Product Monograph - PHL-Ipratropium
ACTION AND CLINICAL PHARMACOLOGY
Ipratropium bromide, a quaternary ammonium derivative of atropine, is an anticholinergic drug which has 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 from the peak. Bronchodilation is still evident 8 hours after inhalation.
In acute and maintenance therapy of chronic reversible airways obstruction, ipratropium has been shown to provide additive bronchodilating effects to theophylline and beta-adrenoceptor agonists (sympathomimetic amines). Repeated inhalation of ipratropium has not been linked to tolerance towards bronchodilating effects.
In controlled 12-week studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema), significant improvements in pulmonary function (FEV1 and FEF25-75% in increases of 15% or more) occurred within 15 minutes, reached a peak in 1 to 2 hours, and persisted for periods of 4 to 5 hours in the majority of patients, with 25 to 38% of the patients demonstrating increases of at least 15% at 7 to 8 hours. Continued effectiveness of ipratropium solution was demonstrated throughout the 12-week period. In addition, significant changes in forced vital capacity (FVC) have been demonstrated.
Additional controlled 12-week studies were conducted to evaluate the safety and efficacy of ipratropium solution administered concomitantly with bronchodilator solutions of orciprenaline or salbutamol, compared with the administration of each of the beta agonists alone. Combined therapy produced significant additional responses in FEV1, FVC and FEF25-75%. On combined therapy, the median duration of 15% improvement in FEV1 was 5 to 7 hours, compared with 3 to 4 hours in patients receiving a beta agonist alone.
Significant alterations in mucociliary clearance of tracheobronchial secretions (sputum) were not observed in short term clinical trials. Systemic absorption of ipratropium bromide is poor and the blood levels reached are very low. Metabolic studies in healthy volunteers show an average elimination half-life of 3.5 hours (range 1.5 to 4 hours). The drug is transformed to some 8 metabolites with little or no anticholinergic activity.
INDICATIONS AND CLINICAL USE
phl-IPRATROPIUM (ipratropium bromide) solution administered either alone or with a $2-adrenergic stimulant solution is indicated as a bronchodilator for the maintenance treatment of bronchospasm associated with, or for the therapy of, acute exacerbations of chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. phl-IPRATROPIUM solution, when used in conjunction with a $2-adrenergic stimulant solution such as fenoterol or salbutamol, is indicated for acute asthmatic attacks. Ipratropium bromide solution is to be administered by compressed air or oxygen driven nebulizers.
CONTRAINDICATIONS
Known hypersensitivity to phl-IPRATROPIUM (ipratropium bromide), to any of the product ingredients, or to atropinics.
WARNINGS
Ipratropium bromide solution in the 20-mL multidose bottle contains preservatives (benzalkonium chloride and disodium ethylene diamine tetraacetic acid – EDTA-disodium). It has been reported that these preservatives may cause bronchoconstriction in some patients with hyperreactive airways.
The unit dose vials do not contain preservatives.
Patients with Cystic Fibrosis may be more prone to gastrointestinal motility disturbances.
Ipratropium bromide should not be used alone for the abatement of an acute asthmatic attack since the drug has a slower onset of effect than that of an adrenergic $2 agonist.
Glaucoma, Angle-Closure: Care should be taken to ensure that the nebulizer mask fits the patient's face properly and that nebulized solution does not escape into the eyes. In patients with glaucoma or narrow anterior chambers, the administration by nebulizer of a combined ipratropium/$2-agonist solution should be avoided unless measures (e.g. use of swimming goggles or use of a nebulizer with a mouth piece) are taken to ensure that nebulized solution does not reach the eye. There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, angle closure glaucoma) when nebulized ipratropium either alone or in combination with an adrenergic $2 agonist solution has escaped into the eyes. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.
Pregnancy: The safety of ipratropium in pregnancy has not been established. The benefits of using ipratropium bromide when pregnancy is confirmed or suspected must be weighed against possible hazards to the fetus. Studies in rats, mice and rabbits showed neither embryotoxic nor teratogenic effects.
Lactation: No specific studies have been conducted on excretion of this drug in breast milk. Benefits of ipratropium bromide use during lactation should therefore be weighed against the possible effects on the infant.
Children: The efficacy and safety of ipratropium bromide in children younger than 5 years has not
been established.
PRECAUTIONS
< Ipratropium bromide solution (Bottles and UDVs) is intended for inhalation with suitable nebulizing devices and should not be taken orally or administered parenterally.
< Patients should be instructed in the proper use of the nebulizer.
< Caution is advised against accidental release of the solution into the eyes.
< In patients with glaucoma, prostatic hypertrophy or urinary retention, ipratropium bromide should be used with caution.
< If a reduced response to ipratropium bromide becomes apparent, the patient should seek medical advice.
< Ipratropium bromide solution, when administered to patients with acute severe asthma, should be used with concomitant $2-adrenergic stimulant therapy.
< Immediate hypersensitivity reactions may occur after administration of ipratropium bromide solution, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema.
Use with other Drugs: In patients receiving other anticholinergic drugs, ipratropium bromide should be used with caution because of possible additive effects.
Ipratropium bromide solution with preservatives (i.e., from the 20 mL multidose bottle) should not be mixed with sodium cromoglycate, as this produces a cloudy solution caused by complexation between the preservatives and sodium cromoglycate. If the patient's condition requires the administration of sodium cromoglycate, it should be given in combination with ipratropium bromide solution without preservatives (i.e., from the unit dose vial).
ADVERSE REACTIONS
Because of the low systemic absorption of ipratropium bromide, anticholinergic side effects, such as tachycardia and palpitations, ocular accomodation 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.
Acute Administration: The frequency of adverse reactions recorded in 214 patients receiving ipratropium bromide solution was as follows:
ADVERSE EFFECT % OF PATIENTS
Dry mouth or throat 9.3 Bad taste 5.1 Tremor 4.2 Exacerbation of symptoms 4.2 Burning eyes 0.9 Nausea 0.9 Sweating 0.9 Cough 0.9 Headache 0.5 Palpitations 0.5
The adverse effect judged to be most severe was exacerbation of bronchospasm. This occurred in 8 patients treated with ipratropium bromide solution alone, 6 of whom withdrew from the clinical studies.
Bronchospasm occurred in 3 patients with acute severe asthma who received ipratropium bromide solution alone. In two patients, this was reversed after therapy with a $2 sympathomimetic solution. The third patient received no other therapy.
The following table compares the incidence of adverse effects of the combination of ipratropium bromide and a $2 agonist (either fenoterol or salbutamol) solution with that of the $2 agonist alone.
Adverse Effect Ipratropium+$2 Agonist $2 agonist
(% of 94 patients) (% of 96 patients)
Tremor 31.9 26.0 Dry Mouth 16.0 28.1 Bad Taste 16.0 13.5 Vomiting 2.1 2.1 Palpitations 2.1 1.0 Headache 1.1 2.1 Cough 1.1 0.0 Flushing 1.1 0.0 Dizziness 0.0 1.0 Numbness in Leg 0.0 1.0
Chronic Administration: The frequency of adverse reactions reported as possibly related to ipratropium bromide treatment in 219 COPD patients participating in long-term (12-week) controlled clinical trials was as follows:
ADVERSE EFFECT % OF PATIENTS
Dry Mouth 2.7 Coughing 1.8 Dyspnea 1.8 Headache 1.8 Urinary Retention 1.4 Tremor 0.9 Nausea 0.9 Palpitation 0.9 Sputum Increased 0.9 Rhinitis 0.9 Eye Pain 0.9
The following other adverse events were reported as possibly related to drug treatment in one patient each: bronchitis, bronchospasm, chest pain, depression, fatigue, flu-symptoms, hypoaesthesia, increased saliva, insomnia, nervousness, pain, paraesthesia, pharyngitis, somnolence, tachycardia and urticaria.
The frequency of adverse reactions reported as possibly related to drug treatment in >1% of COPD patients participating in long-term (12-week) controlled clinical trials that compared the efficacy and safety of ipratropium+$2 agonists (metaproterenol or salbutamol) vs the $2 agonist alone, was as follows:
Adverse Effect Ipratropium + $2 Agonist $2 agonist
(% of patients) (% of patients)
(n=208) (n=417)
Headache 4.3 1.7 Tremor 3.8 3.4 Nervousness 3.8 1.9 Dyspnea 2.4 3.4 Dry mouth 2.4 1.0 Bronchitis 2.9 2.9 Dizziness 1.4 1.9 Coughing 1.4 1.0 Taste perversion 1.9 1.2 Insomnia 1.9 0.2 Dysuria 1.0 0.2 Nausea 1.0 1.7 Abnormal vision 0.5 1.2 Chest pain 1.4 0.7 Constipation 1.4 0.0 Dysphonia 1.0 0.2 Dyspepsia 1.0 0.0 Bronchospasm aggravated 1.0 0.7 Micturition frequency 1.0 0.2
There have been isolated reports of ocular effects such as mydriasis, increased intraocular pressure, and acute glaucoma associated with the escape of nebulized ipratropium bromide (alone or in combination with a $2 agonist solution) into the eyes.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Doses of ipratropium bromide up to 1.2 mg (approximately 30 times the therapeutic dose) have been administered by inhaler without the appearance of serious systemic anticholinergic effects. Should signs of serious anticholinergic toxicity appear, cholinesterase inhibitors may be considered.
DOSAGE AND ADMINISTRATION
Counselling by physicians on smoking cessation should be the first step in treating patients with chronic obstructive pulmonary disease (COPD) who smoke, independent of the clinical presentation i.e. chronic bronchitis (with or without airflow limitation) or emphysema. Cessation of smoking produces dramatic symptomatic benefits and has been shown to confer a survival advantage.
In adults, the average single dose of phl-IPRATROPIUM (ipratropium bromide) solution is 250–500 :g of ipratropium bromide. In children, aged 5–12 years, the recommended dose is 125–250 :g of ipratropium bromide. In most cases, dilution of the dose with sterile preservative-free saline is not necessary. However, volumes of ipratropium bromide solution less than 2 mLs are not appropriate for nebulization and must be diluted with saline or another suitable nebulizer solution to make up a total fill volume of 2-5 mL (see PHARMACEUTICAL INFORMATION).
Nebulization should take place using a gas flow (oxygen or compressed air) of 6–10 L/min and the solution nebulized to dryness over a 10–15 minute period. The Hudson UpdraftTM, Bennett Twin Jet®, Debilbiss, Pari Compressors and Inspiron Mini-Neb® nebulizers, with facemask or mouthpiece have been used. The manufacturers' instructions concerning cleaning and maintenance of the nebulizer should be strictly followed.
Treatment with phl-IPRATROPIUM solution may be repeated every 4–6 hours as necessary.
Daily doses exceeding 2 mg in adults should be given under medical supervision.
For the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, the recommended dose is 500 :g of phl-IPRATROPIUM solution given 3-4 times per day.
N+ CH(CH3)2
CH3
OOCCH
C6H5
CH2OH Br-PHARMACEUTICAL INFORMATION
Drug Substance
Common Name: Ipratropium Bromide (BAN, USAN, rINN) Chemical Name: (8r)-3" hydroxy-8-Isopropyl-1"H, 5"H-tropanium bromide Structural Formula:
Molecular Formula: C20H30NO3Br
Molecular Weight: 412.37
Description: White crystalline substance with a bitter taste. Freely soluble in water and in alcohol; insoluble in chloroform and in ether. In neutral and acid solutions the substance is rather stable; in alkaline solutions the ester bond is rapidly hydrolyzed. Melting point: 230/C, with decomposition.
Composition
1-mL Unit Dose Vial (single use): Ipratropium bromide 250 :g/mL (0.025%) in normal saline (9 mg/mL [0.9%] sodium chloride solution).
2-mL Unit Dose Vial (single use): Ipratropium bromide 125 :g/mL (0.0125%) in normal saline (9 mg/mL [0.9%] sodium chloride solution).
2-mL Unit Dose Vial (single use): Ipratropium bromide 250 :g/mL (0.025%) in normal saline (9 mg/mL [0.9%] sodium chloride solution).
20-mL Bottle (multidose): Ipratropium bromide 250 :g/mL (0.025%) in normal saline (9 mg/mL [0.9%] sodium chloride solution) with benzalkonium chloride and EDTA-disodium as preservatives.
Stability and Storage Recommendations
1 mL or 2 mL Unit Dose Vials: Unopened unit dose vials of phl-IPRATROPIUM solution should be stored at controlled room temperature (between 15/ and 25/C) and protected from heat and light. If required, the solution should be diluted with a preservative-free sterile sodium chloride solution 0.9% and used immediately. Any solution remaining in the vial must be discarded.
The solution is physically compatible with Alupent® (orciprenaline sulfate), Berotec® (fenoterol hydrobromide) or salbutamol sulfate (6 mg/mL) solutions. If such mixtures are prepared, they should be diluted with preservative-free sterile sodium chloride solution 0.9% and used immediately. Any unused portion of such combined solutions must be discarded.
20-mL Bottles: Unopened bottles of phl-IPRATROPIUM solution should be stored at controlled room temperature (between 15/ and 25/C). Solutions diluted with preservative-free sterile Sodium Chloride Inhalation Solution, USP 0.9% should be used within 24 hours from time of dilution when stored at room temperature and within 48 hours when stored in the refrigerator.
A controlled Preservative Challenge test, done in accordance with the current USP guideline for Preservative Efficacy Testing, indicated that bottles of Ipratropium Inhalation Solution, opened and closed several times, simulating patient use, were stable for up to 28 days when stored at room temperature (15/-25/C).
Controlled laboratory experiments using mixtures of the ipratropium bromide solution with Alupent® (orciprenaline sulfate), Berotec® (fenoterol hydrobromide) or salbutamol sulfate (6 mg/mL preserved with benzalkonium chloride) solutions and diluted with a sterile bacteriostatic sodium chloride solution 0.9% (i.e. normal saline), preserved with benzalkonium chloride, indicated that such mixtures were stable for 7 days at room temperature. For the preparation of such mixtures, it is recommended that only sterile solutions of bacteriostatic sodium chloride 0.9% preserved with 0.01% benzalkonium chloride be used to maintain the level of preservative in the mixture. The safety of preservatives other than benzalkonium chloride has not been established. Incompatibilities: phl-IPRATROPIUM solution with preservatives (i.e. from the 20 mL multidose bottle) should not be mixed with sodium cromoglycate solution, as this produces a cloudy solution caused by complexation between the preservatives and sodium cromoglycate. If the patient's condition requires the administration of sodium cromoglycate, it should be given in combination with phl-IPRATROPIUM solution without preservatives (i.e. from the unit dose vial).
AVAILABILITY OF DOSAGE FORMS
1 mL Unit Dose Vial: phl-IPRATROPIUM (ipratropium bromide) solution provided as 1 mL of clear, colourless solution containing 250 :g/mL (0.025%) ipratropium bromide in isotonic solution, presented in a plastic single use vial. Each vial contains a total of 250 :g of ipratropium bromide. Available is cartons of 10 and 20 vials.
2 mL Unit Dose Vial (125 :g/mL): phl-IPRATROPIUM solution provided as 2 mL of clear, colourless solution containing 125 :g/mL (0.0125%) ipratropium bromide in isotonic solution, presented in a plastic single use vial. Each vial contains a total of 250 :g of ipratropium bromide. Available is cartons of 10 and 20 vials.
2 mL Unit Dose Vial (250 :g/mL): phl-IPRATROPIUM solution provided as 2 mL of clear, colourless solution containing 250 :g/mL (0.025%) ipratropium bromide in isotonic solution, presented in a plastic single use sterule (vial). Each vial contains a total of 500 :g of ipratropium bromide. Available in cartons of 10 and 20 vials.
20 mL Bottle: phl-IPRATROPIUM solution provided as 20 mL of clear, colourless or almost colourless solution containing 250 :g/mL (0.025%) ipratropium bromide in isotonic solution. This solution is preserved with benzalkonium chloride 250 :g/mL and EDTA-disodium 500 :g/mL at a pH of 3.4, and is presented in an amber glass bottle with screwcap.
INFORMATION FOR THE PATIENT
phl-IPRATROPIUM (Ipratropium Bromide) Solution (20 mL Bottle)
PLEASE READ THIS INFORMATION CAREFULLY AND COMPLETELY BEFORE YOU USE phl-IPRATROPIUM
What is phl-IPRATROPIUM Solution (20 mL Bottle)
phl-IPRATROPIUM solution is a bronchodilator which relieves the wheezing and shortness of breath caused by chronic bronchitis or by asthma. For the treatment of asthma, phl-IPRATROPIUM must be used in conjunction with some other bronchodilating medication. phl-IPRATROPIUM contains 250 :g/mL (0.025%) ipratropium bromide and the preservatives benzalkonium chloride and disodium ethylene diamine tetraacetic acid (EDTA-disodium). It is available only on prescription.
Before starting treatment with phl-IPRATROPIUM, be certain that you are completely familiar with the use and proper care of your nebulizer.
What is COPD?
COPD (Chronic Obstructive Pulmonary Disease) is a type of lung disease in which there is permanent narrowing of the airways, leading to breathing difficulties. In many patients, this narrowing of the airways is a result of many years of cigarette smoking. Smoking cessation produces symptomatic benefits and will slow the progression of chronic bronchitis (which is a form of COPD). COPD can be helped by medication as well.
What is Asthma?
Asthma is a disease in which the airways can become temporarily narrowed, leading to breathing difficulties. This narrowing of the airways is due to inflammation, which causes swelling and irritation of the airways and tightening of the muscles around the airways. The narrowed airway can be relieved with the help of medication.
It is important to know that the treatment of COPD and Asthma may be different for each patient. Your doctor will most likely discuss with you the best plan for the treatment of your particular condition. This plan may include taking other medication(s) in addition to phl-IPRATROPIUM. It is necessary that you follow your doctor’s directions for the treatment of your condition. If you have any questions about how you should treat your condition at home, you should consult your doctor.
What you should tell your doctor before you use phl-IPRATROPIUM solution?
It is very important to tell your doctor the following:
< If you may be pregnant or wish to become pregnant;
< If you are breast feeding;
< If you are taking any medications, including those you can buy without a prescription and including eye drops;
< If you have any other medical problems such as difficult urination or enlarged prostate; < If you have eye problems, such as glaucoma or eye pain;
< If you have any special allergies to foods or drugs.
Usage Instructions (20 mL Bottle)
Your doctor or pharmacist will tell you how to prepare your phl-IPRATROPIUM solution for inhalation. If you are told to dilute phl-IPRATROPIUM solution, you must do so immediately before you plan to use the solution.
In most cases, dilution of the dose with sterile preservative-free saline is not necessary. However, volumes of ipratropium bromide solution less than 2 mLs are not appropriate for nebulization and must be diluted with saline or another suitable nebulizer solution to make up a total fill volume of 2-5 mL.
- 1) Immediately before you plan to use the nebulizer, using a syringe, withdraw the prescribed dose (usually ½ to 2 mL [cc]) of phl-IPRATROPIUM solution from the bottle and add to the nebulizer chamber. Do not store the prescribed dose in the syringe for later use.
- 2)
If your doctor has instructed you to use another inhalation solution in combination with phl-
IPRATROPIUM solution, you should add the appropriate amount of that solution to the nebulizer chamber as well.
- 3) Add sodium chloride solution to the chamber, if you have been directed to do so by your physician or pharmacist.
- 4) Gently shake the nebulizer chamber and connect it to the mouthpiece or face mask. Then connect the nebulizer tube to the air or oxygen pump and begin therapy. 5) Breathe calmly and deeply through the mask or mouthpiece until no more mist is formed in the nebulizer chamber. This usually takes 10-15 minutes. It is very important to adjust the face mask, if required, to prevent the mist from getting in your eyes.
- 6) Store your re-capped bottle of phl-IPRATROPIUM solution and sodium chloride solution in the refrigerator until the next treatment.
- 7) Follow the instructions provided by the nebulizer and air pump manufacturers for the proper care and maintenance of the equipment. Keep the nebulizer, nebulizer tube and face mask clean to minimize microbial contamination.
Please Remember
< Do not exceed the prescribed dose or frequency of treatments.
< Do not mix this medication with any other medications in the nebulizer unless instructed to do so by your doctor or pharmacist.
< This medication has been prescribed for you and should not be given to other people.
< Keep out of the reach of children.
< The solution is intended for inhalation only. Do not inject or drink it.
< Do not let the nebulized mist get into your eyes. Patients with glaucoma should use swimming goggles or a nebulizer with a mouthpiece to prevent nebulized solution from getting to the eyes.
As well as its desired effects, phl-IPRATROPIUM solution, like any medication, may cause some unwanted effects.
If you experience a dry mouth or bad taste, sucking on a sour candy or rinsing your mouth may help.
Check with your doctor if the dry mouth or bad taste persists or if you experience constipation.
Consult your doctor immediately if you experience any of the following:
< Increased wheezing or tightness in the chest;
< Swelling of the tongue or lips;
< Difficulty in swallowing;
< Fast or irregular heart beat;
< Blurred vision or pain in the eyes;
< Difficult or painful urination;
< Skin rash.
If you do not get the expected relief from your treatment, you should contact your doctor.
Remember to tell any other doctor, dentist or pharmacist you consult that you are taking this medication.
If you have any questions about phl-IPRATROPIUM solution or your nebulizer, contact your doctor or pharmacist.