Atrovent® HFA Inhalation Aerosol

Ipratropium Bromide

Bronchodilator

Boehringer Ingelheim

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

Atrovent Monograph PDF download here.

 

CPS:PIS_m072500

Date of Preparation: June 19, 2003

Date of Revision: January 22, 2004

 

 

Pharmacology

ATROVENT (ipratropium bromide), a quaternary ammonium derivative of atropine is an anticholinergic drug having bronchodilator properties. On inhalation 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 induces bronchodilator effect lasting for some 6 hours.

     Significant alterations on airway mucous secretion, mucociliary clearance of sputum, or gas exchange have not been observed. Systemic absorption of ATROVENT is poor and the blood levels reached are very low. Metabolic studies with ATROVENT in healthy volunteers show an average elimination half-life of 3.5 hours (range 1.5-4). The drug is transformed to some 8 metabolites with little or no anticholinergic activity.

     In controlled 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (COPD, chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV₁ and FEF_25-75% increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for periods of 3 to 4 hours in the majority of patients and up to 6 hours in some patients.

     ATROVENT HFA Inhalation Aerosol is a CFC-free formulation which uses hydrofluoroalkane 134a (HFA-134a) as propellant. It replaces the original formulation of ATROVENT Inhalation Aerosol which used chlorofluorocarbons (CFC) as propellant. Clinical trials with a treatment duration of up to one year in which the HFA and the CFC formulations have been compared have shown the two formulations to be therapeutically equivalent.

 

Indications

ATROVENT HFA (ipratropium bromide) inhalation aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.

 

Contraindications

ATROVENT HFA (ipratropium bromide) inhalation aerosol should not be taken by patients hypersensitive to ipratropium bromide, atropinics or any other aerosol components.

 

Warnings

ATROVENT (ipratropium bromide) inhalation aerosol should not be used for the abatement of the acute episodes of bronchospasm where rapid response is required, since the drug has a slower onset of effect than that of an adrenergic β₂-agonist aerosol.

     Care should be taken to ensure that ATROVENT 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 bromide, either alone or in combination with an adrenergic beta₂-agonist, has been released into the eyes.

     Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.

     Immediate hypersensitivity reactions may occur after administration of ATROVENT metered dose aerosol, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

     Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.

 

Precautions

 

General

To ensure optimal delivery of ATROVENT (ipratropium bromide) 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.

     When using the new formulation of ATROVENT inhalation aerosol (HFA) for the first time, some patients may notice that the taste is slightly different from that of the CFC-containing formulation. Patients should be made aware of this when changing from one formulation to the other. They should also be told that the formulations have been shown to be interchangeable and that the difference in taste has no consequences in terms of the safety or the efficacy of the new formulation.

     Caution is advised against the release of the aerosol into the eyes.

     In patients with narrow-angle glaucoma, prostatic hyperplasia, urinary retention or bladder neck obstruction, ATROVENT should be used with caution.

     If a reduced response to ATROVENT becomes apparent, the patient should seek medical advice.

     Immediate hypersensitivity reactions may occur after administration of ATROVENT metered dose aerosol (see Warnings).

 

Pregnancy

The safety of ATROVENT inhalation aerosol in pregnancy has not been established. The benefits of using ATROVENT when pregnancy is present or suspected must be weighed against possible hazards caused to the fetus. Studies in rats, mice and rabbits showed no embryotoxic nor teratogenic effects.

 

Lactation

No specific studies have been conducted on excretion of this drug in breast milk. Benefits of ATROVENT inhalation aerosol use during lactation should therefore be weighed against possible effects on the infant.

 

Drug Interactions

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

     Xanthine derivatives and beta₂-adrenergic agents may enhance the effect of ATROVENT inhalation aerosol.

 

Adverse Effects

 Table 1 summarizes the adverse events reported with a frequency of at least 1% in the ATROVENT HFA clinical trial safety data set, which includes a total of 1231 patients, of which 787 were treated with Atrovent HFA at total daily doses of 20 μ g to 320 μ g for up to 4 months. Figures for Atrovent CFC from the same data set are given for comparison. The adverse events reported are on the whole those that might be expected in a population of patients with COPD or asthma that is being treated with an inhaled anticholinergic. The only significant difference between the two placebo formulations is in the reporting frequency for “taste perversion”, which was higher for placebo HFA than placebo CFC.

     The most frequent non-respiratory adverse events reported in clinical trials were headache, nausea and dryness of the mouth/throat.

     Anticholinergic side effects such as tachycardia and palpitation, supraventricular tachycardia and atrial fibrillation, tremor, ocular accommodation disturbances, gastrointestinal motility disturbances and urinary retention are rare and reversible, although the risk of urinary retention may be increased in patients with pre-existing outflow tract obstruction.

     There have been isolated reports of ocular events such as mydriasis, increased intraocular pressure, glaucoma and eye pain associated with the release of aerosolized ATROVENT (ipratropium bromide) into the eyes.

     Ocular side effects have been reported (see Warnings).

     As with other inhaled therapy including bronchodilators, cough, local irritation and in very rare instances exacerbation of symptoms and paradoxical bronchospasm has been observed.

     Allergic-type reactions such as skin rash, angioedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions may occur in rare cases.

     The adverse event profile was also examined in a total of 3250 patients that were treated in clinical trials with formulations of ATROVENT other than HFA (e.g. unit dose vials, capsules). The nature and frequency of adverse events in this extended population were similar to ATROVENT HFA with the exception that gastro-intestinal motility disorders (constipation, diarrhoea and vomiting) were common adverse events while nausea was rare.

CPS:atroventhfainhalationaerosol_t1Click here for Table 1

Table 1: Atrovent HFA Inhalation Aerosol

Commonly Reported^a  Adverse Events

 

	Atrovent					Placebo
Formulation	CFC		HFA			CFC		HFA
No. of patients exposed	N=431		N=787			N=106		N=126
	n	%	n	%	n	%	n	%
Respiratory System Disorders
Any AE Within the Body System	165	38	305	39	34	32	38	30
Rhinitis	40	9	59	7	7	7	5	4
Bronchitis	33	8	67	9	5	5	32
Dyspnoea	34	8	57	7	5	5	4	3
Coughing	25	6	46	6	4	4	7	6
Chronic obstructive airways disease	26	6	37	5	9	8	8	6
Upper Resp Tract Infection	17	4	44	6	8	8	8	6
Pharyngitis	23	5	38	5	1	<1	4	3
Asthma	14	3	36	5	0	0	0	0
Sinusitis	8	2	10	1	2	2	3	2
Body as a Whole—General Disorders
Any AE Within the Body System	62	14	134	17	11	10	16	13
Headache	32	7	59	7	7	7	7	6
Pain	8	2	24	3	0	0	4	3
Influenza-like symptoms	6	1	24	3	0	0	3	2
Back pain	7	2	8	1	1	<1	1	<1
Chest pain	6	1	10	1	0	0	0	0
Fatigue	3	<1	9	1	1	<1	1	<1
Gastro-intestinal System Disorders
Any AE Within the Body System	47	11	97	12	6	6	6	5
Nausea	7	2	23	3	2	2	1	<1
Mouth dry	7	2	18	2	0	0	2	2
Diarrhoea	6	1	15	2	0	0	0	0
Abdominal pain	7	2	13	2	1	<1	0	0
Vomiting	5	1	15	2	0	0	0	0
Constipation	6	1	7	<1	1	<1	1	<1
Dyspepsia	6	1	7	<1	1	<1	0	0
Central and Peripheral Nervous System Disorders
Any AE Within the Body System	24	6	34	4	4	4	5	4
Dizziness	6	1	15	2	1	<1	2	2
Dysphonia	8	2	7	<1	0	0	1	<1
Special Senses Other, Disorders
Any AE Within the Body System	18	4	28	4	0	0	8	6
Taste Perversion	18	4	28	4	0	0	8	6
Urinary System Disorders
Any AE Within the Body System	10	2	15	2	5	5	4	3
Urinary tract infection	8	2	7	<1	2	2	1	<1
Musculo-skeletal System Disorders
Any AE Within the Body System	14	3	13	2	2	2	2	2
Myalgia	7	2	4	<1	2	2	1	<1
Vision disorders
Any AE Within the Body System	6	1	20	3	3	3	0	0
Conjunctivitis	3	<1	11	1	0	0	0	0

 

 ^a Commonly reported adverse events are those that were reported with a frequency of at least 1% in the global safety data set regardless of relationship to treatment.

 

Legend:AE: Adverse event.n=No. of patients reporting AE.%=Percentage of patients reporting AE.CFC: Chlorofluorocarbon formulation.HFA: Alternative Propellant, hydrofluoroalkane formulation. Adverse events occurring prior to the first intake of test treatment are not included. Treatment was the last treatment the patient received prior to the onset or worsening of the adverse event.

 

 

Overdose

 

 

Symptoms

Doses of ATROVENT (ipratropium bromide) up to 1.2 mg (60 puffs) have been administered by inhalation without the appearance of serious systemic anticholinergic effects. Minor systemic manifestations of anticholinergic action, including dry mouth, visual accomodation disturbances and increase of heart rate may occur.

 

 

Treatment

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

 

Dosage

The optimal maintenance dosage must be individually determined. The recommended dosage is 2 metered doses (actuations) (40 µg) 3 or 4 times daily. Some patients may need up to 4 metered doses (actuations) (80 µg) at a time to obtain maximum benefit during early treatment. The maximum daily dose should not exceed 12 metered doses (actuations) (240 µg) and the minimum interval between doses should not be less than 4 hours.

     There are no clinical studies in COPD patients to support a recommendation to use a spacer device with ATROVENT HFA.

     ATROVENT HFA is recommended for the use in patients 18 years and older.

Stability and Storage Recommendations: The aerosol canister should be stored at room temperature (15-30°C); the contents are stable up to the expiration date stamped on the label.  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.

 

Supplied

Each metal canister with mouthpiece (oral adaptor) contains: 200 actuations of ipratropium bromide. Each valve depression actuation delivers 20 µg of ipratropium bromide. Nonmedicinal ingredients: citric acid, ethanol, propellant (1,1,1,2 – Tetrafluoroethane (HFA 134a)), and water. Store at room temperature (15-30°C).