Included as part of the PRECAUTIONS section.
Local Nasal Effects
In clinical studies of 3 to 52 weeks' duration epistaxis was observed more
frequently in patients treated with RHINOCORT AQUA (budesonide) Nasal Spray than those who
received placebo [see ADVERSE REACTIONS].
In clinical studies with budesonide administered intranasally, the development
of localized infections of the nose and pharynx with Candida albicans
has occurred. When such an infection develops, it may require treatment with
appropriate local or systemic therapy and discontinuation of treatment with
RHINOCORT AQUA (budesonide) Nasal Spray. Patients using RHINOCORT AQUA (budesonide) Nasal Spray over several
months or longer should be examined periodically for evidence of Candida
infection or other signs of adverse effects on the nasal mucosa.
Nasal Septal Perforation
Instances of nasal septum perforation have been reported following the intranasal
application of corticosteroids, including budesonide [see ADVERSE REACTIONS].
Impaired Wound Healing
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred.
Hypersensitivity Reactions Including Anaphylaxis
Hypersensitivity reactions including anaphylactic reaction, urticaria, rash,
dermatitis, angioedema and pruritus may occur [see CONTRAINDICATIONS
and ADVERSE REACTIONS, Post-marketing Experience].
Patients who are on drugs that suppress the immune system are more susceptible
to infections than healthy individuals. Chicken pox and measles, for example,
can have a more serious or even fatal course in susceptible children or adults
using corticosteroids. In such children or adults who have not had these diseases
or been properly immunized, particular care should be taken to avoid exposure.
How the dose, route, and duration of corticosteroid administration affect the
risk of developing a disseminated infection is not known. The contribution of
the underlying disease and/or prior corticosteroid treatment to the risk is
also not known. If exposed to chicken pox, therapy with varicella zoster immune
globulin (VZIG) or pooled intravenous immunoglobulin (WIG), as appropriate,
may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts
for complete VZIG and IG prescribing information). If chicken pox develops,
treatment with antiviral agents may be considered.
The clinical course of chicken pox or measles infection in patients on intranasal or inhaled corticosteroids has not been studied. While there is no data with intranasal corticosteroids, a clinical study has examined the immune responsiveness to the varicella vaccine in asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension.
An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., betai-agonists, leukotriene receptor antagonists, or cromones). The percentage of patients developing a seroprotective antibody titer ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%) compared to patients treated with non-corticosteroids asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections; or ocular herpes simplex.
Hypothalamic-Pituitary-Adrenal Axis Effects
Hypercorticism and Adrenal Suppression: When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of RHINOCORT AQUA (budesonide) Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.
The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, fatigue, weakness, nausea, vomiting, hypotension, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids should be weaned off slowly when transferred to topical corticosteroids and carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.
Interactions with Strong Cytochrome P450 3A4 Inhibitors
Caution should be exercised when considering the co-administration of RHINOCORT
AQUA Nasal Spray with ketoconazole and other known strong CYP3A4 inhibitors
(e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,
nelfinavir, saquinavir, telithromycin) because adverse effects related to increased
systemic exposure to budesonide may occur [see DRUG INTERACTIONS, CLINICAL
Effect on Growth
Intranasal corticosteroids, including budesonide may cause a reduction in growth
velocity when administered to pediatric patients. Monitor the growth routinely
of pediatric patients receiving long-term treatment with RHINOCORT AQUA (budesonide) Nasal
Spray. To minimize the systemic effects of intranasal corticosteroids, including
RHINOCORT AQUA (budesonide) Nasal Spray, titrate each patient's dosage to the lowest one
that effectively controls his/her symptoms [see Use In Specific Populations,
Glaucoma and Cataracts
Glaucoma, increased intraocular pressure and cataracts have been reported following
the intranasal application of corticosteroids, including budesonide. Therefore,
close monitoring is warranted in patients with a change in vision or with a
history of increased intraocular pressure, glaucoma, and/or cataracts [see ADVERSE
Patient Counseling Information
[See FDA-Approved Patient Labeling]
Patients being treated with RHINOCORT AQUA (budesonide) Nasal Spray should receive the following
information and instructions. This information is intended to aid the patient
in the safe and effective use of the medication. It is not a disclosure of all
possible adverse or intended effects. For proper use of RHINOCORT AQUA (budesonide) Nasal
Spray and to attain maximum improvement, the patient should read and follow
the accompanying FDA Approved Patient Labeling.
Local Nasal Effects
Patients should be advised that epistaxis and localized infections with Candida
albicans occurred in the nose and pharynx in some patients. If candidiasis
develops, it should be treated with appropriate local or systemic therapy and
discontinue treatment with RHINOCORT AQUA (budesonide) Nasal spray. In addition, nasal corticosteroids
are associated with nasal septal perforation and impaired wound healing. Patients
who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should
not use RHINOCORT AQUA (budesonide) Nasal Spray until healing has occurred [see WARNINGS
Hypersensitivity including Anaphylaxis
Patients should be advised that hypersensitivity reactions including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus have been reported with use of RHINOCORT AQUA (budesonide) Nasal Spray. Discontinue
RHINOCORT AQUA (budesonide) Nasal Spray if such reactions occur [see CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Patients who are on immunosuppressant doses of corticosteroids should be warned
to avoid exposure to chickenpox or measles and, if exposed, to consult their
physician without delay. Patients should be informed of potential worsening
of existing tuberculosis, fungal, bacterial, viral, or parasitic infection,
or ocular herpes simplex [see WARNINGS AND PRECAUTIONS].
Reduced Growth Velocity
Patients should be advised that intranasal corticosteroids, including budesonide,
may cause a reduction in growth velocity when administered to pediatric patients.
Physicians should closely follow the growth of children and adolescents taking
corticosteroids by any route [see WARNINGS AND PRECAUTIONS].
Glaucoma and Cataracts
Patients should be advised that long-term use of intranasal corticosteroids,
including budesonide, may increase the risk of some eye problems (cataracts
and glaucoma). Patients should inform his/her healthcare provider if a change
in vision is noted while using RHINOCORT AQUA (budesonide) Nasal Spray [see WARNINGS
Patients should use RHINOCORT AQUA (budesonide) Nasal Spray at regular intervals since its
effectiveness depends on its regular use. Patients may note an improvement in
nasal symptoms within 10 hours of first using RHINOCORT AQUA (budesonide) Nasal Spray. Maximum
benefit may not be achieved until approximately 2 week after initiation of treatment
[see DOSAGE AND ADMINISTRATION].
Patients should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve after two weeks, or if the condition worsens. Patients who experience recurrent episodes of epistaxis (nosebleeds) or nasal septum discomfort while taking this medication should contact their physician. For proper use of RHINOCORT AQUA (budesonide) Nasal Spray and to attain maximum improvement, the patient should read and follow the accompanying patient information carefully. Do not use RHINOCORT AQUA (budesonide) Nasal Spray after the labeled number of sprays have been used (does not include priming) or after the expiration date shown on the carton or bottle label.
How to use RHINOCORT AQUA (budesonide) Nasal Spray
Patients should be carefully instructed on the use of this drug product to
assure optimal dose delivery [see PATIENT INFORMATION].
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week oral study in Sprague-Dawley rats, a statistically significant
increase in the incidence of gliomas was observed in the male rats receiving
an oral dose of budesonide 50 mcg/kg/day (approximately twice the maximum recommended
daily intranasal dose in adults and children on a mcg/m2 basis).
No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately
equal to the maximum recommended daily intranasal dose in adults and children
on a mcg/m2 basis, and in female rats at oral doses up to 50 mcg/kg
approximately two times the maximum recommended daily intranasal dose in adults
and children on a mcg/m2 basis). In two additional two-year studies
in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an
oral dose of 50 mcg/kg (approximately twice the maximum recommended daily intranasal
dose in adults and children on a mcg/m2 basis). However, in the male
Sprague-Dawley rats, budesonide caused a statistically significant increase
in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately
twice the maximum recommended daily intranasal dose in adults and children on
a mcg/m2 basis). The concurrent reference corticosteroids (prednisolone
and triamcinolone acetonide) in these two studies showed similar findings.
There was no evidence of a carcinogenic effect when budesonide was administered
orally for 91-weeks to mice at doses up to 200 mcg/kg/day (approximately 3 times
the maximum recommended daily intranasal dose in adults and children on a mcg/m2
Budesonide was not mutagenic or clastogenic in six different test systems:
Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat
In rats, budesonide had no effect on fertility at subcutaneous doses up to
80 mcg/kg (approximately 3 times the maximum recommended daily intranasal dose
in adults on mcg/m2 basis).
At a subcutaneous dose of 20 mcg/kg/day (less than the maximum recommended
daily intranasal dose in adults on a mcg/m2 basis), decreases in maternal body
weight gain, prenatal viability, and viability of the young at birth and during
lactation were observed. No such effects were noted at 5 mcg/kg (less than the
maximum recommended daily intranasal dose in adults on a mcg/m2 basis).
Use In Specific Populations
Teratogenic Effects: Pregnancy Category B. The impact of budesonide
on human pregnancy outcomes has been evaluated through assessments of birth
registries linked with maternal usage of inhaled budesonide (i.e., PULMICORT
TURBUHALER) and intranasally administered budesonide (i.e., RHINOCORT AQUA (budesonide) Nasal
Spray). The results from population-based prospective cohort epidemiological
studies reviewing data from three Swedish registries covering approximately
99% of the pregnancies from 1995- 2001 (i.e., Swedish Medical Birth Registry;
Registry of Congenital Malformations; Child Cardiology Registry) indicate no
increased risk for overall congenital malformations from the use of inhaled
or intranasal budesonide during early pregnancy.
Congenital malformations were studied in 2,014 infants born to mothers reporting
the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks
after the last menstrual period), the period when most major organ malformations
occur.1 The rate of overall congenital malformations was similar
compared to the general population rate (3.8 % vs. 3.5%, respectively). The
number of infants born with orofacial clefts and cardiac defects was similar
to the expected number in the general population (4 children vs. 3.3 and 18
children vs. 17-18, respectively). In a follow-on study bringing the total number
of infants to 2,534, the rate of overall congenital malformations among infants
whose mothers were exposed to inhaled budesonide during early pregnancy was
not different from the rate for all newborn babies during the same period (3.6%).2
A third study from the Swedish Medical Birth Registry of 2,968 pregnancies exposed
to inhaled budesonide, the majority of which were first trimester exposures,
reported gestational age, birth weight, birth length, stillbirths, and multiple
births similar for exposed infants compared to nonexposed infants.3
Congenital malformations were studied in 2,113 infants born to mothers reporting
the use of intranasal budesonide in early pregnancy. The rate of overall congenital
malformations was similar compared to the general population rate (4.5% vs.
3.5%, respectively). The adjusted odds ratio (OR) was 1.06 (95% CI 0.86-1.31).
The number of infants born with orofacial clefts was similar to the expected
number in the general population (3 children vs. 3, respectively). The number
of infants born with cardiac defects exceeded that expected in the general population
(28 children vs. 17.8 respectively). The systemic exposure from intranasal budesonide
is 6-fold less than from inhaled budesonide and an association of cardiac defects
was not seen with higher exposures of budesonide.
Despite the animal findings, it would appear that the possibility of fetal
harm is remote if the drug is used during pregnancy. Nevertheless, because the
studies in humans cannot rule out the possibility of harm, RHINOCORT AQUA (budesonide) Nasal
Spray should be used during pregnancy only if clearly needed.
Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities
at a subcutaneous dose in rabbits that was approximately 2 times the maximum
recommended daily intranasal dose in adults on a mcg/m2 basis and
at a subcutaneous dose in rats that was approximately 16 times the maximum recommended
daily intranasal dose in adults on a mcg/m2 basis. No teratogenic
or embryocidal effects were observed in rats when budesonide was administered
by inhalation at doses up to approximately 8 times the maximum recommended daily
intranasal dose in adults on a mcg/m2 basis.
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born
of mothers receiving corticosteroids during pregnancy. Such infants should be
Budesonide is secreted in human milk. Data with budesonide delivered via dry
powder inhaler indicates that the total daily oral dose of budesonide available
in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled
by the mother [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations,
Nursing]. No studies have been conducted in breastfeeding women specifically
with RHINOCORT AQUA Nasal Spray; however, the dose of budesonide available to
the infant in breast milk, as a percentage of the maternal dose, would be expected
to be similar. RHINOCORT AQUA (budesonide) Nasal Spray should be used in nursing women only
if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding
for the mother and infant against the potential risks of minimal budesonide
exposure in the infant. Dosing considerations include prescription or titration
to the lowest clinically effective dose and use of RHINOCORT AQUA (budesonide) Nasal Spray
immediately after breastfeeding to maximize the time interval between dosing
and breastfeeding to minimize infant exposure.
Safety and effectiveness in pediatric patients below 6 years of age have not been established.
Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied.
The growth of pediatric patients receiving intranasal corticosteroids, including RHINOCORT AQUA (budesonide) Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of intranasal corticosteroids, including RHINOCORT AQUA (budesonide) Nasal Spray, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.
A one-year placebo-controlled clinical growth study was conducted in 229 pediatric patients (ages 4 through 8 years of age) to assess the effect of RHINOCORT AQUA (budesonide) Nasal Spray (single-daily dose of 64 mcg, the recommended starting dose for children ages 6 years and above) on growth velocity. From a population of 141 patients receiving RHINOCORT AQUA (budesonide) Nasal Spray and 67 receiving placebo, the point estimate for growth velocity with RHINOCORT AQUA (budesonide) Nasal Spray was 0.25 cm/year lower than that noted with placebo (95% confidence interval ranging from 0.59 cm/year lower than placebo to 0.08 cm/year higher than placebo).
In a study of asthmatic children 5-12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter (0.433 inch) reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.
The systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs. Pharmacokinetic studies have demonstrated that in both adults and children, systemic exposure to budesonide at the highest recommended doses of RHINOCORT AQUA (budesonide) Nasal Spray would be expected to be no greater than exposure at the lowest recommended doses via a dry powder inhaler. Therefore, the systemic effects (HPA axis and growth) of budesonide delivered from RHINOCORT AQUA (budesonide) Nasal Spray would be expected to be no greater than what is reported for inhaled budesonide when administered via the dry powder inhaler.
The potential for RHINOCORT AQUA (budesonide) Nasal Spray to cause growth suppression in
susceptible patients or when given at doses above 64 mcg daily cannot be ruled
out. The recommended dosage range in patients 6 to 11 years of age is 64 to
128 mcg per day [see DOSAGE AND ADMINISTRATION].
Of the 2,461 patients in clinical studies of RHINOCORT AQUA (budesonide) Nasal Spray, 5% were 60 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, except for an adverse reaction reporting frequency of epistaxis that increased with age. Further, other reported clinical experience has not identified any other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Formal pharmacokinetic studies using RHINOCORT AQUA (budesonide) Nasal Spray have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.