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Budesonide

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(CAS: 188062-50-2)

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Manufacturer: AstraZeneca LP

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 C 25 H 34 O 6 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 ˇÁ 10 3 .

What is budesonide?

ˇ¤Budesonide is in a class of drugs called corticosteroids. Budesonide works in the intestines to reduce inflammation, tissue damage, and diarrhea.
ˇ¤Budesonide is used to treat mild to moderate Crohn's disease.
ˇ¤Budesonide may also be used for purposes other than those listed in this medication guide.

RHINOCORT AQUA 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.

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 (16(alpha)-hydroxyprednisolone and 6(beta)-hydroxybudesonide) are formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalyzed biotransformation. Known metabolic inhibitors of CYP3A4 (eg, 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 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 radiolabeled 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 16(alpha)-hydroxyprednisolone (24%) and 6(beta)-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 22S form. The terminal half-life, 2 to 3 hours, was similar for both epimers and it appeared to be independent 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 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.

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.

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 Nasal Spray 32 mcg 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 Nasal Spray 32 mcg and the maximum recommended dose for pediatric patients (<12 years of age) is 128 mcg per day administered as two sprays per nostril once daily of RHINOCORT AQUA Nasal Spray 32 mcg (see HOW SUPPLIED ).

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.

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 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.

REFERENCES

  1. Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93:392-395.
  2. Ericson A, Kallen B. Use of drugs during pregnancy: unique Swedish registration method that can be improved. Swedish Medical Products Agency 1999;1:8-11.
  3. Norjavaara E, Gerhardsson de Verdier M. Normal pregnancy outcomes in a population-based study including 2968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111:736-742.