WARNINGS
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, eg, joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be 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.
Patients who are on drugs which 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 non-immune children or adults on immunosuppressant doses of corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects 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, prophylaxis with varicella zoster immune globulin (VZIG) 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.
Precautions
General
Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see PRECAUTIONS, Pediatric Use).
Rarely, immediate and/or delayed hypersensitivity reactions may occur after the intranasal administration of budesonide. Rare instances of wheezing, nasal septum perforation, and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including budesonide.
Although systemic effects have been minimal with recommended doses of RHINOCORT AQUA Nasal Spray, any such effect is dose dependent. Therefore, larger than recommended doses of RHINOCORT AQUA Nasal Spray should be avoided and the minimal effective dose for the patient should be used (see DOSAGE AND ADMINISTRATION). When used at larger doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of RHINOCORT AQUA Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.
In clinical studies with budesonide administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local or systemic therapy and discontinuation of treatment with RHINOCORT AQUA Nasal Spray. Patients using RHINOCORT AQUA 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.
RHINOCORT AQUA Nasal Spray should be used with caution, if at all, in patients with active or quiescent tuberculous infection, untreated fungal, bacterial, or systemic viral infections, or ocular herpes simplex.
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.
Hepatic dysfunction influences the pharmacokinetics of budesonide, similar to the effect on other corticosteroids, with a reduced elimination rate and increased systemic availability (see CLINICAL PHARMACOLOGY, Special Populations).
Information for Patients
Patients being treated with RHINOCORT AQUA Nasal Spray should receive the following information and instructions. Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles and, if exposed, to obtain medical advice.
Patients should use RHINOCORT AQUA Nasal Spray at regular intervals since its effectiveness depends on its regular use (see DOSAGE AND ADMINISTRATION).
An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA Nasal Spray. This time to onset is supported by an environmental exposure unit study in seasonal allergic rhinitis patients which demonstrated that RHINOCORT AQUA Nasal Spray led to a statistically significant improvement in nasal symptoms compared to placebo by 10 hours. Further support comes from a clinical study of patients with perennial allergic rhinitis which demonstrated a statistically significant improvement in nasal symptoms for both RHINOCORT AQUA Nasal Spray and for the active comparator (mometasone furoate) compared to placebo by 8 hours. Onset was also assessed in this study with peak nasal inspiratory flow rate and this endpoint failed to show efficacy for either active treatment. Although statistically significant improvements in nasal symptoms compared to placebo were noted within 8-10 hours in these studies, about one half to two thirds of the ultimate clinical improvement with RHINOCORT AQUA Nasal Spray occurs over the first 1-2 days, and maximum benefit may not be achieved until approximately 2 weeks after initiation of treatment. Initial assessment for response should be made during this time frame and periodically until the patient’s symptoms are stabilized.
The patient 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 this unit and to attain maximum improvement, the patient should read and follow the accompanying patient instructions carefully.
It is important to shake the bottle well before each use. The RHINOCORT AQUA Nasal Spray 32 mcg bottle has been filled with an excess to accommodate the priming activity. The bottle should be discarded after 120 sprays following initial priming, since the amount of budesonide delivered per spray thereafter may be substantially less than the labeled dose. Do not transfer any remaining suspension to another bottle.
Drug Interactions
The main route of metabolism of budesonide, as well as other corticosteroids, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a potent inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased by more than seven-fold. Concomitant administration of other known inhibitors of CYP3A4 (eg, itraconazole, clarithromycin, erythromycin, etc.) may inhibit the metabolism of, and increase the systemic exposure to, budesonide (see WARNINGS and PRECAUTIONS, General). Care should be exercised when budesonide is coadministered with long-term ketoconazole and other known CYP3A4 inhibitors.
Omeprazole, an inhibitor of CYP2C19, did not have effects on the pharmacokinetics of oral budesonide, while cimetidine, primarily an inhibitor of CYP1A2, caused a slight decrease in budesonide clearance and corresponding increase in its oral bioavailability.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in the male rats receiving an oral dose of 50 mcg/kg (approximately twice the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (approximately equal to and two times the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis, respectively). 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 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.
In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 3 times the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis).
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 hematocyte culture.
In rats, budesonide caused a decrease in prenatal viability and viability of the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). No such effects were noted at 5 mcg/kg (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).
Pregnancy:
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 (ie, PULMICORT TURBUHALER) and intranasally administered budesonide (ie, RHINOCORT AQUA 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 (ie, 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. 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%). 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.
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.
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits and 500 mcg/kg in rats (approximately 2 and 16 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mcg/kg (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. In addition, because there is an increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
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 should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
Nursing Mothers
It is not known whether budesonide is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when RHINOCORT AQUA Nasal Spray is administered to nursing women.
Pediatric Use
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 Nasal Spray, should be monitored routinely (eg, via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including RHINOCORT AQUA 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 (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 Nasal Spray and 67 receiving placebo, the point estimate for growth velocity with RHINOCORT AQUA 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).
The potential for RHINOCORT AQUA 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).
Geriatric Use
Of the 2,461 patients in clinical studies of RHINOCORT AQUA 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 event reporting frequency of epistaxis which 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.
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