Side Effects of Pulmicort Flexhaler (budesonide)

Pulmicort Flexhaler (budesonide) is a man-made glucocorticoid steroid related to the naturally-occurring hormone, cortisol or hydrocortisone which is produced in the adrenal glands used to treat asthma by inhalation. 

Glucocorticoid steroids such as cortisol or budesonide have potent anti-inflammatory actions that reduce inflammation and hyper-reactivity (spasm) of the airways caused by asthma. When used as an inhaler, the budesonide goes directly to the inner lining of the inflamed airways to exert its effects. 

Only 39% of an inhaled dose of budesonide is absorbed into the body, and the absorbed budesonide contributes little to the effects on the airways. While some improvement in the symptoms of asthma may occur within 24 hours, it may take a few weeks to obtain the maximum therapeutic benefits of Pulmicort Flexhaler when used to treat asthma.

Common side effects of Pulmicort Flexhaler include

• mild cough,
• wheezing,
• oral candidiasis or thrush (a fungal infection of the throat),
• hoarseness,
• sore throat, and
• changes in voice. 

Serious side effects of Pulmicort Flexhaler include

• weakened bones and ultimately osteoporosis and fractures,
• suppression of the adrenal glands, and
• hypersensitivity reactions (anaphylaxis, rash, contact dermatitis, itching, angioedema, and bronchospasm).

Drug interactions of Pulmicort Flexhaler include strong liver enzyme inhibitors (CYP 3A4 inhibitors) such as ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin because the concentration in blood of budesonide may rise increasing the probability of an individual experiencing more side effects.

Studies of pregnant women using inhaled budesonide during early pregnancy do not show an increase in the rate of fetal abnormalities. Nevertheless, since these studies cannot exclude the possibility of rare effects on the fetus, inhaled Pulmicort Flexhaler should be used with caution during pregnancy. 

Budesonide like other drugs of its class is secreted in breast milk. It is unknown if the small amounts that may appear in breast milk have effects on the infant. The benefits of breastfeeding an infant should be weighed against the possible risks associated with using Pulmicort Flexhaler in a nursing mother.

• The most commonly noted side effects associated with inhaled budesonide are mild cough or wheezing; these effects may be minimized by using a bronchodilator inhaler, for example, albuterol (Ventolin HFA), prior to the budesonide.
• Oral candidiasis or thrush (a fungal infection of the throat) may occur in 1 in 25 persons who use budesonide without a spacer device on the inhaler. The risk is even higher with large doses, but is less in children than in adults.
• Hoarseness or sore throat also may occur in 1 in 10 persons. Using a spacer device on the inhaler and washing the mouth out with water following each use reduces the risk of both thrush and hoarseness.
• Less commonly, alterations in voice may occur.

High doses of inhaled glucocorticoid steroids may decrease the formation and increase the breakdown of bone leading to weakened bones and ultimately osteoporosis and fractures. High doses may suppress the body's ability to make its own natural glucocorticoid in the adrenal gland. It is possible that these effects are shared by budesonide.

People with suppression of their adrenal glands (which can be tested for by the doctor) need increased amounts of glucocorticoid steroids orally or intravenously during periods of high physical stress, for example, during infections, to prevent serious illness and shock.

Hypersensitivity reactions, which have been reported with the issue of inhaled budesonide include

• anaphylaxis,
• rash,
• contact
• dermatitis,
• itching,
• angioedema, and
• bronchospasm.

Use of budesonide should be discontinued if such reactions occur.

Systemic and inhaled corticosteroid use may result in the following:

• Candida albicans infection
• Hypersensitivity Including Anaphylaxis
• Immunosuppression
• Hypercorticism and Adrenal Suppression
• Reduction in Bone Mineral Density
• Growth Effects
• Glaucoma and Cataracts
• Eosinophilic conditions and Churg-Strauss

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Pulmicort Flexhaler (budesonide inhalation powder)

Patients 6 years and older

• The incidence of common adverse reactions in Table 1 is based upon pooled data reported in patients treated with Pulmicort Flexhaler (budesonide inhalation powder) 180 or 90 mcg in two double blind, placebo-controlled clinical trials in which 226 patients (106 females and 120 males) with mild to moderate asthma, previously receiving bronchodilators, inhaled corticosteroids, or both, were treated with Pulmicort Flexhaler (budesonide inhalation powder), administered as 360 mcg twice daily for 12 weeks.
• In these trials, the patients on Pulmicort Flexhaler had a mean age of 28 years (range 6-80 years) and were predominantly Caucasian (59.7%) and Asian (31.4%).
• Table 1 includes all adverse reactions (regardless of investigator causality assessment) that occurred at a rate of ≥ 1% in the Pulmicort Flexhaler (budesonide inhalation powder) group and more commonly than the placebo group.

Table 1 : Adverse Reactions occurring at an incidence of ≥ 1% and more commonly than placebo in the Pulmicort Flexhaler (budesonide inhalation powder) group: pooled data from two 12-week, double-blind, placebo-controlled clinical asthma trials in patients 6 years and older

Long-Term Safety in Patients 6 years of age and older

• Non-placebo controlled long-term studies in children (at doses up to 360 mcg daily), and adolescent and adult subjects (at doses up to 720 mcg daily), treated for up to one year with Pulmicort Flexhaler (budesonide inhalation powder), revealed a similar pattern and incidence of adverse events.

Pulmicort Turbuhaler; a different Pulmicort DPI

The following adverse reactions occurred in placebo-controlled clinical trials with similar or lower doses with inhaled budesonide via a different Pulmicort dry powder inhaler with an incidence of ≥ 1% in the budesonide group and were more common than in the placebo group:

• ≥ 3%: respiratory infection, sinusitis, headache, pain, back pain, fever.
• ≥ 1-3%: neck pain, syncope, abdominal pain, dry mouth, vomiting, weight gain, fracture, myalgia, hypertonia, migraine, ecchymosis, insomnia, infection, taste perversion, voice alteration.

Higher doses of inhaled budesonide (800 mcg twice daily) via a different Pulmicort dry powder inhaler resulted in an increased incidence of voice alteration, flu syndrome, dyspepsia, gastroenteritis, nausea, and back pain, compared with doses of 400 mcg twice daily.

In a 20-week trial in adult asthmatics who previously required oral corticosteroids, the incidence of adverse reactions was evaluated with 400 mcg twice daily (N=53) and 800 mcg twice daily (N=53) of inhaled budesonide via a different Pulmicort dry powder inhaler and compared with placebo (N=53).

In considering these data, the increased average duration of exposure for inhaled budesonide patients (78 days for inhaled budesonide vs. 41 days for placebo) should be taken into account.

Adverse reactions, regardless of investigator causality assessment, reported in more than five patients in the budesonide group and which occurred more commonly than the placebo group in decreasing order of frequency include:

• respiratory infection,
• sinusitis,
• headache,
• oral candidiasis,
• pain,
• asthenia,
• dyspepsia,
• arthralgia,
• cough increased,
• nausea and
• rhinitis.

Post-marketing Experience

The following adverse reactions have been reported during post-approval use of Pulmicort Flexhaler (budesonide inhalation powder). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Immune system disorders: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema, bronchospasm, rash, contact dermatitis, urticaria, and cough, wheezing or bronchospasm in patients with severe milk protein hypersensitivity
• Endocrine disorders: symptoms of hypocorticism and hypercorticism
• Eye disorders: cataracts, glaucoma, increased intraocular pressure
• Psychiatric disorders: psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety
• Respiratory, thoracic, and mediastinal disorders: throat irritation
• Skin and subcutaneous tissue disorders: skin bruising

Inhibitors of Cytochrome P4503A4

• The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4).
• After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased.
• Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide.
• Caution should be exercised when considering the co-administration of Pulmicort Flexhaler (budesonide inhalation powder) with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin).