DRUGS & SUPPLEMENTS

Ipratropium Bromide

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Ipratropium Bromide uses


1  INDICATIONS AND USAGE

Ipratropium Bromide is indicated for use inpatients with chronic obstructive pulmonary disease (COPD) on a regularaerosol bronchodilator who continue to have evidence of bronchospasmand who require a second bronchodilator.

Ipratropium Bromide Inhalation Spray is a combinationof an anticholinergic and beta2‑adrenergicagonist indicated for:

  • Patients with chronic obstructive pulmonary disease (COPD)on a regular aerosol bronchodilator who continue to have evidenceof bronchospasm and who require a second bronchodilator (1)

2  DOSAGE AND ADMINISTRATION

The recommended dose of Ipratropium Bromide is one inhalationfour times a day. Patients may take additional inhalations as required;however, the total number of inhalations should not exceed six in24 hours.

Prior to first use, theCOMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMATinhaler and the unit is primed. When using the unit for the firsttime, patients are to actuate the inhaler toward the ground untilan aerosol cloud is visible and then repeat the process three moretimes. The unit is then considered primed and ready for use. Ifnot used for more than 3 days, patients are to actuate the inhaleronce to prepare the inhaler for use. If not used for more than 21 days,patients are to actuate the inhaler until an aerosol cloud is visibleand then repeat the process three more times to prepare the inhalerfor use [see Patient Counseling Information (17)].

Safety and efficacy of additional doses of COMBIVENTRESPIMAT beyond six inhalations/24 hours have not been studied. Also,safety and efficacy of extra doses of Ipratropium Bromide or albuterol inaddition to the recommended doses of Ipratropium Bromide have not beenstudied.

For oral inhalation only

  • One inhalation four times a day, not to exceed six inhalationsin 24 hours (2)
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3  DOSAGE FORMS AND STRENGTHS

Ipratropium Bromide consists of a COMBIVENTRESPIMAT inhaler and an aluminum cylinder (COMBIVENT RESPIMAT cartridge)containing a combination of Ipratropium Bromide bromide (as the monohydrate)and albuterol sulfate. The Ipratropium Bromide cartridge is only intendedfor use with the Ipratropium Bromide inhaler.

Each actuation from the Ipratropium Bromide inhaler delivers20 mcg Ipratropium Bromide bromide (monohydrate) and 100 mcg albuterol (equivalentto 120 mcg albuterol sulfate) from the mouthpiece.

  • Inhalation spray: 20 mcg Ipratropium Bromide bromide (monohydrate)and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) peractuation with the Ipratropium Bromide inhaler (3)

4  CONTRAINDICATIONS

Ipratropium Bromide is contraindicated in the following conditions[ see Warnings and Precautions (5.6) ]:

  • Hypersensitivity to any of the ingredients in COMBIVENTRESPIMAT
  • Hypersensitivity to atropine or any of its derivatives
  • Hypersensitivity to any of the ingredients in COMBIVENTRESPIMAT (4)
  • Hypersensitivity to atropine or any of its derivatives (4)

5  WARNINGS AND PRECAUTIONS

  • Paradoxical bronchospasm: Discontinue COMBIVENT RESPIMATimmediately and treat with alternative therapy if paradoxical bronchospasmoccurs
  • Patients with cardiovascular system disorders: Use withcaution because of beta-adrenergic stimulation (5.2)
  • Ocular effects: Advise patients to avoid spraying into eyesand to contact a physician if blurred vision, halos, or other visualdisturbances occur. Monitor patients with narrow-angle glaucoma. (5.3)
  • Urinary retention: Use with caution in patients with prostatichyperplasia or bladder-neck obstruction (5.4)
  • Hypersensitivity reactions including anaphylaxis: DiscontinueCOMBIVENT RESPIMAT and institute alternative therapy if immediatehypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm,anaphylaxis, or oropharyngeal edema occur (5.6)
  • Coexisting conditions: Use with caution in patients withconvulsive disorders, hyperthyroidism, or diabetes mellitus (5.7)

5.1  Paradoxical Bronchospasm

Ipratropium Bromide can produce paradoxicalbronchospasm that can be life-threatening. If it occurs, therapy withCOMBIVENT RESPIMAT should be discontinued immediately and alternativetherapy instituted.

5.2  Cardiovascular Effect

The albuterol sulfate contained in COMBIVENTRESPIMAT, like other beta‑adrenergic agonists, can produce a clinicallysignificant cardiovascular effect in some patients, as measured bypulse rate, blood pressure, and/or symptoms. If these symptoms occur,COMBIVENT RESPIMAT may need to be discontinued. There is some evidencefrom post-marketing data and published literature of rare occurrencesof myocardial ischemia associated with albuterol. In addition, beta‑adrenergicagonists have been reported to produce electrocardiogram changes,such as flattening of the T wave, prolongation of the QTc interval,and ST segment depression. Therefore, Ipratropium Bromide should beused with caution in patients with cardiovascular disorders; especiallycoronary insufficiency, cardiac arrhythmias, and hypertension [ see Drug Interactions (7.2) ].

5.3  Ocular Effects

Ipratropium Bromide bromide, a component of COMBIVENTRESPIMAT, is an anticholinergic and may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma. Therefore, Ipratropium Bromide should be used with caution in patientswith narrow-angle glaucoma [ see Drug Interactions (7.1) ].

Patients should avoid spraying Ipratropium Bromide intothe eyes. If a patient sprays Ipratropium Bromide into their eyes theymay cause acute eye pain or discomfort, temporary blurring of vision,mydriasis, visual halos, or colored images in association with redeyes from conjunctival or corneal congestion. Advise patients to consulttheir physician immediately if any of these symptoms develop whileusing Ipratropium Bromide.

5.4  Urinary Retention

Ipratropium Bromide bromide, a component of COMBIVENTRESPIMAT, is an anticholinergic and may cause urinary retention. Therefore,caution is advised when administering this medication to patientswith prostatic hyperplasia or bladder-neck obstruction [ see Drug Interactions ].

5.5  Do Not Exceed RecommendedDose

Fatalities havebeen reported in association with excessive use of inhaled sympathomimeticdrugs in patients with asthma. The exact cause of death is unknown,but cardiac arrest following an unexpected development of a severeacute asthmatic crisis and subsequent hypoxia is suspected [ see Drug Interactions (7.2) ].

5.6  HypersensitivityReactions Including Anaphylaxis

Hypersensitivity reactions including urticaria, angioedema,rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occurafter administration of Ipratropium Bromide bromide or albuterol sulfate. In clinical trials and post-marketing experience with ipratropiumcontaining products, hypersensitivity reactions such as skin rash,pruritus, angioedema of tongue, lips and face, urticaria, laryngospasm and anaphylactic reactions have beenreported [ see Adverse Reactions (6.1, 6.2) ]. If such a reaction occurs, therapy with COMBIVENTRESPIMAT should be stopped at once and alternative treatment shouldbe considered [ see Contraindications (4) ].

5.7  Coexisting Conditions

Ipratropium Bromide contains albuterol sulfate,a beta2-adrenergic sympathomimetic amine and,therefore, should be used with caution in patients with convulsivedisorders, hyperthyroidism, or diabetes mellitus, and in patientswho are unusually responsive to sympathomimetic amines.

5.8  Hypokalemia

Beta2‑adrenergicagonists may produce significant hypokalemia in some patients (possiblythrough intracellular shunting) which has the potential to produceadverse cardiovascular effects. The decrease in serum potassium isusually transient, not requiring supplementation [ see Drug Interactions (7.2) ].

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6  ADVERSE REACTIONS

Use of albuterol, a beta2-adrenergic agonist,may be associated with the following:

  • Paradoxical bronchospasm [ see Warningsand Precautions ]
  • Cardiovascular effects [ see Warnings andPrecautions (5.2) ]
  • Hypersensitivity reactions, including anaphylaxis [ see Contraindications (4) and Warnings and Precautions (5.6) ]
  • Hypokalemia [ see Warnings and Precautions (5.8) ]
Albuterol is a component of COMBIVENTRESPIMAT.

Use of Ipratropium Bromide bromide,an anticholinergic, may result in the following:

  • Ocular effects [ see Warnings and Precautions (5.3) ]
  • Urinary retention [ see Warnings and Precautions (5.4) ]
Ipratropium Bromide bromide is a componentof Ipratropium Bromide.

Most common (≥2%) adverse reactions for COMBIVENTRESPIMAT (20/100 mcg) are upper respiratory infection, nasopharyngitis,cough, bronchitis, headache, and dyspnea (6)

 

To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1  Clinical TrialsExperience

COMBIVENT RESPIMAT12-Week Clinical Trials

The safety data described in Table 1 below are derivedfrom one 12-week, randomized, multi-center, double-blind, double-dummy,parallel-group trial that compared Ipratropium Bromide,CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), and ipratropiumbromide delivered by the RESPIMAT inhaler (20 mcg) administered fourtimes a day in 1460 adult COPD patients (955 males and 505 females)40 years of age and older. Of these patients, 486 were treated withCOMBIVENT RESPIMAT. The Ipratropium Bromide group was composed of mostlyCaucasian (88.5%) patients with a mean age of 63.8 years, and a meanpercent predicted FEV1 at screening of 41.5%.Patients with narrow-angle glaucoma, symptomatic prostatic hypertrophyor bladder-neck obstruction were excluded from the trial.

Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates inthe clinical trials of another drug and may not reflect the ratesobserved in practice.

Table 1shows all adverse reactions that occurred with a frequency of ≥2%in the Ipratropium Bromide treatment group in the 12-week COPD trial. The frequency of the corresponding adverse reactions in the CFC-propelledCOMBIVENT Inhalation Aerosol and Ipratropium Bromide bromide delivered bythe RESPIMAT inhaler groups is included for comparison. The ratesare derived from all reported adverse reactions of that type not presentat baseline, whether considered drug-related or not by the clinicalinvestigator.

Body System (Event) 12-Week

Ipratropium-Controlled Trial

  Ipratropium Bromide

(20/100 mcg)

 

CFC-propelled COMBIVENT InhalationAerosol

(36/206 mcg)

Ipratropium Bromide bromide by theRESPIMAT Inhaler

(20 mcg)

  [n=486] [n=491] [n=483]
Patients with any adverse reaction 46 52 45
Respiratory, thoracic and mediastinaldisorders      
         Cough

Dyspnea

 

3

2

2

2

2

3

Nervous system disorders      
    

Headache 3

2

3

Infections and infestations      
  Bronchitis

Nasopharyngitis

Upper Respiratoryinfection

3

4

3

3

3

4

1

4

3

Adverse reactions that occurred in<2% in the Ipratropium Bromide (20/100 mcg) group observed in this12-week trial include: Vascular disorders: hypertension; Nervous system disorders: dizziness and tremor; Musculoskeletaland connective tissue disorder: muscle spasmsand myalgia; Gastrointestinal disorders: diarrhea, nausea, dry mouth, constipation, and vomiting; General disorders and administration site conditions: asthenia, influenza-like illness, and chest discomfort; Eye disorders: eye pain; Metabolism and nutritional disorders: hypokalemia; Cardiac disorders: palpitations andtachycardia; Skin and subcutaneous tissue disorders: pruritus and rash; Respiratory, thoracicand mediastinal disorders ; pharyngolaryngeal painand wheezing.

A separate 12-weektrial evaluated a higher than approved dose of COMBIVENT RESPIMATin 1118 COPD patients. Patients were randomized to COMBIVENT RESPIMAT(40/200 mcg) (n=345), CFC-propelled COMBIVENT Inhalation Aerosol (36/206mcg) (n=180), Ipratropium Bromide delivered by the RESPIMAT (40 mcg) (n=252)or placebo (n=341). The overall incidence and nature of adverse reactionsobserved were similar to the adverse reactions seen with COMBIVENTRESPIMAT 20/100 mcg.

COMBIVENT RESPIMATLong Term (48-week) Safety Trial

Long term chronic use safety data for COMBIVENT RESPIMATwere obtained from one 48-week, randomized, multi-center, open-label,parallel-group trial that compared Ipratropium Bromide (20/100 mcg),CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) and the freecombination of Ipratropium Bromide bromide (34 mcg) and albuterol (180 mcg)HFA inhalation aerosols administered 4 times a day in 465 adult COPDpatients (273 males and 192 females) 40 years of age and older. Ofthese patients, 157 were treated with Ipratropium Bromide. The COMBIVENTRESPIMAT group was composed of mostly Caucasian (93.5%) patients witha mean age of 62.9 years, and a mean percent predicted FEV1 at screening of 47.0%. An evaluation of the safetydata from the trial revealed that most adverse reactions were similarin type and rate between treatment groups. However, cough occurredmore frequently in patients enrolled in the Ipratropium Bromide group(7.0%) compared to those in the CFC-propelled COMBIVENT InhalationAerosol (2.6%) or the free combination of Ipratropium Bromide bromide andalbuterol HFA inhalation aerosols (3.9%) groups.

In addition to the adverse reactions reported in thecontrolled clinical trial with Ipratropium Bromide, adverse reactioninformation concerning CFC-propelled COMBIVENT Inhalation Aerosolis derived from two 12-week controlled clinical trials (N=358 forCFC-propelled COMBIVENT Inhalation Aerosol). Adverse reactions reportedin ≥2% of patients in the CFC-propelled COMBIVENT Inhalation Aerosoltreatment group include: bronchitis, upper respiratory tract infection,headache, dyspnea, cough, pain, respiratory disorder, sinusitis, pharyngitisand nausea. Adverse reactions reported in <2% of patients in theCFC-propelled COMBIVENT Inhalation Aerosol treatment group include:edema, fatigue, hypertension, dizziness, nervousness, tremor, dysphonia,insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation,tachycardia, arthralgia, angina, increased sputum, taste perversion,urinary tract infection, dysuria, dry throat and bronchospasm.

6.2  Post-Marketing Experience

In addition to the adverse reactions reportedduring clinical trials, the following adverse reactions have beenidentified during post approval use of CFC-propelled COMBIVENT InhalationAerosol. Since CFC-propelled Combivent Inhalation Aerosol and CombiventRespimat contain the same active ingredients, one should take intoaccount the fact that the adverse reactions seen with CFC-propelledCombivent Inhalation Aerosol could also occur with Ipratropium Bromide. Because these events are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate theirfrequency or establish a causal relationship to drug exposure.

Eye disorders: glaucoma, blurred vision, mydriasis, conjunctival hyperemia,halo vision, accommodation disorder, ocular irritation and cornealedema

Gastrointestinal disorders : gastrointestinalmotility disorder, drying of secretions, stomatitis and mouth edema

Immune system disorders: hypersensitivity

Investigations: intraocularpressure increased, blood pressure diastolic decreased and blood pressuresystolic increased

Musculoskeletal andconnective tissue disorders : muscular weakness

Psychiatricdisorders: CNS stimulation, mental disorder

Respiratory, thoracic, and mediastinal disorders: throat irritation, paradoxical bronchospasm, wheezing,nasal congestion and pharyngeal edema

Skin and subcutaneous tissue disorders : angioedema, hyperhidrosis, and skinreaction

Urinary disorders: urinary retention

Cardiacdisorders: myocardial ischemia

Allergic-type reactions such as skin reactions includingrash, pruritus, and urticaria (including giant urticaria), angioedemaincluding that of tongue, lips and face, laryngospasm, and anaphylacticreaction have also been reported with CFC-propelled COMBIVENT InhalationAerosol, with positive re-challenge in some cases [ see Warnings and Precautions (5.6) ].

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

Metabolicacidosis has been reported with use of albuterol-containing products.

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7  DRUG INTERACTIONS

Ipratropium Bromide has been used concomitantlywith other drugs, including beta-adrenergic bronchodilators, methylxanthines,and oral and inhaled steroids, commonly used in the treatment of chronicobstructive pulmonary disease. There are no formal studies fully evaluatingthe interaction effects of Ipratropium Bromide and these drugs withrespect to safety and effectiveness.

  • Anticholinergics: May interact additively with concomitantlyused anticholinergic medications. Avoid administration of COMBIVENTRESPIMAT with other anticholinergic-containing drugs
  • Beta-adrenergic agonists: May increase the risk of adversecardiovascular effects. Avoid coadministration of COMBIVENT RESPIMATand other sympathomimetic agents (7.2)
  • Beta-blockers: Inhibit the effect of albuterol. Consideralternative therapy in patients with hyperreactive airways (7.3)
  • Diuretics: Electrocardiographic changes and/or hypokalemiaassociated with diuretics may worsen with concomitant use of beta-agonists. Consider monitoring potassium levels. (7.4)
  • Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants:May potentiate effect of albuterol on the vascular system. Consideralternative therapy in patients taking MAOs or tricyclic antidepressants. (7.5)

7.1  AnticholinergicAgents

There is the potentialfor an additive interaction with concomitantly used anticholinergicmedications. Therefore, avoid coadministration of COMBIVENT RESPIMATwith other anticholinergic-containing drugs as this may lead to anincrease in anticholinergic adverse effects [ seeWarnings and Precautions (5.3, 5.4) ].

7.2  Beta‑adrenergic Agonists

Caution is advised in the coadministration of COMBIVENTRESPIMAT and other sympathomimetic agents due to the increased riskof adverse cardiovascular effects [ see Warningsand Precautions ].

7.3  Beta-receptor BlockingAgents

Beta-receptorblocking agents and albuterol inhibit the effect of each other. Beta-receptorblocking agents should be used with caution in patients with hyperreactiveairways.

7.4  Diuretics

The ECG changes and/or hypokalemia whichmay result from the administration of non‑potassium sparing diuretics can be acutely worsened by beta2-agonists, especially when the recommended dose of thebeta2-agonist is exceeded. Although the clinicalsignificance of these effects is not known, caution is advised inthe coadministration of beta-agonist‑containing drugs, such as COMBIVENTRESPIMAT, with non‑potassium sparing diuretics. Consider monitoringpotassium levels.

7.5  Monoamine OxidaseInhibitors or Tricyclic Antidepressants

Ipratropium Bromide should be administered with extremecaution to patients being treated with monoamine oxidase inhibitorsor tricyclic antidepressants or within 2 weeks of discontinuationof such agents because the action of albuterol on the cardiovascularsystem may be potentiated. Consider alternative therapy in patientstaking MAOs or tricyclic antidepressants [ see Warningsand Precautions (5.2) ].

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8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

TeratogenicEffects: Pregnancy Category C.

Ipratropium Bromide Inhalation Spray
There are no adequate and well-controlled studies ofCOMBIVENT RESPIMAT InhalationSpray, Ipratropium Bromide bromide, or albuterol sulfate, in pregnant women. Animal reproduction studies have not been conducted with COMBIVENTRESPIMAT. However, albuterol sulfate has been shown to be teratogenicin mice and rabbits. Ipratropium Bromide Inhalation Spray should beused during pregnancy only if the potential benefit justifies thepotential risk to the fetus.

Ipratropium Bromide bromide
Oral reproduction studies were performed in mice, rats and rabbitsat doses approximately 340, 68,000 and 17,000 times, respectively,the maximum recommended human daily inhalation dose (MRHDID) in adults(on a mg/m2 basis at maternal doses ineach species of 10, 1000 and 125 mg/kg/day, respectively). Inhalationreproduction studies were conducted in rats and rabbits at approximately100 and 240 times, respectively, the MRHDID in adults (on a mg/m2 basis at maternal doses of 1.5 and 1.8 mg/kg/day,respectively). These studies demonstrated no evidence of teratogeniceffects as a result of Ipratropium Bromide bromide. Embryotoxicity was observedas increased resorption in rats at oral doses approximately 6100 timesMRHDID in adults (on a mg/m2 basis at maternaldoses of 90 mg/kg/day and above). This effect is not considered relevantto human use due to the large doses at which it was observed and thedifference in route of administration.

Albuterol
Albuterolhas been shown to be teratogenic in mice and rabbits. A reproductionstudy in CD-1 mice given albuterol subcutaneously showed cleft palateformation in 5 of 111 fetuses at approximately equivalent tothe MRHDID in adults (on a mg/m2 basisat a maternal dose of 0.25 mg/kg/day) and in 10 of 183 (9.3%) fetusesat approximately 14 times the MRHDID in adults (on a mg/m2 basis at a maternal dose of 2.5 mg/kg/day). Nonewas observed at less than MRHDID in adults (on a mg/m2 basis at a maternal dose of 0.025 mg/kg/day). Cleftpalate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5mg/kg/day isoproterenol (positive control). A reproductive studywith oral albuterol in Stride Dutch rabbits revealed cranioschisisin 7 of 19 (37%) fetuses at approximately 1,100 times the MRHDID inadults (on a mg/m2 basis at a maternaldose of 50 mg/kg/day).

8.2  Labor and Delivery

Because of the potential for beta-agonist interference with uterinecontractility, use of Ipratropium Bromide for the treatment of COPDduring labor should be restricted to those patients in whom the benefitsclearly outweigh the risk.

8.3  Nursing Mothers

It is not known whether the components of Ipratropium Bromide areexcreted in human milk.

Ipratropium Bromide bromide

Because lipid-insolublequaternary cations pass into breast milk, caution should be exercisedwhen Ipratropium Bromide is administered to a nursing mother.

Albuterol

Because of the potentialfor tumorigenicity shown for albuterol in animal studies, a decisionshould be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.

8.4  Pediatric Use

Safetyand effectiveness of Ipratropium Bromide in pediatric patients havenot been established. Ipratropium Bromide is indicated for use in patientswith COPD on a regular aerosol bronchodilator who continue to haveevidence of bronchospasm and who require a second bronchodilator. This disease does not normally occur in children.

8.5  Geriatric Use

Inthe 12-week trial in COPD, 48% of Ipratropium Bromide clinical trialpatients were 65 years of age or over. In general, there were no markeddifferences between the proportion of patients with adverse reactionsfor the Ipratropium Bromide and CFC-propelled COMBIVENT InhalationAerosol treated patients. Cardiac and lower respiratory disordersoccurred less frequently in the patients under the age of 65 and werebalanced across treatment groups.

No overall differences in effectiveness were observed among treatmentgroups. Based on available data, no adjustment of COMBIVENT RESPIMATdosage in geriatric patients is warranted.

10  OVERDOSAGE

The effectsof overdosage are expected to be related primarily to albuterol sulfate. Acute overdosage with Ipratropium Bromide bromide by inhalation is unlikelysince Ipratropium Bromide bromide is not well absorbed systemically afterinhalation or oral administration. Manifestations of overdosage withalbuterol may include anginal pain, hypertension, hypokalemia, tachycardiawith rates up to 200 beats per minute, metabolic acidosis, and exaggerationof the pharmacologic effects listed in the Adverse Reactions section[ see Adverse Reactions (6) ]. As with all beta2-adrenergicagonist aerosol medications, cardiac arrest and even death may beassociated with abuse.

Treatment of overdosage consists of discontinuation of COMBIVENTRESPIMAT together with institution of appropriate medical and supportivetherapy. Dialysis is not appropriate treatment for overdosage of albuterolas an inhalation aerosol; the judicious use of a cardiovascular beta‑receptorblocker, such as metoprolol tartrate may be indicated.

11  DESCRIPTION

Ipratropium Bromide is a combination of ipratropiumbromide (as the monohydrate) and albuterol sulfate.

Ipratropium Bromide bromide is an anticholinergic bronchodilatorchemically described as 8-azoniabicyclo[3.2.1] octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-,bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary ammoniumcompound chemically related to atropine. Ipratropium Bromide bromide is awhite to off-white crystalline substance, freely soluble in waterand methanol, sparingly soluble in ethanol, and insoluble in lipophilicsolvents such as ether, chloroform, and fluorocarbons.

The structural formula is:

C20H30BrNO3-H2O    ipratropium bromide    Mol. Wt. 430.4

Albuterol sulfate, chemically known as (1,3-benzenedimethanol,α'-[[(1,1dimethylethyl) amino] methyl]-4-hydroxy, sulfate (2:1)(salt),(±)- is a relatively selective beta2-adrenergicbronchodilator. Albuterol is the official generic name in the UnitedStates. The World Health Organization recommended name for the drugis salbutamol. Albuterol sulfate is a white to off-white crystallinepowder, freely soluble in water and slightly soluble in alcohol, chloroform,and ether.

The structural formulais:

(C13H21NO3)2-H2SO4    albuterol sulfate    Mol. Wt. 576.7

The drug product, Ipratropium Bromide, iscomposed of a sterile, aqueous solution of Ipratropium Bromide bromide andalbuterol sulfate filled into a 4.5 mL plastic container crimped intoan aluminum cylinder (COMBIVENT RESPIMAT cartridge) for use with theCOMBIVENT RESPIMAT inhaler. Excipients include water for injection,benzalkonium chloride, edetate disodium, and hydrochloric acid. TheCOMBIVENT RESPIMAT cartridge is only intended for use with the COMBIVENTRESPIMAT inhaler. The Ipratropium Bromide inhaler is a hand held, pocketsized oral inhalation device that uses mechanical energy to generatea slow moving aerosol cloud of medication from a metered volume ofthe drug solution. The Ipratropium Bromide inhaler has an orange-coloredcap.

When used with the COMBIVENTRESPIMAT inhaler, each cartridge containing 4 grams of a sterile aqueoussolution delivers the labeled number of metered actuations afterpreparation for use. Each actuation from the Ipratropium Bromide inhalerdelivers 20 mcg Ipratropium Bromide bromide (monohydrate) and 100 mcg albuterol(equivalent to 120 mcg albuterol sulfate) in 11.4 mcL of solutionfrom the mouthpiece. As with all inhaled drugs, the actual amountof drug delivered to the lung may depend on patient factors, suchas the coordination between the actuation of the inhaler and inspirationthrough the delivery system. The duration of inspiration should beat least as long as the spray duration (1.5 seconds).

Prior to first use, the Ipratropium Bromide cartridgeis inserted into the Ipratropium Bromide inhaler and the unit is primed. When using the unit for the first time, patients are to actuate theinhaler toward the ground until an aerosol cloud is visible and thenrepeat the process three more times. The unit is then considered primedand ready for use. If not used for more than 3 days, patients areto actuate the inhaler once to prepare the inhaler for use. If notused for more than 21 days, patients are to actuate the inhaler untilan aerosol cloud is visible and then repeat the process three moretimes to prepare the inhaler for use [ see PatientCounseling Information (17) ].

ipratropium-structure albuterol-structure

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

Ipratropium Bromide: Ipratropium Bromide isa combination of the anticholinergic Ipratropium Bromide bromide and the beta2-adrenergic agonist albuterol sulfate. The mechanismsof action described below for the individual components apply to COMBIVENTRESPIMAT. The two classes of medications are both bronchodilators. Simultaneous administration of both an anticholinergic (ipratropiumbromide) and a beta2-sympathomimetic (albuterolsulfate) is designed to produce a greater bronchodilator effect thanwhen either drug is utilized alone at its recommended dosage. Theefficacy of Ipratropium Bromide is likely to be due to a local effecton the muscarinic and beta2-adrenergic receptorsin the lung.

Ipratropium Bromide bromide

Ipratropium Bromide bromide is an anticholinergic (parasympatholytic)agent which, based on animal studies, appears to inhibit vagally mediatedreflexes by antagonizing the action of acetylcholine, the transmitteragent released at the neuromuscular junctions in the lung. Anticholinergicsprevent the increases in intracellular concentration of Ca++ whichis caused by interaction of acetylcholine with the muscarinic receptorson bronchial smooth muscle.

Albuterol sulfate

In vitro studies and in vivo pharmacology studies have demonstrated that albuterol has a preferentialeffect on beta2-adrenergic receptors comparedwith isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchialsmooth muscle, recent data indicate that there is a population ofbeta2-receptors in the human heart which comprisebetween 10% and 50% of cardiac beta-adrenergic receptors. The precisefunction of these receptors, however, is not yet established [ see Warnings and Precautions ].

Activationof beta2-adrenergic receptors on airway smoothmuscle leads to the activation of adenylyl cyclase and to an increasein the intracellular concentration of cyclic-3',5'-adenosine monophosphate(cyclic AMP). This increase of cyclic AMP leads to the activationof protein kinase, which inhibits the phosphorylation of myosin andlowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the tracheato the terminal bronchioles. Albuterol acts as a functional antagonistto relax the airway irrespective of the spasmogen involved, thus protectingagainst all bronchoconstrictor challenges. Increased cyclic AMP concentrationsare also associated with the inhibition of release of mediators frommast cells in the airway.

Albuterolhas been shown in most clinical trials to have more bronchial smoothmuscle relaxation effect than isoproterenol at comparable doses whileproducing fewer cardiovascular effects. However, all beta‑adrenergicagonist drugs, including albuterol sulfate, can produce a significantcardiovascular effect in some patients [ see Warningsand Precautions (5.2) ].

12.2  Pharmacodynamics

Ipratropium Bromide bromide

Cardiovascular effects

At recommended doses, Ipratropium Bromide bromide does not produce clinicallysignificant changes in pulse rate or blood pressure.

Ocular effects

Instudies without a positive control, Ipratropium Bromide bromide did not alterpupil size, accommodation or visual acuity.

Mucociliary clearance and respiratory secretions

Controlled clinical studies have demonstrated that ipratropiumbromide does not alter either mucociliary clearance or the volumeor viscosity of respiratory secretions.

Albuterol sulfate

Cardiovascular effects

Controlled clinical trials and other clinical experience have shownthat inhaled albuterol, like other beta-adrenergic agonist drugs,can produce a significant cardiovascular effect in some patients,as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographicchanges.

12.3  Pharmacokinetics

Ipratropium Bromide bromide

Ipratropium Bromide bromide is a quaternary amine and hence,it is not readily absorbed into the systemic circulation either fromthe surface of the lung or from the gastrointestinal tract as confirmedby blood level and renal excretion studies.

The half-life of elimination is about 2 hours afterinhalation or intravenous administration. Ipratropium Bromide bromide is minimallybound to plasma albumin and α1-acid glycoprotein. It is partially metabolized to inactiveester hydrolysis products. Following intravenous administration, approximatelyone-half of the dose is excreted unchanged in the urine.

Albuterol sulfate

Albuterol is longer acting than isoproterenol in mostpatients because it is not a substrate for the cellular uptake processesfor catecholamines, nor for metabolism by catechol-O-methyl transferase. Instead, the drug is conjugatively metabolized to albuterol 4'-O-sulfate.

Intravenous pharmacokinetics of albuterolwas studied in a comparable group of 16 healthy male volunteers; themean terminal half-life following a 30-minute infusion of 1.5 mg was3.9 hours with a mean clearance of 439 mL/min/1.73 m2.

Ipratropium Bromide Inhalation Spray

In a 12-week randomized, multicenter, double-blind,double-dummy parallel group trial, 108 US patients with COPD receivingeither Ipratropium Bromide or CFC-propelled COMBIVENTInhalation Aerosol (36/206 mcg) four times daily participated in pharmacokineticevaluations. Plasma Ipratropium Bromide concentrations were low with an averagepeak plasma concentration of 33.5 pg/mL from Ipratropium Bromide. Themajority of the study participants exhibited levels below the lowerlimit of quantitation (<10 pg/mL) by 4 to 6 hours following dosing. The steady state systemic exposure obtained for Ipratropium Bromide bromidefollowing Ipratropium Bromide was comparable to that of CFC-propelledCOMBIVENT Inhalation Aerosol. Ipratropium Bromide plasma AUC and total amountof drug excreted unchanged in urine (Ae) ratios for COMBIVENT RESPIMAT/CFC-propelledCOMBIVENT Inhalation Aerosol were 1.04 and 1.18, respectively. Foralbuterol the steady-state systemic exposure was less from COMBIVENTRESPIMAT compared to that of CFC-propelled COMBIVENT Inhalation Aerosol. Albuterol plasma AUC and urine Ae ratios for COMBIVENT RESPIMAT/CFC-propelledCOMBIVENT Inhalation Aerosol were 0.74 and 0.86, respectively.

Pharmacokinetic drug-drug interaction betweenipratropium bromide and albuterol sulfate was evaluated in a crossoverstudy in 12 healthy male volunteers who received CFC-propelled COMBIVENTInhalation Aerosol and the two active components separately as individualtreatments. Results from this study indicated that the coadministrationof these two components from a single canister did not significantlyalter the systemic absorption of either component, indicating lackof any pharmacokinetic interaction between these two drugs.

Specific Populations

Age

Consistent withCFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), patientsreceiving Ipratropium Bromide (20/100 mcg) aged 65 years and over hadhigher steady state systemic exposures than patients aged under 65years for both Ipratropium Bromide (AUC = 166 vs. 105 pg-hr/mL, Cmax = 38.5 vs. 30.1 pg/mL) and albuterol (AUC = 5.44vs. 3.27 ng-hr/mL, Cmax = 1.19 vs. 0.74 ng/mL).

Gender

The AUC- and Cmax-values for ipratropiumwere 131 pg.hr/mL and 35.4 pg/mL in males and 123 pg.hr/mL and 31.7pg/mL in females, respectively. The AUC- and Cmax-values for albuterol were 4.0 ng-hr/mL and 0.89 ng/mL in males and4.2 ng-hr/mL and 0.93 ng/mL in females, respectively.

Hepatic and Renal Impairment

The pharmacokinetics of Ipratropium Bromide or Ipratropium Bromide bromidehas not been studied in patients with hepatic or renal insufficiency.

Drug-Drug Interactions

No specific pharmacokinetic studies were conducted toevaluate potential drug-drug interactions with other medications.

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

Ipratropium Bromide bromide

Two-year oral carcinogenicity studies in rats and micehave revealed no carcinogenic activity at doses up to 6 mg/kg/day in adults on a mg/m²basis, respectively).

Resultsof various mutagenicity/clastogenicity studies (Ames test, mouse dominantlethal test, mouse micronucleus test, and chromosome aberration ofbone marrow in Chinese hamsters) were negative.

Fertility of male or female rats at oral doses up to50 mg/kg/day (approximately 3400 times the MRHDID in adults on a mg/m²basis) was unaffected by Ipratropium Bromide bromide administration. At anoral dose of 500 mg/kg/day (approximately 34,000 times the MRHDIDin adults on a mg/m² basis), Ipratropium Bromide bromide produced a decreasein the conception rate.

Albuterol

Like other agents in its class, albuterol caused a significant dose-relatedincrease in the incidence of benign leiomyomas of the mesovarium ina 2-year study in the rat at dietary doses of 2, 10, and 50 mg/kg/day(approximately 20, 110, and 560 times the MRHDID on a mg/m² basis).In another study this effect was blocked by the coadministration ofpropranolol. The relevance of these findings to humans is not known. An 18-month study in mice at dietary doses up to 500 mg/kg/day (approximately2800 times the MRHDID on a mg/m² basis) and a 99-week study in hamstersat oral doses up to 50 mg/kg/day (approximately 470 times the MRHDIDon a mg/m² basis) revealed no evidence of tumorigenicity. Studieswith albuterol revealed no evidence of mutagenesis.

Reproduction studies in rats with albuterol sulfaterevealed no evidence of impaired fertility.

14  CLINICAL STUDIES

The efficacy of Ipratropium Bromide (20/100 mcg) was evaluated inCOPD patients in one randomized, double-blind, double-dummy parallelgroup trial. This was a 12-week trial in a total of 1460 adult patients(955 males and 505 females) conducted to demonstrate the efficacyand safety of Ipratropium Bromide (20/100 mcg) in COPD. All patientswere required to have a clinical diagnosis of COPD, be at least 40years of age or older, to have an FEV1 of lessthan or equal to 65% predicted and an FEV1/FVCratio of less than or equal to 0.7 at screening, and a smoking historyof greater than 10 pack-years prior to entering the trial. Patientswith narrow-angle glaucoma, symptomatic prostatic hypertrophy, orbladder neck obstruction were excluded from the trial. The majorityof the patients (89%) were Caucasian, had a mean age of 64 years,a mean percent predicted pre-bronchodilator FEV1 of 41% and FEV1/FVC ratio of 0.45. The patientswere randomized to one of the following active treatments COMBIVENTRESPIMAT (20/100 mcg) (n=486), CFC-propelled COMBIVENT InhalationAerosol (36/206 mcg) (n=491), and Ipratropium Bromide bromide delivered bythe RESPIMAT (20 mcg) (n=483) administered four times a day. Datafrom 1424 patients were used in the efficacy analyses.

There were three primary efficacy variables:(i) Mean FEV1 over 0 to 6 hours post-dose definedas the AUC of the change from test-day baseline in FEV1 over 0 to 6 hours post-dose divided by 6 hours (FEV1 AUC0-6h); (ii) Mean FEV1 over 0 to 4 hours post-dose defined as the AUC of the change fromtest-day baseline in FEV1 over 0 to 4 hourspost-dose divided by 4 hours (FEV1 AUC0-4h), and (iii) Mean FEV1 over4 to 6 hours post-dose defined as the AUC of the change from test-daybaseline in FEV1 over 4 to 6 hours post-dosedivided by 2 hours (FEV1 AUC4-6h). Test-day baseline was the FEV1 recordedprior to inhaling the dose of randomized treatment on test day.

The three primary efficacy comparisons were:(i) Non-inferiority of Ipratropium Bromide (20/100 mcg) to CFC-propelledCOMBIVENT Inhalation Aerosol (36/206 mcg) for the FEV1 AUC0-6h on Test Day 85; (ii) Superiorityof Ipratropium Bromide (20/100 mcg) to Ipratropium Bromide RESPIMAT (20 mcg)for the FEV1 AUC0-4h on Test Day 85, to demonstrate the contribution of albuterol inthe combination product, and (iii) Non-inferiority of COMBIVENT RESPIMAT(20/100 mcg) in comparison to Ipratropium Bromide RESPIMAT (20 mcg) for FEV1 AUC4-6h on Test Day 85, to demonstratethe contribution of Ipratropium Bromide in the combination product. Non-inferioritywas declared if the lower bound of the 95% confidence interval forthe point estimate for the difference of Ipratropium Bromide minusthe comparator was more than -50 mL.

Ipratropium Bromide (20/100 mcg) was shown to be non-inferior to CFC-propelledCOMBIVENT Inhalation Aerosol (36/206 mcg) in terms of mean FEV1 AUC0-6h. The LS mean (mL) (95%CI) of the treatment difference was -3 (-22, 15). The FEV1 AUC0-4h for COMBIVENT RESPIMAT(20/100 mcg), was superior to that of Ipratropium Bromide bromide [LS mean(mL) (95% CI) of the treatment difference was 47 mL (28, 66)] andthe mean FEV1 AUC4-6h for Ipratropium Bromide (20/100 mcg) was non-inferior to that ofipratropium bromide [LS mean (mL) (95% CI) of the treatment differencewas -17 (-39, 5)]. The FEV1 results on TestDays 1, 29, 57, and 85 are shown in Figure 1.

In this trial, Ipratropium Bromide (20/100 mcg) was shownto be clinically comparable (statistically non-inferior) to CFC-propelledCOMBIVENT Inhalation Aerosol (36/206 mcg).

Additionally, in this trial, no differences in theseefficacy comparisons were identified in males and females or in patientsover 65 years of age versus those under 65 years of age. There weretoo few African-American subjects to adequately assess differencesin effects in that population.

The median time to onset of bronchodilation, defined as an FEV1 increase of 15% or greater from test-day baseline,for the Ipratropium Bromide (20/100 mcg) group occurred at 13 minutespost-dose on Day 1.

The means are adjustedfor treatment baseline and investigator site. A separate ANCOVA wasfitted for each time point.

The imputation method fordata missing because the patient withdrew from the trial was LastVisit Carried Forward.

The imputation method for datamissing at the end of test days depends on why the data were missing.

A second study was conducted in 1118 COPDpatients using a higher than approved dose of Ipratropium Bromide. Patients were randomized to Ipratropium Bromide (40/200 mcg) (n=345),CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=180), ipratropiumdelivered by the RESPIMAT (40 mcg) (n=252) or placebo (n= 341). Thestudy was supportive, particularly for safety [ seeAdverse Reactions (6.1) ].

figure-1

16  HOW SUPPLIED/STORAGEAND HANDLING

COMBIVENTRESPIMAT Inhalation Spray is supplied in a carton containing one COMBIVENTRESPIMAT cartridge and one Ipratropium Bromide inhaler.

The Ipratropium Bromide cartridge is providedas an aluminum cylinder with a tamper protection seal on the cap. The Ipratropium Bromide cartridge is only intended for use with theCOMBIVENT RESPIMAT inhaler.

TheCOMBIVENT RESPIMAT inhaler is a cylindrical shaped plastic inhalationdevice with a gray colored body and a clear base. The clear base isremoved to insert the cartridge. The inhaler contains a dose indicator. The orange colored cap and the written information on the label ofthe gray inhaler body indicate that it is labeled for use with theCOMBIVENT RESPIMAT cartridge.

Ipratropium Bromide Inhalation Spray isavailable as:

Ipratropium Bromide Inhalation Spray: 120metered actuations (NDC 0597-0024-02))

The Ipratropium Bromide cartridge has a net fill weightof 4 grams and when used with the Ipratropium Bromide inhaler, is designedto deliver the labeled number of  metered actuations after preparationfor use. Each actuation from the Ipratropium Bromide inhaler delivers20 mcg Ipratropium Bromide bromide (monohydrate) and 100 mcg albuterol (equivalentto 120 mcg albuterol sulfate) from the mouthpiece.

When the labeled number of metered actuations has beendispensed from the inhaler, the RESPIMAT locking mechanism will beengaged and no more actuations can be dispensed.

After assembly, the Ipratropium Bromide inhaler shouldbe discarded at the latest 3 months after first use or when the lockingmechanism is engaged, whichever comes first.

Keep out of reach of children. Do not spray into eyes.

Storage

Store at 25°C(77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Avoid freezing.

17  PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patientlabeling (Instructions for Use)

Paradoxical Bronchospasm

Inform patientsthat Ipratropium Bromide can produce paradoxical bronchospasm thatcan be life-threatening. If paradoxical bronchospasm occurs, patientsshould discontinue using Ipratropium Bromide.

Ocular Effects

Caution patients to avoid sprayingthe aerosol into their eyes and be advised that this may result inprecipitation or worsening of narrow‑angle glaucoma, mydriasis, increasedintraocular pressure, acute eye pain or discomfort, temporary blurringof vision, visual halos or colored images in association with redeyes from conjunctival and corneal congestion. Patients should alsobe advised that should any combination of these symptoms develop,they should consult their physician immediately.

Since dizziness, accommodation disorder,mydriasis, and blurred vision may occur with use of Ipratropium Bromide,patients should be cautioned about engaging in activities requiringbalance and visual acuity such as driving a car or operating appliancesor machinery.

Urinary Retention

Inform patients that COMBIVENT RESPIMATmay cause urinary retention and should be advised to consult theirphysician if they experience difficulty with urination.

Adverse Effects Associatedwith Beta2-agonists

Inform patients of adverse effectsassociated with beta2-agonists, such as palpitations,chest pain, rapid heart rate, tremor, or nervousness.

Frequency of Use

The action of COMBIVENT RESPIMATshould last 4 to 5 hours or longer. Ipratropium Bromide should notbe used more frequently than recommended. Safety and efficacy ofadditional doses of Ipratropium Bromide beyond six inhalations in 24 hourshave not been studied. Patients should be told not to increase thedose or frequency of Ipratropium Bromide without consulting a physician. Patients should be instructed that if they find that treatment withCOMBIVENT RESPIMAT becomes less effective for symptomatic relief,their symptoms become worse, and/or they need to use the product morefrequently than usual, medical attention should be sought immediately.

Concomitant DrugUse

Remindpatients that while taking Ipratropium Bromide, other inhaled drugsshould be taken only as directed by a physician.

Pregnancy

Patients who are pregnant ornursing should contact their physician about the use of COMBIVENTRESPIMAT.

Preparation for Use and Priming

Instruct patients that priming COMBIVENTRESPIMAT is essential to ensure appropriate content of the medicationin each actuation.

When using the unit for the first time, the Ipratropium Bromide cartridgeis inserted into the Ipratropium Bromide inhaler and the unit is primed. Ipratropium Bromide patients are to actuate the inhaler toward theground until an aerosol cloud is visible and then repeat the processthree more times. The unit is then considered primed and ready foruse. If not used for more than 3 days, patients are to actuate theinhaler once to prepare the inhaler for use. If not used for morethan 21 days, patients are to actuate the inhaler until an aerosolcloud is visible and then repeat the process three more times to preparethe inhaler for use.

Distributedby:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Address medical inquiries to: (800) 542-6257 or 800 459-9906 TTY.

RESPIMAT® is a registeredtrademark of and used under license from Boehringer Ingelheim InternationalGmbH

COMBIVENT® is a registered trademark of BoehringerIngelheim Pharmaceuticals, Inc.

Copyright © 2016 Boehringer Ingelheim InternationalGmbH

ALL RIGHTS RESERVED

OT24008IF132016

304000-04

Instructionsfor Use

COMBIVENT® RESPIMAT® (COM beh vent - RESpeh mat)

(ipratropium bromide and albuterol)

inhalation spray

For Oral Inhalation Only

Do not spray Ipratropium Bromide into your eyes

Read these Instructions forUse before you start using Ipratropium Bromide and each time you geta refill. There may be new information. This leaflet does not takethe place of talking to your doctor about your medical condition oryour treatment.

Use Ipratropium Bromide exactly as prescribed by your doctor. Do not change your dose or how often you use Ipratropium Bromide withouttalking with your doctor.

Tell your doctor about all of themedicines you take. Ipratropium Bromide may affect the way somemedicines work and some other medicines may affect the way COMBIVENTRESPIMAT works. Do not use other inhaled medicines with COMBIVENTRESPIMAT without talking to your doctor.

The Ipratropium Bromide inhaler has a slowmoving mist that helps you inhale the medicine.

Do not turn the clear base beforeinserting the cartridge.

  • Store Ipratropium Bromide at room temperature 68°F to 77°F(20°C to 25°C).
  • Do not freeze your Ipratropium Bromide cartridge and inhaler.
  • If Ipratropium Bromide has not been used for more than 3days, release 1 puff towards the ground.
  • If Ipratropium Bromide has not been used for more than 21days, repeat steps 4 to 6 under the “Prepare for first use” untila mist is visible. Then repeat steps 4 to 6 three more times.
  • Keep your Ipratropium Bromide cartridge and inhaler out ofthe reach of children.
How to care foryour Ipratropium Bromide inhaler

Clean the mouthpiece, including the metalpart inside the mouthpiece, with a damp cloth or tissue only, at leastonce a week. Any minor discoloration in the mouthpiece does not affectyour Ipratropium Bromide inhaler.

When to get a new COMBIVENT RESPIMATinhaler

  • Your inhaler contains 120 puffs (120 doses); or if you havea sample, your inhaler contains 60 puffs (60 doses) instead.
  • The dose indicator shows approximately how much medicineis left.
  • When the dose indicator enters the red area of the scaleyou need to get a refill; there is approximately medicine for 7 daysleft (if you have a sample, there is approximately medicine for 3days left).
  • When the dose indicator reaches the end of the red scale,your Ipratropium Bromide is empty and automatically locks. At thispoint, the clear base cannot be turned any further.
  • Three months after insertion of cartridge, throw away theCOMBIVENT RESPIMAT even if it has not been used, or when the inhaleris locked, or when it expires, whichever comes first.
1. Removeclear base
  • Keep the cap closed.
  • Press the safety catch while firmly pulling off the clearbase with your other hand. Be careful not to touch the piercing element.
  • Write the discard by date on the label (3 months from thedate the cartridge is inserted).
2. Insertcartridge
  • Insert the narrow end of the cartridge into the inhaler.
  • Place the inhaler on a firm surface and push down firmlyuntil it clicks into place.
3. Replaceclear base
  • Put the clear base back into place until it clicks.
  • Do not remove the clear base or the cartridge after it hasbeen put together.
4. Turn
  • Keep the cap closed.
  • Turn the clear base in the direction of the arrows on thelabel until it clicks (half a turn).
5. Open
  • Open the cap until it snaps fully open.
6. Press
  • Point the inhaler toward the ground.
  • Press the dose-release button.
  • Close the cap.
  • If you do not see a mist, repeat steps 4 to 6 until a mistis seen.
  • After a mist is seen, Repeat steps 4 to 6 three moretimes.
  • After complete preparation of your inhaler, it will be readyto deliver the number of puffs on the label.

Daily use (T O P)

Turn
  • Keep the cap closed.
  • Turn the clear base in the direction of thearrows on the label until it clicks (half a turn).
Open
  • OPEN the cap until it snaps fully open.
Press
  • Breathe out slowly and fully.
  • Close your lips around the mouthpiece without covering theair vents.
  • Point the inhaler to the back of your throat.
  • While taking a slow, deep breath through your mouth, Press the dose-release button and continue to breathe in.
  • Hold your breath for 10 seconds or for as long as comfortable.
  • Close the cap until you use your inhaler again.
Answers to CommonQuestions

It is difficult to insert the cartridge deep enough:

Didyou accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release button, then insert the cartridge.

Did you insert the cartridgewith the wide end first? Insert the cartridge with the narrowend first.

I cannot press the dose-release button:

Did you turn the clearbase? If not, turn the clear base in a continuous movementuntil it clicks (half a turn).

Is the dose indicator on the COMBIVENTRESPIMAT pointing to zero?

The COMBIVENT RESPIMATinhaler is locked after 120 puffs (120 doses). If you have a sample,the Ipratropium Bromide inhaler is locked after 60 puffs (60 doses).Prepare and use your new Ipratropium Bromide inhaler.

I cannot turn the clearbase:

Did you turn the clear base already? If the clear basehas already been turned, follow steps “Open” and “Press” under “Dailyuse” to get your medicine.

Is the dose indicator on the COMBIVENTRESPIMAT pointing to zero? The Ipratropium Bromide inhaler islocked after 120 puffs (120 doses). If you have a sample, the COMBIVENTRESPIMAT inhaler is locked after 60 puffs (60 doses). Prepare anduse your new Ipratropium Bromide inhaler.

The dose indicator on theCOMBIVENT RESPIMAT reaches zero too soon:

Did you use COMBIVENT RESPIMATas indicated (1 puff four times daily)? COMBIVENT RESPIMATwill deliver 120 puffs and last 30 days if used at 1 puff four timesdaily. If you have a sample, Ipratropium Bromide will deliver 60 puffsand last 15 days if used at 1 puff four times daily.

Did you turn the clear base beforeyou inserted the cartridge? The dose indicator counts eachturn of the clear base regardless whether a cartridge has been insertedor not.

Did youspray in the air often to check whether the Ipratropium Bromide isworking? Once you have prepared Ipratropium Bromide, no test-sprayingis required if used daily.

Did you insert the cartridge into aused Ipratropium Bromide? Always insert a new cartridge intoa NEW Ipratropium Bromide.

My Ipratropium Bromide spraysautomatically:

Was the cap open when you turned theclear base? Close the cap, then turn the clear base.

Did you press the dose-releasebutton when turning the clear base? Close the cap, so the dose-releasebutton is covered, then turn the clear base.

Did you stop when turning the clearbase before it clicked? Turn the clear base in a continuous movement until it clicks (half a turn).

My COMBIVENTRESPIMAT doesn’t spray:

Did you insert a cartridge? If not, insert a cartridge.

Did you repeat Turn, Open, Press (TOP)less than three times after inserting the cartridge? Repeat Turn, Open, Press (TOP) three times after inserting the cartridge as shown insteps 4 to 6 under “Prepare for first use”.

Is the dose indicator on the COMBIVENTRESPIMAT pointing to 0? You have used up all your medicineand the inhaler is locked.

For more information about COMBIVENT RESPIMATor a video demonstration on how to use Ipratropium Bromide, go to www.combivent.com, or scan the code below. You may alsocall 1-800-542-6257 or (TTY) 1-800-459-9906 for further informationabout Ipratropium Bromide.

This Instructions forUse has been approved by the U.S. Food and Drug Administration.

Distributed by: Boehringer IngelheimPharmaceuticals, Inc., Ridgefield, CT 06877 USA

RESPIMAT® is a registered trademark of andused under license from Boehringer Ingelheim International GmbH

COMBIVENT® is a registered trademarkof Boehringer Ingelheim Pharmaceuticals, Inc.

Copyright© 2016 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

Revised: June 2016

OT24008IF132016

304000-04

combivent-respimat-do-not-turn combivent-respimat-dose-indicator combivent-respimat-qr-code combivent-respimat-1 combivent-respimat-2 combivent-respimat-3 combivent-respimat-4 combivent-respimat-5 combivent-respimat-6 combivent-respimat-turn combivent-respimat-open combivent-respimat-press COMBIVENT RESPIMAT(ipratropium bromide and albuterol) Inhalation Spray

NDC:0597-0024-02

Carton Label

Cartridge Label

Inhaler Front

Inhaler Back

carton cartridge inhaler inhaler-120 COMBIVENT RESPIMAT(ipratropium bromide and albuterol) Inhalation Spray

NDC:0597-0024-59

Professional Sample

Carton Label

Cartridge Label

Inhaler Front

Inhaler Back

Sample Carton cartridge-sample inhaler-sample inhaler-600

Ipratropium Bromide pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Ipratropium Bromide available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.

Price
Apo-Ipravent 250 mcg/ml Solution0.58 USD
Atrovent 0.03 % Spray1.04 USD
Atrovent 0.03% Solution 30ml Nasal Spray96.95 USD
Atrovent 0.03% spray3.11 USD
Atrovent 0.06% Solution 15ml Nasal Spray84.68 USD
Atrovent 0.06% spray5.33 USD
Atrovent HFA 17 mcg/act Aerosol 12.9 gm Inhaler143.59 USD
Atrovent Hfa 20 mcg/dose Metered Dose Aerosol0.1 USD
Atrovent hfa inhaler11.89 USD
Injectable; Injection; Ipratropium Bromide 0.25 mg / ml
Injectable; Injection; Ipratropium Bromide 0.5 mg / ml
Ipratropium 0.03% spray1.73 USD
Ipratropium 0.06% spray2.96 USD
Ipratropium Bromide 0.02% Solution Each Box Contains Twenty-Five 2.5ml Vials45.86 USD
Ipratropium Bromide 0.03% Solution 30ml Bottle53.82 USD
Ipratropium Bromide 0.06% Solution 15ml Bottle46.14 USD
Ipratropium bromide powder100.06 USD
Mylan-Ipratropium 250 mcg/ml Solution0.58 USD
Novo-Ipramide 250 mcg/ml Solution0.58 USD
Pms-Ipratropium 0.03 % Spray0.58 USD
Pms-Ipratropium 250 mcg/ml Solution0.58 USD
Solution; Inhalation; Ipratropium Bromide 0.02%
Solution; Inhalation; Ipratropium Bromide 0.025%
Solution; Nasal; Ipratropium Bromide 0.03%
Solution; Nasal; Ipratropium Bromide 0.06%
Spray, Metered-Dose; Nasal; Ipratropium Bromide 0.021 mg / dose
Spray, Metered-Dose; Nasal; Ipratropium Bromide 0.042 mg / dose

Ipratropium Bromide destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Ipratropium Bromide Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Ipratropium Bromide pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."IPRATROPIUM BROMIDE SOLUTION [WATSON LABORATORIES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ALBUTEROL SULFATE; IPRATROPIUM BROMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "ipratropium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Ipratropium Bromide?

Depending on the reaction of the Ipratropium Bromide after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ipratropium Bromide not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Ipratropium Bromide addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Ipratropium Bromide, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Ipratropium Bromide consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

One visitor reported side effects

Did you get side effects while taking the Ipratropium Bromide drug, or were there no side effects?
According to the survey conducted by website sDrugs.com users, the below-mentioned percentages indicate the number of people experiencing the side effects and the number of people not experiencing the side effects when taking Ipratropium Bromide medicine. Every drug produces minimal side effects, and they are negligible most times, when compared to the desired effect [use] of the medicine. Side effects depend on the dose you are taking, any drug interactions that happen when you are on other medications, if the patient is sensitive, and other associated conditions. If you cannot tolerate the side effects, consult your doctor immediately, so he can either adjust the dose or change the medication.
Visitors%
It has side effects1
100.0%

One visitor reported price estimates

What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sDrugs.com website users shows the following figures about several people who felt the medicine Ipratropium Bromide is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
Visitors%
Not expensive1
100.0%

One visitor reported frequency of use

How often in a day do you take the medicine?
Are you taking the Ipratropium Bromide drug as prescribed by the doctor?

Few medications can be taken 3 times in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sDrugs.com website users about the frequency of taking the drug Ipratropium Bromide is mentioned below.
Visitors%
3 times in a day1
100.0%

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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