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Symbicort (Budesonide Inhalation) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility

Budesonide

Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide.

In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (less than the maximum recommended human daily inhalation dose 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 (less than the maximum recommended human daily inhalation dose 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 (less than the maximum recommended human daily inhalation dose 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 (less than the maximum recommended human daily inhalation dose 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 equal to the maximum recommended human daily inhalation dose 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 equal to the maximum recommended human daily inhalation dose on a mcg/m2 basis). However, it caused a decrease in prenatal viability and viability in 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 human daily inhalation dose on a mcg/m2 basis). No such effects were noted at 5 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Formoterol

Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate.

In a 24-month carcinogenicity study in CD-1 mice, formoterol at oral doses of 0.1 mg/kg and above (approximately 20 times the maximum recommended human daily inhalation dose on a mcg/m2 basis) caused a dose-related increase in the incidence of uterine leiomyomas.

In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 60 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No tumors were seen at 22 mcg/kg (approximately 10 times the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Other beta-agonist drugs, have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.

Formoterol was not mutagenic or clastogenic in Ames Salmonella /microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test.

A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15 mg/kg (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). In a separate study with male rats treated with an oral dose of 15 mg/kg (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No such effect was seen at 3 mg/kg (approximately 1400 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No effect on fertility was detected in female rats at doses up to 15 mg/kg (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis).

OVERDOSAGE

SYMBICORT

SYMBICORT contains both budesonide and formoterol; therefore, the risks associated with overdosage for the individual components described below apply to SYMBICORT. In pharmacokinetic studies, a total of 1920/54 mcg (12 actuations of SYMBICORT 160/4.5) was administered as a single dose to both healthy subjects and patients with asthma and was well tolerated. In a long-term active-controlled safety study, SYMBICORT 160/4.5 was well tolerated for up to 12 months at doses up to twice the highest recommended daily dose.

Clinical signs in dogs that received a single inhalation dose of SYMBICORT (a combination of budesonide and formoterol) in a dry powder included tremor, mucosal redness, nasal catarrh, redness of intact skin, abdominal respiration, vomiting, and salivation; in the rat, the only clinical sign observed was increased respiratory rate in the first hour after dosing. No deaths occurred in rats given a combination of budesonide and formoterol at acute inhalation doses of 97 and 3 mg/kg, respectively (approximately 1200 and 1350 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No deaths occurred in dogs given a combination of budesonide and formoterol at the acute inhalation doses of 732 and 22 mcg/kg, respectively (approximately 30 times the maximum recommended human daily inhalation dose of budesonide and formoterol on a mcg/m2 basis).

Budesonide

The potential for acute toxic effects following overdose of budesonide is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS). Budesonide at five times the highest recommended dose (3200 mcg daily) administered to humans for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.

In mice the minimal inhalation lethal dose was 100 mg/kg (approximately 600 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). In rats there were no deaths following the administration of an inhalation dose of 68 mg/kg (approximately 900 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). The minimal oral lethal dose in mice was 200 mg/kg (approximately 1300 times the maximum recommended human daily inhalation dose on a mcg/m2 basis) and less than 100 mg/kg in rats (approximately 1300 times the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Formoterol

An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta2-agonists; therefore, the following adverse experiences may occur: angina, hypertension or hypotension, palpitations, tachycardia, arrhythmia, prolonged QTc-interval, headache, tremor, nervousness, muscle cramps, dry mouth, insomnia, fatigue, malaise, seizures, metabolic acidosis, hypokalemia, hyperglycemia, nausea and vomiting. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. Formoterol was well tolerated at a delivered dose of 90 mcg/day over 3 hours in adult patients with acute bronchoconstriction and when given three times daily for a total dose of 54 mcg/day for 3 days to stable asthmatics.

Treatment of formoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol. Cardiac monitoring is recommended in cases of overdosage.

No deaths were seen in mice given formoterol at an inhalation dose of 276 mg/kg (more than 62,200 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). In rats the minimum lethal inhalation dose was 40 mg/kg (approximately 18,000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No deaths were seen in mice that received an oral dose of 2000 mg/kg (more than 450,000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). Maximum non-lethal oral doses were 252 mg/kg in young rats and 1500 mg/kg in adult rats (approximately 114,000 times and 675,000 times the maximum recommended human inhalation dose on a mcg/m2 basis).

CONTRAINDICATIONS

SYMBICORT is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

Hypersensitivity to any of the ingredients in SYMBICORT contraindicates its use.

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