Pulmicort Nebuamp 0.5 mg/mL Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

The active ingredient of PULMICORT NEBUAMP, budesonide, is a potent non-halogenated synthetic glucocorticosteroid with strong topical and weak systemic effects.

PULMICORT NEBUAMP has a high topical anti-inflammatory potency and it is rapidly biotransformed in the liver. This favourable 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 PULMICORT NEBUAMP is given at least 2 hours before a bronchial challenge. Pretreatment for 1 - 4 weeks with inhaled budesonide may inhibit the immediate bronchial reaction.

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

INDICATIONS AND CLINICAL USE

Patients with bronchial asthma, who require maintenance treatment with inhaled glucocorticosteroids for control of the underlying airways inflammation and who are unable to efficiently use other inhaled formulations.

CONTRAINDICATIONS

Status asthmaticus; not to be used in primary treatment of acute episodes of asthma or in patients with moderate to severe bronchiectasis;

Known hypersensitivity to any components;

Active or quiescent pulmonary tuberculosis;

Untreated fungal, bacterial or viral infections of the respiratory system.

WARNINGS

Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to inhaled corticosteroids. Particular care is needed in patients who are transferred from systemically active corticosteroids to PULMICORT NEBUAMP and in patients who required high dose emergency corticosteroid therapy. This is important as deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to inhaled corticosteroids. Patients receiving prolonged treatment at the highest recommended dose of inhaled corticosteroids may also be at risk for adrenal insufficiency. 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 severe stress including worsening of asthma attacks, trauma, surgery or infections, particularly gastroenteritis, or other conditions associated with severe electrolyte loss. Although PULMICORT NEBUAMP may provide control of asthmatic symptoms during these periods, it does NOT provide the systemic steroid which is necessary for coping with these emergencies. Additional systemic corticosteroid should be considered during periods of stress or elective surgery.

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 PULMICORT NEBUAMP. These allergies should be symptomatically treated with anti-histamine and/or topical preparations, including topical steroids. 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 nebulization treatment (See DOSAGE AND ADMINISTRATION).

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

PULMICORT NEBUAMP is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

The nebulizer chamber should be cleaned after every administration. Wash the nebulizer chamber and mouthpiece or face mask in hot tap water using a mild detergent. Rinse well and dry by connecting the nebulizer chamber to the compressor or air inlet.

Due to a low output of budesonide, ultrasonic nebulizers should not be used for administration of PULMICORT NEBUAMP.

PRECAUTIONS

Two cases of mortality due to cerebral edema and encephalopathy were reported during clinical trials. There was no apparent cause and effect relationship.

There is still insufficient data for the long-term systemic effect of PULMICORT NEBUAMP. The long-term effects of budesonide in developmental or immunologic processes in the mouth, pharynx, trachea, eyes and lungs are unknown. With the recommended therapeutic doses, the risk/benefit ratio seems to be very low. However, as with any other glucocorticosteroid, patients should be carefully followed up for systemic adverse effects, particularly during long-term therapy. Physicians should closely monitor the growth of children taking corticosteroids by any route and weigh the benefit of corticosteroid therapy and asthma control against the possibility of growth suppression. To minimize the systemic effects, it is important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

In transferring patients from a systemic steroid to PULMICORT NEBUAMP, 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 AND ADMINISTRATION).

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

Treatment with PULMICORT NEBUAMP should not be stopped abruptly, but tapered off gradually (see DOSAGE and ADMINISTRATION: CLINICAL MANAGEMENT).

Pulmonary infiltrates with eosinophilia may occur in patients on PULMICORT NEBUAMP therapy. The causative role of inhalational steroids cannot be ruled out. 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. This may be clinically relevant in patients with severely compromised liver function.

Acetylsalicylic acid 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. Chicken pox 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 intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chicken pox 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 NEBUAMP and the nebulizing equipment.

Adequate oral hygiene is of primary importance in minimizing overgrowth of micro-organisms such as Candida albicans (see DOSAGE AND ADMINISTRATION).

Usage During Pregnancy

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 subcutaneously produced fetal malformations, primarily skeletal defects, in rabbits, rats, and in mice. Results from world-wide post marketing experience indicate inhaled budesonide during pregnancy has no adverse effects on the health of the fetus/new born child. Review of published literature of orally inhaled budesonide, including results from a large case control study performed with cases identified from 3 Swedish health registers showed that there was no association between exposure to inhaled budesonide and overall congenital malformations. Results from a similar study performed with intranasal budesonide, using the same 3 Swedish health registers showed that the use of intranasal budesonide was associated with a subgroup “less severe cardiovascular defects”; however there was no statistically significant association between the use of intranasal budesonide during pregnancy and overall congenital malformations, or overall frequency of cardiovascular defects in the offspring. 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

Nursing Women: Budesonide is excreted in breast milk. The administration of PULMICORT NEBUAMP to women who are breast feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

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, 1000 mg daily. After a 4 mg oral dose the values for C_max (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.

CYP3A4 Inhibitors

The metabolism of budesonide is primarily mediated by CYP3A4, a subfamily of cytochrome P450. CYP3A4 inhibitors like ritonavir and azole antifungals (e.g. ketoconazole and itraconazole) increase the systemic exposure to budesonide. Therefore, concomitant use of budesonide and ritonavir or azole antifungals should be avoided, unless the potential benefit outweighs the risk of systemic corticosteroid side-effects.

ADVERSE REACTIONS

During clinical trials, the most common side effects were cough, throat irritation, hoarseness (2-4%). 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. In rare cases, anaphylactic reactions have been reported following the use of PULMICORT NEBUAMP. Facial skin irritation has occurred in a few cases when a nebulizer with a face mask has been used. To prevent irritation, the facial skin should be washed after use of the face mask. 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.

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.

Systemic effects and oropharyngeal complications caused by budesonide were found to be dose-dependent. In rare cases signs or symptoms of systemic glucocorticosteroid effect, including hypofunction of the adrenal gland and reduction of growth velocity, may occur with inhaled glucocorticosteroids, 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 rare cases, PULMICORT NEBUAMP may provoke bronchoconstriction in hyperreactive patients.

In patients in whom systemic steroids are reduced or stopped, withdrawal symptoms due to decreased systemic activity occur frequently (See DOSAGE AND ADMINISTRATION: CLINICAL MANAGEMENT).

Post-Market Adverse Drug Reactions

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

Cases of growth suppression have been reported for PULMICORT NEBUAMP.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

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, while 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

PULMICORT NEBUAMP should be administered from suitable nebulizers. Due to a low output of budesonide, ultrasonic nebulizers should not be used.

The amount of budesonide suspension delivered to the patient in a nebulizer is variable and dependent upon several factors, including the following:

• nebulization time,
• volume fill,
• the characteristics of the nebulizing equipment,
• the inspiratory/expiratory ratio and tidal volume of the patient,
• the use of either a face-mask or a mouth piece.

Data from ex vivo studies have estimated that the dose of nebulized budesonide delivered to the patient varies between 9-19% of the nominal dose.

The nebulization time and the dose delivered are dependent on flow rate, volume of nebulizer chamber and volume fill.

Nebulization should take place using a gas flow (oxygen or compressed air) of 6 to 10 L/minute and the suspension nebulized over a 10 to 15 minute period. A suitable volume fill for most nebulizers is 2-4 mL. The manufacturer's instructions concerning cleaning and maintenance of the nebulizer should be strictly followed.

Initial Dose

The dosage of PULMICORT NEBUAMP is individual. The initial dose should be:

Children (3 months to 12 years): 0.25 to 0.5 mg twice daily. In some cases, the dosage may be further increased up to 1 mg twice daily.

Adults: usually 1 to 2 mg twice daily. In some cases, the dosage may be further increased.

Maintenance Dose

The maintenance dose is individual. After the desired clinical effect has been obtained, the maintenance dose should be gradually reduced to the smallest amount necessary for control of symptoms.

Dosage Table

0.125 mg 1 mL* - -

0.25 mg 2 mL 1 mL* -

0.5 mg 4 mL 2 mL -

0.75 mg - 3 mL -

1 mg - - 2 mL

* This should be mixed with 0.9% saline to a volume of 2 mL.

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

If only half the contents of an ampoule are used, add Sterile Normal Saline to make up the required volume fill.

Clinical Management

Patients - Non-Steroid Dependent

Treatment with the recommended doses of PULMICORT NEBUAMP 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 the active substance in PULMICORT NEBUAMP into the bronchial mucosa. In these cases, it is desirable to initially give a short (about 2 weeks) oral corticosteroid regimen in addition to PULMICORT NEBUAMP. The oral treatment is started on a rather large dose which is then gradually reduced. Thereafter, treatment with PULMICORT NEBUAMP only is sufficient. Exacerbations of the asthma caused by bacterial infections are controlled by adequate antibiotic regimens and also by increasing the PULMICORT NEBUAMP dosage.

Patients - Steroid Dependent

Transferral of patients dependent upon oral steroids to treatment with PULMICORT NEBUAMP demands special care mainly because of the slow restitution of the disturbed hypothalamic-pituitary-adrenal function caused by extended treatment with oral corticosteroids. When PULMICORT NEBUAMP treatment is initiated, the patient should be in a relatively stable phase. PULMICORT NEBUAMP 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 PULMICORT NEBUAMP, 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 four 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 ten 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 PULMICORT NEBUAMP, 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 PULMICORT NEBUAMP 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 PULMICORT NEBUAMP, 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: Patients should be instructed to rinse their mouths out with water after each nebulization treatment. This will help prevent the occurrence of candidiasis and potential systemic effects. Cleansing dentures has the same effect.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Budesonide

Chemical Name: Budesonide is a mixture of two isomers:

1. 1. Pregna-1,4-diene-3,20-dione,16,17-butylidenebis(oxy)-11,21-dihydroxy-,[11β,16α (R)]

and

1. 2. Pregna-1,4-diene-3,20-dione,16,17-butylidenebis(oxy)-11,21-dihydroxy-,[11β,16α(S)].

Chemical Structure:

Molecular Formula: C₂₅H₃₄O₆

Molecular Weight: 430.5

Description: Budesonide is a glucocorticosteroid and consists of a 1:1 mixture of two epimers, 22R and 22S. It is a white to off-white fine powder and is freely soluble in chloroform, sparingly soluble in ethanol, practically insoluble in water and in heptane. Budesonide melts at 224°C to 231.5°C, with decomposition.

Composition

mg/mL

Active:

budesonide

0.125, 0.25 or 0.5

Non-medicinal: citric acid

disodium edetate

polysorbate 80

sodium chloride

sodium citrate

water, purified

Storage Recommendations

Store at 5-30°C in an upright position. Keep protected from light. Once envelope is opened, use ampoules within 3 months. Opened ampoules must be used within 12 hours.

AVAILABILITY OF DOSAGE FORMS

PULMICORT NEBUAMP is provided in ampoules made of LD-polyethylene. Each ampoule contains 2 mL suspension of 0.125 mg/mL, 0.25 mg/mL or 0.5 mg/mL. Sheets of 5 ampoules are packed in an envelope of foil laminate. Four envelopes are packed in each carton.