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

 
 



DRUG INTERACTIONS

In clinical studies, concurrent administration of SYMBICORT and other drugs, such as short-acting beta2-agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with SYMBICORT.

Inhibitors of Cytochrome P4503A4

The main route of metabolism of corticosteroids, including budesonide, a component of SYMBICORT, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of SYMBICORT with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions ].

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

SYMBICORT should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of SYMBICORT, on the vascular system may be potentiated by these agents. In clinical trials with SYMBICORT, a limited number of COPD and asthma patients received tricyclic antidepressants, and, therefore, no clinically meaningful conclusions on adverse events can be made.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of SYMBICORT, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non−potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of SYMBICORT with non-potassium-sparing diuretics.

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, single doses of 960/54 mcg (12 actuations of SYMBICORT 80/4.5) and 1280/36 mcg (8 actuations of 160/4.5), were administered to patients with COPD. 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 astma. In a long-term active-controlled safety study in asthma patients, SYMBICORT 160/4.5 was administered for up to 12 months at doses up to twice the highest recommended daily dose. There were no clinically significant adverse reactions observed in any of these studies.

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 Warnings and Precautions (5) ]. 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: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. No clinically significant adverse reactions were seen when formoterol was delivered to adult patients with acute bronchoconstriction at a dose of 90 mcg/day over 3 hours or to stable asthmatics 3 times a day at a total dose of 54 mcg/day for 3 days.

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 nonlethal 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

The use of SYMBICORT is contraindicated in the following conditions:

  • •Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
  • •Hypersensitivity to any of the ingredients in SYMBICORT.

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