Rhinocort Aqua

Serious side effects have been reported with Rhinocort Aqua. See the “Drug Precautions” section.

Common side effects of Rhinocort Aqua include:

• nosebleeds
• sore throat
• breathing difficulties such as wheezing, or chest tightening
• coughing
• nasal irritation

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the side effects of Rhinocort Aqua. Ask your healthcare provider or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Grapefruit and grapefruit juice may interact with Rhinocort Aqua and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor before using them if you are taking Rhinocort Aqua.

Avoid being near people who are sick or have infections. Call your doctor for preventive treatment if you are exposed to chicken pox or measles. These conditions can be serious or even fatal in people who are using budesonide.

Budesonide nasal spray is used to treat an itchy or runny nose, sneezing, or other symptoms caused by hay fever (allergic rhinitis). It is a steroid (cortisone-like medicine) that works by preventing the inflammation that occurs with allergic reactions.

This medicine is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of budesonide nasal spray in children younger than 6 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of budesonide nasal spray in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Desmopressin

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac
• Acemetacin
• Amtolmetin Guacil
• Bemiparin
• Boceprevir
• Bromfenac
• Bufexamac
• Bupropion
• Celecoxib
• Ceritinib
• Choline Salicylate
• Clonixin
• Cobicistat
• Conivaptan
• Darunavir
• Dexibuprofen
• Dexketoprofen
• Diclofenac
• Diflunisal
• Dipyrone
• Droxicam
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Flufenamic Acid
• Flurbiprofen
• Ibuprofen
• Idelalisib
• Indomethacin
• Ketoprofen
• Ketorolac
• Lornoxicam
• Loxoprofen
• Lumacaftor
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Morniflumate
• Nabumetone
• Nadroparin
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Oxaprozin
• Oxyphenbutazone
• Parecoxib
• Phenylbutazone
• Piketoprofen
• Piroxicam
• Pixantrone
• Pranoprofen
• Proglumetacin
• Propyphenazone
• Proquazone
• Ritonavir
• Rofecoxib
• Salicylic Acid
• Salsalate
• Sodium Salicylate
• Sulindac
• Telaprevir
• Tenoxicam
• Tiaprofenic Acid
• Tolfenamic Acid
• Tolmetin
• Valdecoxib

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Erythromycin
• Ketoconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Cataracts, history of or
• Glaucoma, history of—Use with caution. May make these conditions worse.

• Chicken pox (includes recent exposure) or
• Herpes simplex infection of the eye or
• Infections (virus, bacteria, fungus, or parasite), any type and untreated or
• Measles (includes recent exposure) or
• Tuberculosis, active or history of—Can reduce the body's ability to fight off these infections.

• Injury to the nose, recent or
• Nose surgery, recent or
• Sores or ulcers in the nose, recent—This medicine may prevent proper healing of these conditions.

• Liver disease—Use with caution. Effects may be increased because of slower removal of the medicine from the body.

Systemic and intranasal corticosteroids use may result in the following:

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.

The incidence of common adverse reactions in Table 1 is based upon two U.S. and five non-U.S. controlled clinical trials in 1,526 patients with seasonal or perennial rhinitis in adults and children ≥ 6 years treated with Rhinocort Aqua Nasal Spray at doses up to 400 mcg once daily for 3-6 weeks. This population included 745 females and 781 males with a mean age of 31 years (range of 6-85 years, 349 were 6 < 18 years). The racial distribution of patients receiving Rhinocort Aqua Nasal Spray was 93% white, 3% black and 4% other. Table 1 describes adverse reactions occurring at an incidence of 2% or greater and more commonly among Rhinocort Aqua Nasal Spray-treated patients than in placebo-treated patients in controlled clinical trials.

A similar adverse reaction profile was observed in the subgroup of pediatric patients 6 to 12 years of age. These patients are included in Table 1.

Two to three percent (2-3%) of patients in clinical trials discontinued because of adverse reactions. Systemic corticosteroid side effects were not reported during controlled clinical studies with Rhinocort Aqua Nasal Spray.

If recommended doses are exceeded, or if individuals are particularly sensitive, symptoms of hypercorticism, ie, Cushing’s Syndrome, and adrenal suppression could occur.

Post-marketing Experience

The following adverse reactions have been reported during post-approval use of Rhinocort Aqua Nasal Spray. 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, urticaria, rash, dermatitis, angioedema and pruritus), [see Warnings and Precautions (5.2) and Contraindications (4)]

Eye disorders: glaucoma, increased intraocular pressure, cataracts [see Warnings and Precautions (5.7)]

Respiratory, thoracic, and mediastinal disorders: nasal septum perforation, anosmia, pharynx disorders (throat irritation, throat pain, swollen throat, burning throat, and itchy throat), and wheezing

Cardiac disorders: palpitations

Musculoskeletal and connective tissue disorders: growth suppression [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]

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 (i.e., PULMICORT TURBUHALER) and intranasally administered budesonide (i.e., 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 (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 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 carefully observed.

Nursing Mothers

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 (12.3)]. 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 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 Nasal Spray immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure.

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 (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 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 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 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).

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 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 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 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 (2)].

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 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.

Hepatic Impairment

Formal pharmacokinetic studies using Rhinocort Aqua 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.

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.

Its structural formula is:

Budesonide is a white to off-white, odorless powder that is practically insoluble in water and in heptane, 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 Nasal Spray is an unscented, metered-dose, manual-pump spray formulation containing a micronized suspension of budesonide in an aqueous medium. Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, and purified water are contained in this medium; hydrochloric acid is added to adjust the pH to a target of 4.5.

Rhinocort Aqua Nasal Spray delivers 32 mcg of budesonide per spray.

Each bottle of Rhinocort Aqua Nasal Spray 32 mcg contains 120 metered sprays after initial priming.

Prior to initial use, the container must be shaken gently and the pump must be primed by actuating eight times. If used daily, the pump does not need to be reprimed. If not used for two consecutive days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with two sprays or until a fine spray appears.

Mechanism of Action

Budesonide is an anti-inflammatory corticosteroid that exhibits 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. The clinical significance of this is unknown.

The activity of Rhinocort Aqua Nasal Spray is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in seasonal and perennial allergic rhinitis is not well known. Inflammation is an important component in the pathogenesis of seasonal and perennial allergic rhinitis. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in seasonal and perennial allergic rhinitis.

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.

HPA Axis Effects:

The effects of Rhinocort Aqua Nasal Spray on adrenal function have been evaluated in several clinical trials. In a four-week clinical trial, 61 adult patients who received 256 mcg daily of Rhinocort Aqua Nasal Spray demonstrated no significant differences from patients receiving placebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscular cosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements in patients receiving up to 400 mcg daily. Similar results were seen in a study of 150 children and adolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mcg daily for up to 12 months.

After treatment with the recommended maximal daily dose of Rhinocort Aqua Nasal Spray (256 mcg) for seven days, there was a small, but statistically significant decrease in the area under the plasma cortisol-time curve over 24 hours (AUC0-24h) in healthy adult volunteers.

A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration of Rhinocort Aqua Nasal Spray doses ranging from 100-800 mcg daily for up to four days in 78 healthy adult volunteers. The clinical relevance of these results is unknown.

Pharmacokinetics

Absorption

After intranasal administration of a single dose of Rhinocort Aqua Nasal Spray (128 mcg), the mean peak plasma concentration of approximately 0.3 nmol/L occurs about 0.5 hours post-dose. 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

The volume of distribution of budesonide was approximately 2-3 L/kg. It was 85-90% bound to plasma proteins. The volume of distribution for the 22R epimer is almost twice that of the 22S epimer. Protein binding was constant over a concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of Rhinocort Aqua Nasal Spray. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Excretion/Elimination

The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 2/3 of an intranasal radiolabeled dose was recovered in the urine and the remainder in the feces. No unchanged budesonide was detected in the urine.

Specific Populations

Geriatric

The pharmacokinetics of Rhinocort Aqua Nasal Spray in geriatric patients have not been specifically studied.

Pediatric

Following 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 of 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.

Nursing Mothers

The disposition of budesonide when delivered by oral inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant was approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant) [see Use in Specific Populations, Nursing Mothers (8.3)].

Renal or Hepatic Impairment

The pharmacokinetics of budesonide have not been investigated in patients with renal impairment. Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The relevance of this finding to intranasally administered budesonide has not been established.

Drug-Drug Interactions

Inhibitors of cytochrome P450 enzymes

Ketoconazole: Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide [see Warnings and Precautions (5.5) and Drug Interactions (7.1)].

Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

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 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 hepatocyte culture.

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).

Animal Toxicology and/or Pharmacology

Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) and at a subcutaneous dose of 500 mcg/kg in rats (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 doses up to 250 mcg/kg (approximately 8 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).

Before using Rhinocort Aqua, tell your doctor if you have been sick or had an infection of any kind. Also tell your doctor if you have liver disease, glaucoma or cataracts, herpes simplex infection of your eyes, tuberculosis, sores or ulcers in your nose, or if you have recently had injury of or surgery on your nose.

It may take up to 2 weeks of using Rhinocort Aqua before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after a week of treatment.

Budesonide can lower the blood cells that help your body fight infections. Avoid being near people who are sick or have infections. Call your doctor for preventive treatment if you are exposed to chicken pox or measles. These conditions can be serious or even fatal in people who are using Rhinocort Aqua.

Avoid getting Rhinocort Aqua in your eyes. If this does happen, rinse with water and call your doctor.

Steroid medicines can affect growth in children. Talk with your doctor if you think your child is not growing at a normal rate while using Rhinocort Aqua.