20746lbl

RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
RHINOCORT® AQUA (budesonide)
NASAL SPRAY 32 mcg and 64 mcg
Unannotated Proposed Package Insert
NDA 20-746
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
RHINOCORT® AQUA (budesonide)
NASAL SPRAY 32 mcg and 64 mcg
For Intranasal Inhalation Only
DESCRIPTION
Budesonide, the active ingredient of RHINOCORT AQUA Nasal Spray, is an anti-inflammatory
synthetic corticosteroid.
It is designated chemically as [(RS)-11-beta, 16-alpha, 17, 21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16, 17-acetal with butyraldehyde]. Budesonide is provided as the mixture of two epimers (22R and 22S).
The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5.
CH 2CH 2CH 3
CH 2CH 2CH 3
Budesonide is a white to off-white, odorless powder that is practically insoluble in water and inheptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 x 103.
RHINOCORT AQUA is an unscented, metered-dose, manual-pump spray formulation containing amicronized suspension of budesonide in an aqueous medium. Microcrystalline cellulose andcarboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassiumsorbate and purified water are contained in this medium; hydrochloric acid is added to adjust the pHto a target of 4.5.
RHINOCORT AQUA Nasal Spray is available in two dose strengths which deliver 32 mcg and 64mcg, respectively, of budesonide per spray.
Each bottle of RHINOCORT AQUA Nasal Spray 32 mcg contains 60 or 120 metered sprays afterinitial priming.
Each bottle of RHINOCORT AQUA Nasal Spray 64 mcg contains 120 metered sprays after initialpriming.
Prior to initial use, the container must be shaken gently and the pump must be primed by actuatingeight times. If used daily, the pump does not need to be reprimed. If not used for two consecutive RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinsethe applicator and reprime with two sprays or until a fine spray appears.
CLINICAL PHARMACOLOGY
Budesonide is a synthetic corticosteroid having potent glucocorticoid activity and weak
mineralocorticoid activity. In standard in-vitro and animal models, budesonide has approximately a
200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-
inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic
activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25
times more potent when administered orally in the rat thymus involution assay. In glucocorticoid
receptor affinity studies, the 22R form was twice as active as the 22S epimer.
The precise mechanism of corticosteroid actions in seasonal and perennial allergic rhinitis is notknown. Corticosteroids have been shown to have a wide range of inhibitory activities against multiplecell types (e.g. mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators(e.g. histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic mediated inflammation.
Corticosteroids affect the delayed (6 hour) response to an allergen challenge more than the histamine-associated immediate response (20 minute). The clinical significance of these findings is unknown.
Pharmacokinetics: The pharmacokinetics of budesonide have been studied following nasal, oral and
intravenous administration. Budesonide is relatively well absorbed after both inhalation and oral
administration, and is rapidly metabolized into metabolites with low corticosteroid potency. The
clinical activity of RHINOCORT AQUA Nasal Spray is therefore believed to be due to the parent
drug, budesonide. In-vitro studies indicate that the two epimeric forms of budesonide do not
interconvert.
Absorption: Following intranasal administration of RHINOCORT AQUA, the mean peak plasma
concentration occurs at approximately 0.7 hours. Compared to an intravenous dose, approximately
34% of the delivered intranasal dose reaches the systemic circulation, most of which is absorbed
through the nasal mucosa. While budesonide is well absorbed from the GI tract, the oral
bioavailability of budesonide is low (~10%) primarily due to extensive first pass metabolism in the
liver.
Distribution: Budesonide has a volume of distribution of approximately 2-3 L/kg. The volume of
distribution for the 22R epimer is almost twice that of the 22S epimer. Protein binding of budesonide
in vitro is constant (85 -90%) over a concentration range (1-100 nmol/L) which exceeded that
achieved after administration of recommended doses. Budesonide shows little to no binding to
glucocorticosteroid binding globulin. It rapidly equilibrates with red blood cells in a concentration
independent manner with a blood/plasma ratio of about 0.8.
Metabolism: Budesonide is rapidly and extensively metabolized in humans by the liver. Two major
metabolites (16α-hydroxyprednisolone and 6β-hydroxybudesonide) are formed via cytochrome P450
3A isoenzyme-catalyzed biotransformation. Known metabolic inhibitors of cytochrome P450 3A
(e.g., ketoconazole), or significant hepatic impairment, may increase the systemic exposure of
unmetabolized budesonide (see WARNINGS and PRECAUTIONS). In-vitro studies on the binding
of the two primary metabolites to the glucocorticoid receptor indicate that they have less than 1% of
the affinity for the receptor as the parent compound budesonide. In-vitro studies have evaluated sites
of metabolism and showed negligible metabolism in skin, lung, and serum. No qualitative difference
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
between the in-vitro and in-vivo metabolic patterns could be detected.
Elimination: Budesonide is excreted in the urine and feces in the form of metabolites. After
intranasal administration of a radio labeled dose, 2/3 of the radioactivity was found in the urine and
the remainder in the feces. The main metabolites of budesonide in the 0-24 hour urine sample
following IV administration are 16α-hydroxyprednisolone (24%) and 6β-hydroxybudesonide (5%).
An additional 34% of the radioactivity recovered in the urine was identified as conjugates.
The 22R form was preferentially cleared with clearance value of 1.4 L/min vs. 1.0 L/min for the 22Sform. The terminal half-life, 2 to 3 hours, was similar for both epimers and it appeared to beindependent of dose.
Special Populations
Geriatric: No specific pharmacokinetic study has been undertaken in subjects >65 years of age.
Pediatric: After administration of RHINOCORT AQUA Nasal Spray, the time to reach peak drug
concentrations and plasma half-life were similar in children and in adults. Children had plasma
concentrations approximately twice those observed in adults due primarily to differences in weight
between children and adults.
Gender: No specific pharmacokinetic study has been conducted to evaluate the effect of gender on
budesonide pharmacokinetics. However, following administration of 400 mcg RHINOCORT AQUA
Nasal Spray to 7 male and 8 female volunteers in a pharmacokinetic study, no major gender
differences in the pharmacokinetic parameters were found.
Race: No specific study has been undertaken to evaluate the effect of race on budesonide
pharmacokinetics.
Renal Insufficiency: The pharmacokinetics of budesonide have not been investigated in patients
with renal insufficiency.
Hepatic Insufficiency: Reduced liver function may affect the elimination of corticosteroids. The
pharmacokinetics of orally administered budesonide were affected by compromised liver function as
evidenced by a doubled systemic availability. The relevance of this finding to intranasally
administered budesonide has not been established.
Pharmacodynamics: A 3-week clinical study in seasonal rhinitis, comparing RHINOCORT Nasal
Inhaler, orally ingested budesonide, and placebo in 98 patients with allergic rhinitis due to birch pollen,
demonstrated that the therapeutic effect of RHINOCORT Nasal Inhaler can be attributed to the
topical effects of budesonide.
The effects of RHINOCORT AQUA Nasal Spray on adrenal function have been evaluated in severalclinical trials. In a four-week clinical trial, 61 adult patients who received 256 mcg daily ofRHINOCORT AQUA Nasal Spray demonstrated no significant differences from patients receivingplacebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscularcosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements inpatients receiving up to 400 mcg daily. Similar results were seen in a study of 150 children andadolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mcg daily for up to twelve RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
After treatment with the recommended maximal daily dose of RHINOCORT AQUA (256 mcg) forseven days, there was a small, but statistically significant decrease in the area under the plasmacortisol-time curve over 24 hours (AUC 0-24h) in healthy adult volunteers.
A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration ofRHINOCORT AQUA doses ranging from 100-800 mcg daily for up to four days in 78 healthy adultvolunteers. The clinical relevance of these results is unknown.
Clinical Trials: The therapeutic efficacy of RHINOCORT AQUA Nasal Spray has been evaluated
in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration.
The number of patients treated with budesonide in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantlyCaucasian.
Overall, the results of these clinical trials showed that RHINOCORT AQUA Nasal Sprayadministered once daily provides statistically significant reduction in the severity of nasal symptoms ofseasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion.
In some studies, improvement versus placebo has been shown to occur within 24 hours of initiatingtreatment with RHINOCORT AQUA Nasal Spray. Maximum benefit is generally not achieved until2 weeks after initiation of treatment.
INDICATIONS AND USAGE
RHINOCORT AQUA Nasal Spray is indicated for the management of nasal symptoms of seasonal or
perennial allergic rhinitis in adults and children six years of age and older.
CONTRAINDICATIONS
Hypersensitivity to any of the ingredients in this preparation contraindicates the use of RHINOCORT
AQUA Nasal Spray.
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, e.g. 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 thanhealthy individuals. Chicken pox and measles, for example, can have a more serious or even fatalcourse in non-immune children or adults on immunosuppressant doses of corticosteroids. In suchchildren or adults, who have not had these diseases, particular care should be taken to avoid RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
exposure. How the dose, route and duration of corticosteroid administration affects the risk ofdeveloping a disseminated infection is not known. The contribution of the underlying disease and/orprior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxiswith varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxiswith pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package insertsfor complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviralagents 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 intranasaladministration of budesonide. Rare instances of wheezing, nasal septum perforation, and increasedintraocular pressure have been reported following the intranasal application of corticosteroids,including budesonide.
Although systemic effects have been minimal with recommended doses of RHINOCORT AQUANasal Spray, any such effect is dose dependent. Therefore, larger than recommended doses ofRHINOCORT AQUA Nasal Spray should be avoided and the minimal effective dose for the patientshould be used (see DOSAGE and ADMINISTRATION). When used at larger doses, systemiccorticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changesoccur, the dosage of RHINOCORT AQUA Nasal Spray should be discontinued slowly consistentwith accepted procedures for discontinuing oral corticosteroid therapy.
In clinical studies with budesonide administered intranasally, the development of localized infectionsof the nose and pharynx with Candida albicans has occurred only rarely. When such an infectiondevelops, it may require treatment with appropriate local or systemic therapy and discontinuation oftreatment with RHINOCORT AQUA Nasal Spray. Patients using RHINOCORT AQUA Nasal Sprayover several months or longer should be examined periodically for evidence of Candida infection orother signs of adverse effects on the nasal mucosa.
RHINOCORT AQUA Nasal Spray should be used with caution, if at all, in patients with active orquiescent tuberculous infection, untreated fungal, bacterial, or systemic viral infections, or ocularherpes simplex.
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experiencedrecent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid untilhealing has occurred.
Hepatic dysfunction influences the pharmacokinetics of budesonide, similar to the effect on othercorticosteroids, with a reduced elimination rate and increased systemic availability (see CLINICALPHARMACOLOGY, 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.
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
Patients should use RHINOCORT AQUA Nasal Spray at regular intervals since its effectivenessdepends on its regular use (see DOSAGE and ADMINISTRATION).
An improvement in nasal symptoms may be seen within the first 24 hours after initiation of treatment.
Maximum benefit is generally not achieved until 2 weeks after initiation of treatment. Initialassessment for response should be made during this time frame and periodically until the patient’ssymptoms are stabilized.
The patient should take the medication as directed and should not exceed the prescribed dosage. Thepatient should contact the physician if symptoms do not improve after two weeks, or if the conditionworsens. Patients who experience recurrent episodes of epistaxis (nosebleeds) or nasal septumdiscomfort while taking this medication should contact their physician. For proper use of this unit andto attain maximum improvement, the patient should read and follow the accompanying patientinstructions carefully.
It is important to shake the bottle well before each use. The RHINOCORT AQUA Nasal Spray 32mcg bottle should be discarded after 60 or 120 sprays after initial priming and the RHINOCORTAQUA Nasal Spray 64 mcg bottle should be discarded after 120 sprays, after initial priming, since theamount 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 3A (CYP3A). After oral administration of ketoconazole, a potent inhibitor of
cytochrome P450 3A, the mean plasma concentration of orally administered budesonide increased by
more than seven fold. Concomitant administration of other known inhibitors of CYP3A (e.g.
itraconazole, clarithromycin, erythromycin, etc.) may inhibit the metabolism of, and increase the
systemic exposure to, budesonide (see WARNINGS, PRECAUTIONS, General).
Omeprazole, an inhibitor of cytochrome P450 2C19, did not have effects on the pharmacokinetics oforal budesonide, while cimetidine, primarily an inhibitor of cytochrome P450 1A2, caused a slightdecrease 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 upto 200 mcg/kg (approximately 3 times the maximum recommended daily intranasal dose in adults andchildren on a mcg/m2 basis).
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
Budesonide was not mutagenic or clastogenic in six different test systems: Ames,salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosomeaberration 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 duringlactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kgand 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 dosein adults on a mcg/m2 basis).
Pregnancy: Teratogenic Effects: Pregnancy Category C: 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).
There are no adequate and well-controlled studies in pregnant women. RHINOCORT AQUA NasalSpray should be used during pregnancy only if the potential benefit justifies the potential risk to thefetus.
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed tophysiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroidsthan humans. In addition, because there is a natural increase in corticosteroid production duringpregnancy, most women will require a lower exogenous corticosteroid dose and many will not needcorticosteroid treatment during pregnancy.
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 growthvelocity in pediatric patients. This effect has been observed in the absence of laboratory evidence ofhypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a moresensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly usedtests of HPA axis function. The long-term effects of this reduction in growth velocity associated withintranasal 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 beenadequately studied. The growth of pediatric patients receiving intranasal corticosteroids, includingRHINOCORT AQUA Nasal Spray, should be monitored routinely (e.g., via stadiometry). The RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
potential growth effects of prolonged treatment should be weighed against clinical benefits obtainedand the availability of safe and effective noncorticosteroid treatment alternatives. To minimize thesystemic effects of intranasal corticosteroids, including RHINOCORT AQUA Nasal Spray, eachpatient should be titrated to the lowest dose that effectively controls his/her symptoms.
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.
ADVERSE REACTIONS
The incidence of common adverse reactions is based upon two U.S. and five non-U.S. controlled
clinical trials in 1526 patients [110 females and 239 males less than 18 years of age, and 635 females
and 542 males 18 years of age and older] treated with RHINOCORT AQUA Nasal Spray at doses up
to 400 mcg once daily for 3-6 weeks. The table below describes adverse events occurring at an
incidence of 2% or greater and more common among RHINOCORT AQUA Nasal Spray-treated
patients than in placebo-treated patients in controlled clinical trials. The overall incidence of adverse
events was similar between RHINOCORT AQUA and Placebo.
Adverse Event
RHINOCORT AQUA
Placebo Vehicle
A similar adverse event profile was observed in the subgroup of pediatric patients 6 to 12 years ofage.
Two to three percent (2-3%) of patients in clinical trials discontinued because of adverse events.
Systemic corticosteroid side-effects were not reported during controlled clinical studies withRHINOCORT AQUA Nasal Spray.
If recommended doses are exceeded, however, or if individuals are particularly sensitive, symptomsof hypercorticism, i.e., Cushing’s Syndrome, could occur.
Rare adverse events reported from post-marketing experience include: nasal septum perforation,pharynx disorders (throat irritation, throat pain, swollen throat, burning throat, and itchy throat),angioedema, anosmia, and palpitations.
Cases of growth suppression have been reported for intranasal corticosteroids includingRHINOCORT AQUA Nasal Spray (see PRECAUTIONS, Pediatric Use).
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
OVERDOSAGE
Acute overdosage with this dosage form is unlikely since one 60 spray bottle of RHINOCORT
AQUA Nasal Spray 32 mcg only contains approximately 3.2 mg of budesonide, one 120 spray bottle
of RHINOCORT AQUA Nasal Spray 32 mcg contains approximately 5.4 mg of budesonide, and one
120 spray bottle of RHINOCORT AQUA Nasal Spray 64 mcg only contains approximately 10.8 mg
of budesonide. Chronic overdosage may result in signs/symptoms of hypercorticism (see
WARNINGS and PRECAUTIONS).
DOSAGE AND ADMINISTRATION
The recommended starting dose for adults and children 6 years of age and older is 64 mcg per day
administered as one spray per nostril of RHINOCORT AQUA 32 mcg Nasal Spray once daily. The
maximum recommended dose for adults (12 years of age and older) is 256 mcg per day administered
as four sprays per nostril once daily of RHINOCORT AQUA 32 mcg Nasal Spray, or as two sprays
per nostril once daily of RHINOCORT AQUA 64 mcg Nasal Spray, and the maximum recommended
dose for pediatrics (<12 years of age) is 128 mcg per day administered as two sprays per nostril once
daily of RHINOCORT AQUA 32 mcg Nasal Spray or one spray per nostril once daily of
RHINOCORT AQUA Nasal Spray (see HOW SUPPLIED).
Prior to initial use, the container must be shaken gently and the pump must be primed by actuatingeight times. If used daily, the pump does not need to be reprimed. If not used for two consecutivedays, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinsethe applicator and reprime with two sprays or until a fine spray appears.
Individualization of Dosage: It is always desirable to titrate an individual patient to the minimum
effective dose to reduce the possibility of side effects. In adults and children 6 years of age and older,
the recommended starting dose is 64 mcg daily administered as one spray per nostril of
RHINOCORT AQUA Nasal Spray 32 mcg, once-daily. Some patients who do not achieve symptom
control at the recommended starting dose may benefit from an increased dose. The maximum daily
dose is 256 mcg for adults and 128 mcg for pediatric patients (<12 years of age). When the
maximum benefit has been achieved and symptoms have been controlled, reducing the dose may be
effective in maintaining control of the allergic rhinitis symptoms in patients who were initially
controlled on higher doses.
An improvement in symptoms may be seen in some patients within the first 24 hours after initiatingtreatment. Maximum benefit is generally not achieved until 2 weeks after initiation of treatment.
Initial assessment for response should be made during this time frame and periodically until thepatient’s symptoms are stabilized.
Directions for Use: Illustrated Patient's Instructions for Use accompany each package of
RHINOCORT AQUA 32 mcg Nasal Spray or RHINOCORT AQUA 64 mcg Nasal Spray.
HOW SUPPLIED
RHINOCORT AQUA Nasal Spray is available in two strengths (32 mcg and 64 mcg) in a 10 mL
green coated glass bottle with a metered-dose pump spray with a green protection cap and patient
instructions for use. Each spray delivers 32 mcg or 64 mcg of budesonide to the patient.
RHINOCORT AQUA Nasal Spray 32 mcg dose is available in bottles containing 60 or 120 metered
sprays, after initial priming. RHINOCORT AQUA Nasal Spray 64 mcg dose is available in bottles
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999
RHINOCORT® AQUA (budesonide) NASAL SPRAY
DRAFT PRESCRIBING INFORMATION
containing 120 metered sprays, after initial priming.
NDC 0186-1070-06RHINOCORT AQUA Nasal Spray32 mcg, 60 metered sprays.
NDC 0186-1070-08RHINOCORT AQUA Nasal Spray32 mcg, 120 metered sprays.
NDC 0186-0171-08RHINOCORT AQUA Nasal Spray64 mcg, 120 metered sprays.
RHINOCORT AQUA Nasal Spray should be stored at controlled room temperature, 20 to 25°C (68
to 77°F) with the valve up. Do not freeze. Protect from light. Shake gently before use. Do not
spray in eyes.
RHINOCORT® AQUA™ (budesonide) NASAL SPRAY NDA 20-746
Unannotated Package Insert - Revised August 30, 1999

Source: http://shijiebiaopin.com/upload/product/20142921250529.pdf