of severe asthma and while reducing or discontinuing oral corticosteroids, the dosage should be 200 to 400 g daily, given in divided doses twice daily at 100 to 200 g per inhalation.

The maintenance dose is individual and should be the lowest dose which keeps the patient symptom-free. Administration twice daily is usually adequate in stable asthmatics.

Children under 6 years of age: Budesonide via Turbuhaler is not recommended for children in this age group.

Clinical studies in man have shown an improved efficacy for the same amount of budesonide delivered via Turbuhaler inhaler as compared with the pressurized aerosol with Nebuhaler spacer device. It may be possible to reduce the dose of Pulmicort Turbuhaler when the patient is in a stable phase.

In patients where an increased therapeutic effect is desired, an increased dose of Turbuhaler is recommended because of the lower risk of systemic effects as compared with a combined treatment with oral glucocorticosteroids.

Since the effect of budesonide depends on its regular use and on the proper technique of inhalation, patients must be instructed to use their Turbuhaler daily, as prescribed by their physician and not as they feel necessary. They must also be instructed in the correct method which is described in Information for the Patient.

Turbuhaler: Turbuhaler is a breath-activated dry powder inhaler which does not require a coordinated inhalation technique. It contains only the active ingredient budesonide – no propellants or preservatives, and as such, offers those patients sensitive to excipients, an alternate dosage form. Note: The patient may not taste or feel any medication when inhaling from Turbuhaler. This lack of feeling does not mean that the patient is not receiving benefit from Pulmicort Turbuhaler.

Clinical Management: Patients – Nonsteroid Dependent: Treatment with the recommended doses of budesonide usually gives a therapeutic effect within 10 days. However, certain patients might have an excessive collection of mucous secretion in the bronchi which reduces the penetration of budesonide into the bronchial mucosa. In these cases, it is desirable to initially give a short (about 2 weeks) oral corticosteroid regimen in addition to budesonide. The oral treatment is started on a rather large dose which is then gradually reduced. Thereafter, treatment with budesonide only is sufficient. Exacerbations of the asthma caused by bacterial infections are controlled by adequate antibiotic regimens and also by increasing the budesonide dosage.

Patients – Steroid Dependent: Transferral of patients dependent upon oral steroids to treatment with budesonide demands special care mainly because of the slow restitution of the disturbed hypothalamic-pituitary-adrenal function caused by extended treatment with oral corticosteroids. When treatment is initiated, the patient should be in a relatively stable phase. Budesonide is then given in combination with the previously used oral steroid dose for about 10 days. After this period of time, reduction of the oral corticoid dose may be started gradually. The oral dose is thus reduced to the lowest level which, in combination with budesonide, gives a stable respiratory capacity.

In adults, the usual rate of withdrawal of the systemic corticosteroid is the equivalent of 2.5 mg of prednisone every 4 days if the patient is under close observation. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower , approximately 2.5 mg of prednisone (or equivalent) every 10 days. A slow rate of withdrawal cannot be overemphasized. If withdrawal symptoms appear, the previous dosage of the systemic drug should be resumed for a week before further decrease is attempted. During withdrawal, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function. Such patients should be encouraged to continue with budesonide but should be watched carefully for objective signs of adrenal insufficiency such as hypotension and weight loss. If evidence of adrenal insufficiency occurs, the systemic steroid dosage should be boosted temporarily and thereafter further withdrawal should continue more slowly.

In many cases it may be possible to completely replace the oral steroid with budesonide treatment. In other patients, a low oral steroid maintenance dosage may be required. The length of time needed for the body to regain its natural production of corticosteroid in sufficient quantity is often extended. Thus, during severe asthma attacks or physically stressing situations such as severe infections, trauma, and surgical operations, it is necessary to resume systemic steroids (in large dosages) in order to avoid adrenocorticoid insufficiency. Acute exacerbations, especially in connection with increased viscosity and mucous plugging, may require complementary treatment with a short course of oral corticosteroids which are gradually tapered as symptoms subside.

During transfer from oral therapy to budesonide, a lower general steroid action is experienced. The patients might regain earlier symptoms (rhinitis, eczema) or suffer from tiredness, headache, pain in muscles and joints and, occasionally, nausea and vomiting. In these cases, further medical support may be required.

Note: The medication from Turbuhaler is delivered to the lungs as the patient inhales and, therefore, it is important to instruct the patient to breathe in forcefully and deeply through the mouthpiece. When prescribing Turbuhaler to young children it is necessary to ascertain that they can follow the instructions for use. The patient may not taste or feel any medication when using Turbuhaler due to the small amount of drug dispensed.

Patients should be instructed to rinse their mouths out with water after each inhalation. This will help prevent the occurrence of candidiasis. Cleansing dentures has the same effect.

Availability And Storage: Each dry powder inhaler contains: 200 doses of 100, 200 and 400 g or 100 doses of 200 g of micronized budesonide. Each inhalation from Pulmicort Turbuhaler will provide either 100, 200 or 400 g of budesonide active substance; no additives or carrier substances are included. Pulmicort Turbuhaler cannot be refilled and should be discarded when empty. (Shown in Product Recognition Section)

PULMICORT® TURBUHALER® Astra Budesonide Glucocorticosteroid for the Treatment of Bronchial Asthma

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