Combivent® Inhalation Aerosol

Ipratropium Bromide--Salbutamol Sulfate

Bronchodilator

Boehringer Ingelheim

http://www.boehringer-ingelheim.com/corporate/home/home.asp

Combivent Monograph PDF download here.

 

CPS:PIS_m133400

 

 

 

Pharmacology

Combivent Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the β₂-adrenergic bronchodilator, salbutamol sulfate. Each actuation from the valve delivers 20 µg ipratropium bromide and 120 µg salbutamol sulfate (equivalent to 100 µg salbutamol base).

     Ipratropium bromide is a quaternary ammonium derivative of atropine and is an anticholinergic with bronchodilator properties. On inhalation of ipratropium bromide the onset of action is noted within 5 to 15 minutes with a peak response between 1 and 2 hours, lasting about 2 additional hours with subsequent decline. An inhaled dose of 40 µg of ipratropium bromide inhalation aerosol induced bronchodilatation lasting for some 6 hours.

     Salbutamol produces bronchodilation through stimulation of β₂-adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of bronchial muscle fibres. This action is manifested by an improvement in pulmonary function as demonstrated by spirometric measurements.

     In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of 2 inhalations of Combivent Inhalation Aerosol to the 2 active components individually, the coadministration of ipratropium bromide and salbutamol sulfate in a single canister did not potentiate the systemic absorption of either component. From a pharmacokinetic perspective, the synergistic efficacy of Combivent Inhalation Aerosol is due to a local effect on the muscarinic and β₂-adrenergic receptors in the lung.

     In two 12-week controlled clinical trials, 1067 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of Combivent Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and salbutamol sulfate (347 patients). In these studies Combivent Inhalation Aerosol produced significant improvements in pulmonary function as demonstrated by increases in FEV₁ of 15% or more compared with baseline. The median time to onset of a 15% increase was 15 minutes and the median time to peak was 1 hour for Combivent Inhalation Aerosol and its components. The median duration of effect was 4 to 5 hours for Combivent Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for salbutamol sulfate. These studies demonstrated that each component of Combivent Inhalation Aerosol contributed to the efficacy of the combination, especially during the first 4 to 5 hours after dosing, and that Combivent Inhalation Aerosol was significantly more effective than ipratropium bromide or salbutamol sulfate administered alone.

 

Indications

For the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

 

Contraindications

In patients with cardiac tachyarrhythmias, hypertrophic obstructive cardiomyopathy and in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. Combivent should also not be taken by patients hypersensitive to salbutamol sulfate, ipratropium bromide, atropinics or any other aerosol components.

 

Warnings

Pregnancy

The safety of Combivent Inhalation Aerosol in pregnancy has not been established. The benefits of using Combivent when pregnancy is present or suspected must be weighed against possible hazards caused to the fetus.

     Salbutamol, a component of Combivent Inhalation Aerosol, has been shown to be teratogenic in mice when given in doses corresponding to 14 times the human aerosol dose; 5 times the human inhalation dose, 0.2 times the maximum human (child weighing 21 kg) oral dose; and 0.4 times the maximum human oral dose and at doses corresponding to the human nebulization dose.

Lactation

It is not known whether the components of Combivent Inhalation Aerosol are excreted in human milk. As salbutamol is probably secreted in breast milk and because of the potential for tumorigenicity shown for salbutamol in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether salbutamol in breast milk has a harmful effect on the neonate. No specific studies have been conducted on the excretion of ipratropium in breast milk. The benefits of Combivent Inhalation Aerosol use during lactation should therefore be weighed against possible effects on the infant.

Children

The efficacy and safety in children younger than 12 years have not been established.

General: Care should be taken to ensure that Combivent Inhalation Aerosol does not reach the eye. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, glaucoma and eye pain) when aerosolized ipratropium has been released into the eyes. Ocular events have occurred when ipratropium aerosol was used with the standard mouthpiece or with a spacing device. Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.

     Special care and supervision are required in patients with idiopathic hypertrophic subvalvular aortic stenosis, in whom an increase in the pressure gradient between the left ventricle and the aorta may occur, causing increased strain on the left ventricle.

     Care should be taken with patients suffering from cardiovascular disorders, especially coronary insufficiency, recent myocardial infarction, severe organic heart or vascular disorders, cardiac arrhythmias and hypertension; in patients with convulsive disorders, diabetes mellitus, hyperthyroidism, pheochromocytoma, risk of narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction and in patients who are usually responsive to sympathomimetic amines. Fatalities have been reported following excessive use of inhaled sympathomimetic, the exact cause of which is unknown.

     Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.

     In case of acute, rapidly worsening dyspnea (difficulty in breathing) a doctor should be consulted immediately.

     Immediate hypersensitivity reactions may occur after administration of salbutamol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

     In common with other beta-adrenergic agents, salbutamol can induce reversible metabolic changes; these are more pronounced during infusions of the drug and include hyperglycemia and hypokalemia.

     Potentially serious hypokalemia may result from β₂-agonist therapy, mainly from parenteral and nebulized administration. Hypokalemia will increase the susceptibility of digitalis-treated patients to cardiac arrhythmias. Additionally, hypoxia may aggravate the effects of hypokalemia on cardiac rhythm. It is recommended that serum potassium levels be monitored in such situations.

     Large doses of i.v. salbutamol have been reported to aggravate pre-existing diabetes mellitus and may precipitate ketoacidosis. The relevance of these observations to the use of Combivent is unknown.

     Some patients receiving β₂-adrenergic agonist have been reported to have developed severe paradoxical bronchospasm which has been life threatening. The cause of this refractory state is unknown. In this event, the use of the preparation should be discontinued immediately and alternate therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn.

     Combivent Inhalation Aerosol inhaler should be administered with extreme caution to patients being treated with MAO inhibitors or tricyclic antidepressants since the action of salbutamol on the cardiovascular system may be potentiated.

     Beta-adrenergic blocking drugs, especially the noncardioselective ones, may effectively antagonize the action of salbutamol and therefore salbutamol and nonselective beta-blocking drugs, such as propranolol, should not usually be prescribed together.

 

Precautions

 

General

To ensure optimal delivery of Combivent Inhalation Aerosol to the bronchial tree, the patient should be properly instructed by the physician or other health professional in the use of the inhaler.

     In patients with glaucoma, prostatic hypertrophy or urinary retention Combivent should be used with caution. In patients with glaucoma or narrow anterior chambers, care should be taken to ensure that aerosol does not reach the eye. Due care should be taken when a spacing device is employed. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, angle closure glaucoma) when ipratropium bromide either alone or in combination with an adrenergic β₂-agonist has been released into the eyes. Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. In the event that glaucoma is precipitated or worsened, treatment should include standard measure for this condition.

     Like other pressurized aerosol formulations, Combivent Inhalation Aerosol contains fluorocarbon propellants dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane. Such propellants may be hazardous if they are deliberately abused. Inhalation of high concentrations of aerosol sprays has brought about toxic cardiovascular effects and even death, especially under conditions of hypoxia. However, evidence attests to the relative safety of aerosols when used properly and with adequate ventilation. The recommended dose of Combivent Inhalation Aerosol should not be exceeded and the patient should be so informed.

     The concomitant use of Combivent with other sympathomimetic agents is not recommended since such combined use may lead to deleterious cardiovascular effects.

     Immediate hypersensitivity reactions may occur after administration of salbutamol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

 

Drug Interactions

In patients receiving other anticholinergic drugs, Combivent should be used with caution because of possible additive effects.

     Xanthine derivatives and β₂-adrenergic agents may enhance the effect of Combivent Inhalation Aerosol.

     β -agonist induced hypokalemia may be increased by concomitant treatment with xanthine derivatives, glucocorticosteroids, and diuretics. This should be taken into account particularly in patients with severe airway obstruction.

     Hypokalemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin. It is recommended that serum potassium levels are monitored in such situations.

     Other sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with Combivent Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. Such concomitant use must be individualized and not given on a routine basis. If regular coadministration is required then alternative therapy must be considered.

     Combivent Inhalation Aerosol should be administered with extreme caution to patients being treated with MAO inhibitors or tricyclic antidepressants because the action of salbutamol on the vascular system may be potentiated.

     Beta-receptor blocking agents and salbutamol inhibit the effect of each other.

     Inhalation of halogenated hydrocarbon anesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of β -agonists.

Labor and Delivery: It has been reported that high doses of salbutamol, administered i.v., inhibits uterine contractions. Although this effect is extremely unlikely as a consequence of the use of inhaled formulations, it should be kept in mind.

     Oral salbutamol has been shown to delay preterm labor in some reports. There are presently no well-controlled studies which demonstrated that it will stop preterm labor or prevent labor at term. Therefore, cautious use of Combivent Inhalation Aerosol is required in pregnant patients when it is given for relief of bronchospasm so as to avoid interference with uterine contractility.

 

Adverse Effects

Adverse reaction information concerning Combivent Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for Combivent Inhalation Aerosol).

     Adverse reactions, judged by the investigator to be possibly related to drug treatment, as well as adverse events occurring in 1% or more of patients in any group in the two 12-week controlled clinical trials, appear in  Table 1.

CPS:CombiventInhalationAerosol_t1Click here for Table 1

Table 1: Combivent Inhalation Aerosol

Two Double-Blind, Parallel, 12-Week Studies of Patients with COPD

Adverse Reactions/Events Occurring In 1% or More of Patients in Any Group

 

Total Treated	Percentage of Patients
	Combivent N=358	Ipratropium Bromide N=362	Salbutamol Sulfate N=347
Body as a Whole—General
Headache	1.1	1.7	2.0
Gastrointestinal
Mouth Dry	0.8	1.4	1.2
Respiratory (Lower)
Coughing	1.4	1.7	1.2
Bronchitis	1.1	1.9	1.2
Dyspnea	1.1	1.4	1.2
Sputum Increased	0.3a	0.0a	1.2
Respiratory (Upper)
Pharyngitis	0.8a	1.1a	0.3
Special Senses—Other
Taste Perversion	1.1	1.1	0.0

 

 ^a Adverse events; no direct relationship to treatment.

 

 

     Additional adverse reactions reported in less than 1% of the patients receiving Combivent include hypertension, nervousness, tremor, nausea, tachycardia, palpitations, and urinary retention.

     Adverse events observed in less than 1% of the patients receiving Combivent include fatigue, enlarged abdomen, paresthesia, dyspepsia, abscess, sinusitis, and dysuria.

Postmarketing Experience: World-wide safety data, including postmarketing data, spontaneous reports, literature reports, and reports from clinical trials, indicate that, in common with other β -agonist containing products the most frequent undesirable effects of Combivent Inhalation Aerosol are: headache, dizziness, nervousness, tachycardia, fine tremor of skeletal muscles, and palpitations.

     As seen with the use of other β -mimetics, nausea, vomiting, sweating, myalgia, and muscle cramps, and, in rare instances, decrease of diastolic blood pressure, increase of systolic blood pressure, arrhythmias, psychological alterations and potentially serious hypokalemia, particularly after high doses, may occur.

     Anticholinergic side effects such as ocular accommodation disturbances, gastrointestinal motility disturbances and urinary retention are rare and reversible.

     Ocular side effects have been reported (see Precautions).

     Side effects noted as with the use of other inhalation therapy are: cough, local irritation and in very rare instances inhalation-induced bronchospasm has been observed.

     The most frequent nonrespiratory side effects of Combivent Inhalation Aerosol are dryness of mouth and dysphonia.

     Allergic-type reactions such as skin rash, angioedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported in most of the patients who had history of allergy to other drugs and foods including soybean.

     Literature reports regarding adverse events associated with the use of ipratropium or salbutamol inhalation aerosol singly or in combination include, cases of nasal congestion, hoarseness, voice changes, drying of secretions, unusual taste, mucosal ulcers, wheezing, exacerbation of COPD symptoms, angina, heartburn, lightheadedness, drowsiness, insomnia, vertigo, CNS stimulation, coordination difficulty, weakness, itching, hives, angioedema, flushing, alopecia, indigestion, gastrointestinal distress, burning in stomach, diarrhea, and constipation.

 

Overdose

 

 

Symptoms

The effects of overdosage are expected to be related primarily to salbutamol because acute overdosage with ipratropium is unlikely since ipratropium is not well absorbed systemically after aerosol or oral administration. Expected symptoms of overdosage with ipratropium bromide (such as dry mouth, visual accommodation disturbance) are mild and transient in nature.

     Salbutamol overdosage may cause tachycardia, palpitation, tremor, hypertension, hypotension, widening of the pulse pressure, anginal pain, cardiac arrhythmia, hypokalemia, flushing and, in extreme cases, sudden death.

 

 

Treatment

Should signs of serious anticholinergic toxicity appear due to ipratropium, cholinesterase inhibitors may be considered.

     Administration of sedatives, tranquillizers or, in severe cases, intensive therapy may be appropriate for the treatment of overdosage. To antagonize the effect of salbutamol, the judicious use of a cardioselective beta-adrenergic blocking agent, (e.g., metoprolol, atenolol) may be considered, bearing in mind the danger of inducing an asthmatic attack. Serum potassium levels should be monitored.

 

Dosage

Combivent Inhalation Aerosol dosage should be individualized, and patient response should be monitored to determine the requirement for more than a single bronchodilator by the prescribing physician on an ongoing basis.

     Counselling on smoking cessation should be the first step in treating patients with chronic bronchitis who smoke. Smoking cessation produces symptomatic benefits and has been shown to confer a survival advantage by slowing or stopping the progression of chronic bronchitis and emphysema.

     The recommended dosage is 2 inhalations 4 times/day. The maximum daily dose should not exceed 12 inhalations.

 

Supplied

Each actuation delivers from the valve: ipratropium bromide 20 µg and salbutamol sulfate 120 µg (equivalent to 100 µg salbutamol base). Nonmedicinal ingredients: propellants (difluorodichloromethane, monofluorotrichloromethane, tetrafluorodichloroethane) and soya lecithin. Metal canisters containing 100 or 200 doses of Combivent with mouthpiece (oral adaptor).

     The aerosol canisters should be stored at room temperature (15 to 30°C). Avoid excessive humidity. Caution. Contents under pressure. Container may explode if heated. Do not place in hot water or near radiators, stoves or other sources of heat. Do not puncture or incinerate container or store at temperatures over 30°C. Keep out of reach of children.