Combivent Respimat (albuterol and ipratropium) Side Effects, Warnings, and Drug Interactions

Combivent Respimat (albuterol/ipratropium) is a combination of two bronchodilators used to treat chronic obstructive pulmonary disease (COPD) (bronchitis and emphysema) when there is evidence of spasm (narrowing) of the airways (bronchi). 

Common side effects of Combivent Respimat include:

• nervousness,
• tremor,
• headache,
• palpitations,
• fast heart rate,
• elevated blood pressure,
• nausea,
• dizziness,
• heartburn,
• throat irritation,
• nosebleeds,
• worsening of diabetes,
• lowered potassium levels,
• dry mouth,
• cough,
• and difficulty breathing.

Serious side effects of Combivent Respimat include:

• worsening symptoms of benign prostatic hyperplasia (BPH) and narrow-angle glaucoma allergic reactions (rare).
• Symptoms of allergic reactions include:
  • rash,
  • hives,
  • swelling,
  • bronchospasm,
  • or anaphylaxis (shock).
• Rarely, Combivent Respimat can paradoxically precipitate life-threatening bronchospasm.

Drug interactions of Combivent Respimat include:

• other anticholinergic drugs (for example, atropine),
• tricyclic antidepressants,
• monoamine oxidase inhibitors (MAOIs),
• other stimulant medications,
• beta-blockers,
• and loop diuretics. 

There are no adequate studies of Combivent Respimat use during pregnancy. Some reports indicate that beta-agonists may interfere with uterine contractility. It is unknown if Combivent Respimat is excreted in human milk. Consult your doctor before breastfeeding.

Side effects of albuterol/ipratropium combination products are due to the component drugs. Side effects of albuterol include nervousness, tremor, headache, palpitations, fast heart rate, elevated blood pressure, nausea, dizziness, and heartburn. Throat irritation and nosebleeds also can occur. Worsening of diabetes and lowering of potassium also have been reported.

The most common side effects associated with ipratropium are:

• dry mouth,
• cough,
• headache,
• nausea,
• dizziness, and
• difficulty breathing.

Because of its anticholinergic effect, ipratropium may worsen symptoms of benign prostatic hyperplasia, and narrow-angle glaucoma.

Other important side effects include allergic reactions, which may rarely occur and may manifest as:

• rash,
• hives,
• swelling,
• bronchospasm, or
• anaphylaxis (shock).

In rare patients, albuterol/ipratropium can paradoxically precipitate life-threatening bronchospasm.

Adverse reaction information concerning Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for Combivent Inhalation Aerosol) as seen in Table 1.

Table 1 : All Adverse Events (in percentages), from Two Large Double-blind, Parallel, 12-Week Studies of Patients with COPD*

Additional adverse reactions, reported in less than two percent of the patients in the Combivent Inhalation Aerosol treatment group include:

• edema,
• fatigue,
• hypertension,
• dizziness,
• nervousness,
• paresthesia,
• tremor,
• dysphonia,
• insomnia,
• diarrhea,
• dry mouth,
• dyspepsia,
• vomiting,
• arrhythmia,
• palpitation,
• tachycardia,
• arthralgia,
• angina,
• increased sputum,
• taste perversion,
• and urinary tract infection/dysuria.

Allergic-type reactions such as skin reactions including rash, pruritus, and urticaria (including giant urticaria), angioedema including that of tongue, lips and face, laryngospasm and anaphylactic reaction have been reported with Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, with positive rechallenge in some cases. Many of these patients had a history of allergies to other drugs and/or foods including soybean.

Post-Marketing Experience

In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving Atrovent® (ipratropium bromide) Inhalation Aerosol CFC.

Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol) include:

• hypersensitivity,
• pharyngeal edema,
• mouth edema,
• urinary retention,
• mydriasis,
• bronchospasm (including paradoxical bronchospasm),
• cases of precipitation or worsening of:
  • narrow-angle glaucoma,
  • glaucoma,
  • intraocular pressure increased,
  • acute eye pain,
  • halo vision,
  • blurred vision,
  • accommodation disorder,
  • ocular irritation,
  • corneal edema,
  • conjunctival hyperaemia,
  • nasal congestion,
  • drying of secretions,
  • mucosal ulcers,
  • stomatitis,
  • irritation from aerosol,
  • throat irritation,
  • dry throat,
  • wheezing,
  • exacerbation of COPD symptoms,
  • hoarseness,
  • palpitations,
  • heartburn,
  • drowsiness,
  • CNS stimulation,
  • coordination difficulty,
  • flushing, alopecia,
  • hypotension,
  • edema,
  • gastrointestinal distress (diarrhea, nausea, vomiting),
  • gastrointestinal motility disorder,
  • constipation,
  • hypokalemia,
  • mental disorder,
  • hyperhidrosis,
  • muscle spasms,
  • muscular weakness,
  • myalgia,
  • asthenia,
  • myocardial ischemia,
  • diastolic blood pressure decreased,
  • and systolic blood pressure increased.

Metabolic acidosis has been reported with use of albuterol-containing products.

Combivent Inhalation Aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids, commonly used in the treatment of chronic obstructive pulmonary disease. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of Combivent Inhalation Aerosol and these drugs with respect to safety and effectiveness.

Anticholinergic agents

There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid co-administration of Combivent Inhalation Aerosol with other anticholinergic-containing drugs.

Beta-adrenergic agents

Caution is advised in the co-administration of Combivent Inhalation Aerosol and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.

Beta-receptor blocking agents and albuterol inhibit the effect of each other. Beta-receptor blocking agents should be used with caution in patients with hyperreactive airways.

Diuretics

The ECG changes and/or hypokalemia which 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 co-administration of beta-agonist-containing drugs, such as Combivent Inhalation Aerosol, with non-potassium sparing diuretics. Consider monitoring potassium levels.

Monoamine oxidase inhibitors or tricyclic antidepressants

Combivent Inhalation Aerosol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or within two weeks of discontinuation of such agents because the action of albuterol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants.