Duoneb

Overdose

The effects of overdosage with DuoNeb (ipratropium bromide and albuterol sulfate) are expected to be related primarily to albuterol sulfate, since ipratropium bromide is not well-absorbed systemically after oral or aerosol administration. The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of symptoms such as seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmia, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, and exaggeration of pharmacological effects listed in ADVERSE REACTIONS. Hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of DuoNeb (ipratropium bromide and albuterol sulfate). Treatment consists of discontinuation of DuoNeb (ipratropium bromide and albuterol sulfate) together with appropriate symptomatic 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 DuoNeb (ipratropium bromide and albuterol sulfate).

The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 540 times the maximum recommended daily inhalation dose of DuoNeb (ipratropium bromide and albuterol sulfate) on a mg/m² basis). The subcutaneous median lethal dose of albuterol sulfate in mature rats and small young rats is approximately 450 and 2000 mg/kg respectively (approximately 240 and 1100 times the maximum recommended daily inhalation dose of DuoNeb (ipratropium bromide and albuterol sulfate) on a mg/m² basis, respectively). The inhalation median lethal dose has not been determined in animals. The oral median lethal dose of ipratropium bromide in mice, rats and dogs is greater than 1000 mg/kg, approximately 1700 mg/kg and approximately 400 mg/kg, respectively (approximately 1400, 4600, and 3600 times the maximum recommended daily inhalation dose in adults on a mg/m² basis, respectively).

Contraindications

DuoNeb (ipratropium bromide and albuterol sulfate) is contraindicated in patients with a history of hypersensitivity to any of its components, or to atropine and its derivatives.

Undesirable effects

Adverse reaction information concerning DuoNeb (ipratropium bromide and albuterol sulfate) was derived from the 12-week controlled clinical trial.

ADVERSE EVENTS OCCURRING IN ≥ 1% OF ≥ 1 TREATMENT GROUP(S) AND WHERE THE COMBINATION TREATMENT SHOWED THE HIGHEST PERCENTAGE

Additional adverse reactions reported in more than 1% of patients treated with DuoNeb (ipratropium bromide and albuterol sulfate) included constipation and voice alterations.

In the clinical trial, there was a 0.3% incidence of possible allergic-type reactions, including skin rash, pruritus, and urticaria.

Additional information derived from the published literature on the use of albuterol sulfate and ipratropium bromide singly or in combination includes precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, sore throat, and metabolic acidosis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Therapeutic indications

DuoNeb (ipratropium bromide and albuterol sulfate) is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator.

Name of the medicinal product

Fertility, pregnancy and lactation

Pregnancy Category C. Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate formation also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control).

A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Pregnancy Category B. Reproduction studies in CD-1 mice, Sprague-Dawley rats and New Zealand rabbits demonstrated no evidence of teratogenicity at oral doses up to 10, 100, and 125 mg/kg, respectively (approximately 15, 270, and 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Reproduction studies in rats and rabbits demonstrated no evidence of teratogenicity at inhalation doses up to 1.5 and 1.8 mg/kg, respectively (approximately 4 and 10 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). There are no adequate and well-controlled studies of the use of DuoNeb (ipratropium bromide and albuterol sulfate) , albuterol sulfate, or ipratropium bromide in pregnant women. DuoNeb (ipratropium bromide and albuterol sulfate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Qualitative and quantitative composition

DuoNeb (ipratropium bromide and albuterol sulfate) is supplied as a 3-mL sterile solution for nebulization in sterile low-density polyethylene unit-dose vials. Store in pouch until time of use. Supplied in cartons as listed below.

NDC 49502-672-30 30 vials per carton/5 vials per foil pouch

NDC 49502-672-60 60 vials per carton/5 vials per foil pouch

Store between 2°C and 25°C (36°F and 77°F). Protect from light.

DEY®, Napa, CA 94558. FEB 09

Special warnings and precautions for use

In the clinical study of DuoNeb (ipratropium bromide and albuterol sulfate) , paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with both inhaled ipratropium bromide and albuterol products and can be life-threatening. If this occurs, DuoNeb (ipratropium bromide and albuterol sulfate) should be discontinued immediately and alternative therapy instituted.

Fatalities have been reported in association with excessive use of inhaled products containing sympathomimetic amines and with the home use of nebulizers.

DuoNeb (ipratropium bromide and albuterol sulfate) , like other beta adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon for DuoNeb (ipratropium bromide and albuterol sulfate) at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, DuoNeb (ipratropium bromide and albuterol sulfate) , like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate hypersensitivity reactions to albuterol and/or ipratropium bromide may occur after the administration of DuoNeb (ipratropium bromide and albuterol sulfate) as demonstrated by rare cases of urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, and anaphylaxis.

1. Effects Seen with Sympathomimetic Drugs: As with all products containing sympathomimetic amines, DuoNeb (ipratropium bromide and albuterol sulfate) should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Additionally, β-agonists may cause a decrease in serum potassium in some patients, possibly through intracellular shunting. The decrease is usually transient, not requiring supplementation.
2. Effects Seen with Anticholinergic Drugs: Due to the presence of ipratropium bromide in DuoNeb (ipratropium bromide and albuterol sulfate) , it should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction.
3. Use in Hepatic or Renal Disease: DuoNeb (ipratropium bromide and albuterol sulfate) has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in these patient populations.

The action of DuoNeb (ipratropium bromide and albuterol sulfate) should last up to 5 hours. DuoNeb (ipratropium bromide and albuterol sulfate) should not be used more frequently than recommended. Patients should be instructed not to increase the dose or frequency of DuoNeb (ipratropium bromide and albuterol sulfate) without consulting their healthcare provider. If symptoms worsen, patients should be instructed to seek medical consultation.

Patients must avoid exposing their eyes to this product as temporary papillary dilation, blurred vision, eye pain, or precipitation or worsening of narrow-angle glaucoma may occur, and therefore proper nebulizer technique should be assured, particularly if a mask is used.

If a patient becomes pregnant or begins nursing while on DuoNeb (ipratropium bromide and albuterol sulfate) , they should contact their healthcare provider about use of DuoNeb.

See the illustrated Patient's Instruction for Use in the product package insert.

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m² basis). In another study, this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist.

In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleous assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

In 2-year studies in Sprague-Dawley rats and CD-1 mice, ipratropium bromide showed no evidence of tumorigenicity at oral doses up to 6 mg/kg (approximately 15 times and 8 times the maximum recommended daily inhalation dose for adults in rats and mice respectively, on a mg/m² basis).

Ipratropium bromide was not mutagenic in the Ames test and mouse dominant lethal test. Ipratropium bromide was not clastogenic in a mouse micronucleous assay.

A reproduction study in rats demonstrated decreased conception and increased resorptions when ipratropium bromide was administered orally at a dose of 90 mg/kg (approximately 240 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). These effects were not seen with a dose of 50 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

Pregnancy Category C. Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate formation also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control).

A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Pregnancy Category B. Reproduction studies in CD-1 mice, Sprague-Dawley rats and New Zealand rabbits demonstrated no evidence of teratogenicity at oral doses up to 10, 100, and 125 mg/kg, respectively (approximately 15, 270, and 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Reproduction studies in rats and rabbits demonstrated no evidence of teratogenicity at inhalation doses up to 1.5 and 1.8 mg/kg, respectively (approximately 4 and 10 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). There are no adequate and well-controlled studies of the use of DuoNeb (ipratropium bromide and albuterol sulfate) , albuterol sulfate, or ipratropium bromide in pregnant women. DuoNeb (ipratropium bromide and albuterol sulfate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral albuterol sulfate has been shown to delay preterm labor in some reports. Because of the potential of albuterol to interfere with uterine contractility, use of DuoNeb (ipratropium bromide and albuterol sulfate) during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

It is not known whether the components of DuoNeb (ipratropium bromide and albuterol sulfate) are excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when taken as a nebulized solution. Because of the potential for tumorigenicity shown for albuterol sulfate in some animals, a decision should be made whether to discontinue nursing or discontinue DuoNeb (ipratropium bromide and albuterol sulfate) , taking into account the importance of the drug to the mother.

The safety and effectiveness of DuoNeb (ipratropium bromide and albuterol sulfate) in patients below 18 years of age have not been established.

Of the total number of subjects in clinical studies of DuoNeb (ipratropium bromide and albuterol sulfate) , 62 percent were 65 and over, while 19 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Dosage (Posology) and method of administration

The recommended dose of DuoNeb (ipratropium bromide and albuterol sulfate) is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed. Safety and efficacy of additional doses or increased frequency of administration of DuoNeb (ipratropium bromide and albuterol sulfate) beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of DuoNeb (ipratropium bromide and albuterol sulfate) have not been studied.

The use of DuoNeb (ipratropium bromide and albuterol sulfate) can be continued as medically indicated to control recurring bouts of bronchospasm. If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.

A Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor was used to deliver DuoNeb (ipratropium bromide and albuterol sulfate) to each patient in one U.S. clinical study. The safety and efficacy of DuoNeb (ipratropium bromide and albuterol sulfate) delivered by other nebulizers and compressors have not been established.

DuoNeb (ipratropium bromide and albuterol sulfate) should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.

Interaction with other medicinal products and other forms of interaction

Adverse reaction information concerning DuoNeb (ipratropium bromide and albuterol sulfate) was derived from the 12-week controlled clinical trial.

ADVERSE EVENTS OCCURRING IN ≥ 1% OF ≥ 1 TREATMENT GROUP(S) AND WHERE THE COMBINATION TREATMENT SHOWED THE HIGHEST PERCENTAGE

Additional adverse reactions reported in more than 1% of patients treated with DuoNeb (ipratropium bromide and albuterol sulfate) included constipation and voice alterations.

In the clinical trial, there was a 0.3% incidence of possible allergic-type reactions, including skin rash, pruritus, and urticaria.

Additional information derived from the published literature on the use of albuterol sulfate and ipratropium bromide singly or in combination includes precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, sore throat, and metabolic acidosis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications. Caution is, therefore, advised in the coadministration of DuoNeb (ipratropium bromide and albuterol sulfate) with other drugs having anticholinergic properties.

Caution is advised in the co-administration of DuoNeb (ipratropium bromide and albuterol sulfate) and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.

These agents and albuterol sulfate inhibit the effect of each other. β-receptor blocking agents should be used with caution in patients with hyperreactive airways, and if used, relatively selective β1 selective agents are recommended.

The electrocardiogram (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 β-agonists, especially when the recommended dose of the β-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of β-agonist-containing drugs, such as DuoNeb (ipratropium bromide and albuterol sulfate) , with non-potassium sparing diuretics.

DuoNeb (ipratropium bromide and albuterol sulfate) should be administered with extreme 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 albuterol sulfate on the cardiovascular system may be potentiated.