Combivent Inhaler

Combivent indications for use

Prevention and long-term treatment of bronchial asthma, chronic obstructive bronchitis.

Clinical pharmacology

Combivent is a combined preparation with a strong bronchodilatorial effect, resulting from the action of ipratropium bromide and salbutamol included in the composition.

Ipratropium bromide is an anticholinergic agent. It blocks m-cholinoreceptors of smooth muscles of tracheobronchial tree (mainly large and medium bronchi), suppresses reflex bronchoconstriction, reduces secretion of glands of mucous coat of airways. Having structural similarity with acetylcholine molecule, it is its competitive antagonist. Effectively prevents bronchial constriction resulting from inhalation of cigarette smoke, cold air, the action of various bronchospasmodic agents, as well as eliminates bronchial spasm associated with the influence of the vagus nerve.

Salbutamol is a beta2 -adrenergic agent, which acts on the smooth muscles of the airways, causing its relaxation and preventing bronchospasm. It reduces the resistance in the airways, increases the vital capacity of the lungs. Prevents release of histamine, leukotrienes, PGD2 and other biologically active substances from mast cells. In recommended therapeutic doses it does not have negative effect on cardiovascular system, does not cause increase in BP. Compared with the drugs of this group, it has less positive chrono- and inotropic effects. It causes dilation of coronary arteries.

Combined inhalation of ipratropium bromide and salbutamol has a simultaneous local effect on muscarinic and beta2 -adrenergic lung receptors, resulting in increased bronchodilator effect. Systemic absorption is not increased by combined inhalation of ipratropium bromide and salbutamol.

Pharmacology

Ipratropium bromide is rapidly absorbed after inhalation, but systemic bioavailability leaves less than 10% of the dose taken. Binding to plasma proteins (mainly to albumin and glycoprotein) is 9%. 46% of the drug is excreted by the kidneys. T1/2 is about 1.6 h after intravenous administration. Ipratropium bromide does not penetrate the BBB.

Salbutamol is quickly and completely absorbed after inhalation. Cmax of salbutamol in blood plasma is observed after 3 hours. Binding to plasma proteins is 10%. It is subject to presystemic metabolism in the liver and intestinal wall. T1/2 is 3-7 hours. It is excreted by kidneys, mainly unchanged (30% of the dose within 24 hours) and as inactive phenolsulfate metabolite within 72 hours, and with bile. Salbutamol penetrates through HEB to reach concentrations equal to about 5% of the blood plasma level.

Form of production and composition

1 dose of inhalation aerosol contains:

• active substances: ipratropium bromide 20 µg and salbutamol sulfate 120 µg;
• in a 10 ml aerosol can (200 doses), 1 can in a box.

Interaction

Concomitant use of additional beta2 -adrenomimetics, GCS, anticholinergic agents and xanthine derivatives may enhance the bronchodilator effect of Ipramol Steri-Neb on airways and cause severe side effects.

When concomitant treatment with beta-adrenoblockers, a significant decrease in the effectiveness of the drug may be observed.

MAO inhibitors and tricyclic antidepressants may enhance the beta-adrenergic effects of salbutamol and lead to a sharp decrease in BP.

Inhalation anesthesia with anesthetics containing halogenated hydrocarbons, such as halothane, trichloroethylene, and enflurane, may exacerbate the adverse effects of beta2-adrenomimetics on the cardiovascular system, so close monitoring of patients is required. Alternatively, Ipramol Steri-Neb may be discontinued prior to surgery.

Theophylline and other xanthines enhance the likelihood of tachyarrhythmia.

Ipramol Steri-Neb due to hypokalemic effect of salbutamol may enhance the effect of CNS stimulants, increase the probability of glycoside intoxication, enhance cardiotropic effect of thyroid hormones.

Possible increase in heart rate and BP during administration of Ipramol Steri-Neb may cause the need to adjust the dose of hypotensive and antianginal drugs.

Diuretics and GCS increase hypokalemic effect of salbutamol.

Anticholinergic drugs increase the risk of increased intraocular pressure.

Overdose

Manifestations of overdose of ipratropium bromide are unlikely due to low systemic absorption after inhalation or ingestion. As a consequence, all manifestations of overdose are related to the systemic action of salbutamol.

Symptoms: headache, nausea, vomiting, angina, hypertension, hypotension, hypokalemia, hyperkalemia, tachycardia, arrhythmia, chest pain, tremor, hyperemia, anxiety, hallucinations and dizziness.

Treatment: symptomatic, including administration of cardioselective beta-adrenoblockers. However, it should be taken into account that these drugs may increase bronchospasm.

How to take, the course of administration and dosage

Inhaled. Two doses 4 times a day; if necessary, the number of doses may be increased to 12 times a day.

Contraindications

• Hypersensitivity to salbutamol, ipratropium bromide, atropine or their derivatives;
• Hypertrophic obstructive cardiomyopathy;
• Tachyarrhythmia;
• Pregnancy (1st trimester);
• Childhood (under 12 years).
• Caution: closed-angle glaucoma; urinary tract obstruction (including one caused by prostatic hyperplasia); manifest organic diseases of CPPS; pheochromocytoma; hyperthyroidism; diabetes mellitus under control; cystic fibrosis; myocardial infarction (recently diagnosed); pregnancy (II-III trimesters); lactation.

Special directions

To avoid overdose, it is not recommended to exceed the maximum daily dose. Patients should be instructed on the proper use of the drug Combivent with a nebulizer and warn against getting the solution or aerosol in the eyes.

In patients with bronchial asthma or moderate forms of COPD, symptomatic treatment may be preferable to regular use.

Adherence to or intensification of anti-inflammatory therapy to control airway inflammation in patients with bronchial asthma and steroid-dependent forms of COPD should be further analyzed.

Regular use of high doses of beta2 -adrenomimetics, including in Combivent, to control the symptoms of bronchial obstruction may worsen the course of the disease. When bronchial obstruction increases, simply increasing the dose of Combivent over an extended period of time is inadvisable and even dangerous.

To prevent life-threatening worsening of the disease course, the patient’s treatment plan should be reviewed, especially the adequacy of anti-inflammatory therapy with GCS drugs. The use of ipratropium bromide inhalation solution together with beta2 -adrenomimetics has rarely resulted in acute closed-angle glaucoma. Pain or discomfort in the eye, blurred vision, and the appearance of a glaucoma-specific halo in combination with eye redness and edema (from conjunctival to corneal) may be regarded as signs of acute closed angle glaucoma. If these symptoms persist, it is necessary to start treatment with myotics in the form of eye drops and immediately see a specialist.

It should be explained to the patient that in case of acute, rapidly worsening shortness of breath or obvious decrease in response to the drug, it is necessary to consult a doctor.

Treatment with beta2 -adrenomimetics may lead to marked hypokalemia. Particular caution should be exercised in cases of severe airway obstruction, since concomitant treatment with xanthine derivatives, diuretics and GCS may contribute to hypokalemia. Hypokalemia may lead to an increased risk of arrhythmia in patients taking digoxin. In addition, hypoxia may exacerbate the effects of hypokalemia on heart rate. In such situations, it is recommended that serum potassium concentrations be checked.

In patients with cystic fibrosis, the drugCombivent should be prescribed with caution due to the fact that the appearance of symptoms of impaired gastrointestinal motility is possible. Such patients should be warned about the need to inform the physician about any changes in gastrointestinal function.

If greater doses than recommended are required to relieve symptoms of bronchial obstruction (or bronchospasm), the patient’s treatment plan should be reviewed.

Effect on ability to drive and operate machinery. There are no data on the effect on the ability to drive motor transport and/or operate other mechanisms. However, taking into account the possibility of CNS side effects during Combivent treatment, caution should be exercised while driving motor transport and engaging in potentially dangerous activities that require high concentration and quick psychomotor reactions.

Side effects

• tremor (trembling) of the fingers
• rapid heartbeat
• dry mouth.