Pulmicort Turbuhaler Product Monograph

INDICATIONS AND CLINICAL USE

Patients with bronchial asthma:

• In patients who require inhaled steroids;
• In patients for whom a reduction of systemic glucocorticoids is desirable.

CONTRAINDICATIONS

• 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.

WARNINGS

PULMICORT 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.

Particular care is needed in patients who are transferred from systemically active corticosteroids to PULMICORT TURBUHALER (budesonide) and in patients who have 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. Additional systemic corticosteroid should be considered during periods of stress or elective surgery.

Although PULMICORT TURBUHALER 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During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large dosages) immediately and to contact their physicians for further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 PULMICORT TURBUHALER. 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 anti-fungal 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 AND ADMINISTRATION).

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 PULMICORT TURBUHALER 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 PULMICORT TURBUHALER (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 AND ADMINISTRATION).

It is essential that the patient be instructed that PULMICORT TURBUHALER 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 lung are unknown. With the recommended therapeutic doses of PULMICORT TURBUHALER, there is little risk of adverse systemic effects.

A reduction of growth velocity in children or adolescents may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if a child/adolescent’s growth appears slowed. 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 (see DOSAGE AND ADMINISTRATION).

Controlled clinical trials have shown confounding results indicating inhaled corticosteroids may cause a reduction in growth in children and adolescents. In one trial in children aged 3 to 13 years (mean 8.7 years), treated for 3 to 13 years (mean 9.2 years) with budesonide via Turbuhaler^® at a mean daily dose of 412 mcg, no effect was demonstrated on long-term statural growth compared to nonsteroidal therapy. However, in a long-term, double-blind study, children and adolescents (aged 5 to 12 years) treated for 4 to 6 years (mean 4.3 years) with inhaled budesonide via Turbuhaler^® became on average 1.2 cm shorter as adults than those randomized to placebo.

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

Pulmonary infiltrates with eosinophilia may occur in patients on PULMICORT TURBUHALER therapy. Although this is possible in some patients who are administered inhalational steroids, their causative role 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. The intravenous 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 limited importance for PULMICORT TURBUHALER, as after inhalation the oral contribution to the systemic availability is very small.

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 TURBUHALER.

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 TURBUHALER 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.

Children Under 6 Years of Age

PULMICORT TURBUHALER is not presently recommended for children younger than 6 years of age due to limited clinical data in this age group.

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.

Omeprazole

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

ADVERSE REACTIONS

Clinical trials, literature reports and post-marketing experience suggest that the following adverse drug reactions may occur:

• The most common side effects were cough, throat irritation and 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. Rare cases of anaphylactic reaction have been reported following the use of PULMICORT TURBUHALER. 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 behavioural 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 be instituted.
• In rare cases, signs or symptoms of systemic glucocorticosteroid effect including hypofunction of the adrenal gland and oropharyngeal complications and reduction of growth velocity 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.

• Cases of growth suppression have been reported for PULMICORT

  TURBUHALER.

• 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).

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

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 400-2400 mcg daily divided into 2-4 administrations.

The maintenance dose is usually 200-400 mcg twice daily but higher doses may be necessary for longer or shorter periods of time in some patients. The dose of PULMICORT TURBUHALER (budesonide) 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 mcg 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 PULMICORT TURBUHALER should not be stopped abruptly, but tapered off gradually.

Children 6-12 Years

When starting therapy with budesonide in children, during periods of severe asthma and while reducing or discontinuing oral corticosteroids, the dosage should be 200-400 mcg daily, given in divided doses twice daily at 100 to 200 mcg 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

PULMICORT 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 PULMICORT TURBUHALER is recommended because of the lower risk of systemic effects as compared with a combined treatment with oral glucocorticosteroids.

Since the effect of PULMICORT TURBUHALER depends on its regular use and on the proper technique of inhalation, patients must be instructed to use their PULMICORT 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 the INFORMATION FOR THE PATIENT section.

Turbuhaler^®

Turbuhaler^® is a breath-activated dry powder inhaler. It contains only the active ingredient budesonide – no propellants or preservatives. NOTE: The patient may not taste or feel any medication when inhaling from PULMICORT TURBUHALER. This lack of feeling does not mean that the patient is not receiving benefit from PULMICORT TURBUHALER.

Clinical Management

Patients - Non-Steroid Dependent

Treatment with the recommended doses of PULMICORT TURBUHALER 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 TURBUHALER 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 TURBUHALER. The oral treatment is started on a rather large dose which is then gradually reduced. Thereafter, treatment with PULMICORT TURBUHALER only is sufficient. Exacerbations of the asthma caused by bacterial infections are controlled by adequate antibiotic regimens and also by increasing the PULMICORT TURBUHALER dosage.

Patients - Steroid Dependent

Transferal of patients dependent upon oral steroids to treatment with PULMICORT TURBUHALER 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 TURBUHALER treatment is initiated, the patient should be in a relatively stable phase. PULMICORT TURBUHALER 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 TURBUHALER, 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 TURBUHALER, 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 TURBUHALER 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, 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 PULMICORT 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 PULMICORT 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 PULMICORT 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.

PHARMACEUTICAL INFORMATION

Drug Substance

Chemical Structure:

Generic 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)]

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 crystalline 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

PULMICORT TURBUHALER

Ingredient: Budesonide

Strength (mcg/inhalation): 100, 200 or 400

Stability and Storage Recommendations

PULMICORT TURBUHALER should be stored with the cover tightened, at room temperature (15 - 30°C).

AVAILABILITY OF DOSAGE FORMS

PULMICORT TURBUHALER is a dry powder inhaler containing 200 doses of 100 mcg, 200 mcg, and 400 mcg of micronized budesonide. Each inhalation from PULMICORT TURBUHALER will provide either 100 mcg, 200 mcg or 400 mcg of budesonide active substance; no additives or carrier substances are included. PULMICORT TURBUHALER cannot be re-filled and should be discarded when empty.

PHARMACOLOGY

Studies with animals have shown that budesonide has a 2-10 times better ratio between topical anti-inflammatory and systemic glucocorticoid effects than that obtained with beclomethasone dipropionate or triamcinolone acetonide. In the blanching test for topical anti-inflammatory activity in humans, budesonide was about twice as potent as beclomethasone dipropionate. Beclomethasone dipropionate was, however, more active than budesonide with regard to systemic activity as measured by depression of morning plasma cortisol. The favourable topical anti-inflammatory activity to systemic effect ratio demonstrated by budesonide is most probably due to its high glucocorticoid receptor affinity and high first pass metabolism with a short half-life.

Budesonide has been shown to counteract the mainly "IgE" mediated lung anaphylaxis in guinea pigs.

No significant bronchorelaxing activity, either in vitro or in vivo, could be demonstrated. Budesonide did not potentiate beta-mediated bronchorelaxation, and did not affect theophylline-induced relaxation of respiratory airway smooth muscle in guinea pigs.

Budesonide exhibits typical glucocorticoid effects in that subcutaneous administration to adrenalectomized rats induced glycogen deposition in the liver, increased urinary volume and only slightly affected sodium excretion.

Whole body autoradiography in mice has shown budesonide and its metabolites to have a similar distribution pattern to other glucocorticosteroids with a high distribution to endocrine organs.

Human Pharmacokinetics

The maximal plasma concentration after inhalation of 1 mg budesonide from PULMICORT TURBUHALER (budesonide) is about 3.5 nmol/L and is reached after about 20 minutes. The plasma half-life of budesonide is 2.0±0.2 hours, similar to that found after intravenous administration (2.8±1.1 h). Approximately 30% of the metered dose is deposited in the lungs. The systemic bioavailability of budesonide after inhalation from PULMICORT TURBUHALER is 49% of the dose retained by the patient. After oral administration, peak plasma concentrations of unchanged compound were found after about 3 hours. The oral bioavailability is calculated to be 10.7±4.3%. Since budesonide acts locally in the lung, plasma levels are not predictive of therapeutic efficacy or safety.

Budesonide has a volume distribution of approximately 3L/kg. Plasma protein binding averages 85-90%.

In human volunteers who inhaled tritiated budesonide (via metered dose aerosol) 31.8±7.5% of the discharged dose was recovered in the urine (0-96 hours) while during the same period, 15.1±4.3% of the dose could be recovered in the feces. In those subjects who took the compound orally, 45.0±5.0% was recovered in the urine, 29.6±2.5% in the feces.

In vitro studies with human liver have shown that budesonide is rapidly metabolized to more polar compounds than the parent drug. Two major metabolites have been isolated and identified as 6β-hydroxybudesonide and 16α-hydroxyprednisolone. The glucocorticoid activity of these two metabolites was at least 100-fold lower than the parent compound as shown in the rat ear edema test. No qualitative differences between the in vitro and in vivo metabolic patterns could be detected. Negligible biotransformation was observed in human lung and serum preparations.

TOXICOLOGY

Acute Toxicity

Species Sex Route LD₅₀ (mg/kg) After 3 Weeks

mouse male s.c. 35±18

mouse

mouse

male female

p.o. p.o.

>800 >800

rat

rat

rat

male female male

s.c. s.c. p.o.

15.1±4.4 20.3±7.1 ≈400

Surviving animals exhibited a marked decrease in body weight gain.

Toxicity After Repeated Administration of Budesonide To Rats, Rabbits, And Dogs.

All effects observed were consistent with those expected during prolonged corticosteroid exposure.

Teratology and Reproduction Studies

Effects on Pregnancy

Rat:

Daily doses of 20, 100, and 500 mcg/kg body mass were administered subcutaneously to pregnant rats during days 6-15 of gestation. In the high dose group, all of the rats showed a deteriorated general condition including piloerection, drowsiness, decreased food consumption and decreased body mass gain. Fetal loss was increased and pup masses decreased in comparison to the control group. The frequency of fetal abnormalities was also increased. Doses in excess of 100 mcg/kg must be considered teratogenic in the rat.

Daily doses of 0.01, 0.05 and 0.1 - 0.25 mg/kg were administered by inhalation to pregnant rats during days 6-15 of gestation. At the highest dose a slight significant reduction in fetal weight gain was observed, but there was no evidence of any effect on fetal development attributable to budesonide at any dose level.

Rabbit:

Daily doses of 5, 25, and 125 mcg/kg body mass were administered subcutaneously during days 6-18 of gestation. In the low and medium dose groups, food consumption and body mass gain were decreased during the fourth gestational week. Some doses also showed signs of diarrhea and vaginal bleeding. In the high dose group, all doses aborted at the end of the gestation period. In the medium dose group, a marked increase in the frequency of abnormalities, mainly skeletal defects, was observed. Most commonly, defects were skull and vertebral abnormalities.

Effects on Fertility and General Reproductive Performance

Rat:

To evaluate the effect of budesonide on fertility and general reproductive performance, daily doses of 0.01, 0.05, 0.19 mcmol/kg were given subcutaneously to males for 9 weeks prior to and throughout mating. Females received the same doses for two weeks before, throughout gestation and up to 21 days postpartum. The offspring of the high group showed a decrease of peri- and post-natal viability. Dams showed a decrease in body mass gain.

Mutagenicity Studies

Budesonide showed no mutagenic activity in the Ames Salmonella/microsome plate test or in the mouse micronucleus test.

Carcinogenicity

The carcinogenic potential of budesonide was evaluated in long term mouse and rat studies. Chronic Drinking Water Study in Mice

Budesonide was administered in the drinking water for 91 weeks to three groups of CD^®-1 mice at dose levels of 10, 50 and 200 mcg/kg/day.

A statistically significant dose-related decrease in survival was noted for the males only. All other evaluation criteria were comparable in all groups. Upon microscopic examination, a variety of spontaneous lesions was observed which were not related to treatment. No carcinogenic effect was present.

Chronic Drinking Water Study (104 Weeks) with Budesonide in Rats

Three rat carcinogenicity studies have been performed. In the first study, budesonide was administered for 104 weeks in doses of 10, 25 and 50 mcg/kg/day.

A small but statistically significant increase in gliomas was noted in male animals from the high dose group. These results were considered equivocal since the S-D rat is very variable with regard to spontaneous glioma incidence.

To elucidate these results, two further 104 week carcinogenicity studies with budesonide 50 mcg/kg/day were performed, one using male S-D rats, and one using male Fischer rats (which have a lower and less variable incidence of gliomas). Prednisolone and triamcinolone acetonide were used as reference glucocorticoids in both studies.

The results from these new carcinogenicity studies in male rats did not demonstrate an increased glioma incidence in budesonide treated animals, as compared to concurrent controls or reference glucocorticosteroid treated groups.

Compared with concurrent control male S-D rats there was also an increased incidence of liver tumors in the mid and high dose groups in the original study. This finding was confirmed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in the repeat study in male S-D rats thus indicating a class effect of glucocorticosteroids. BIBLIOGRAPHY

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Effects of long-term treatment with inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respiratory Medicine 1994;88:373-381.

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