ALBUTEROL SULFATE- albuterol sulfate solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ALBUTEROL SULFATE (UNII: 021SEF3731) (ALBUTEROL - UNII:QF8SVZ843E)
Available from:
Sandoz Inc.
INN (International Name):
ALBUTEROL SULFATE
Composition:
ALBUTEROL 2.5 mg in 3 mL
Administration route:
RESPIRATORY (INHALATION)
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 2 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm. Albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to any of its components.
Product summary:
Unit-dose plastic vial containing Albuterol Sulfate Inhalation Solution 0.083%, 2.5 mg/3 mL 2. Equivalent to 0.5 mL albuterol (as the sulfate) 0.5% (2.5 mg albuterol) diluted to 3 mL. Supplied in cartons as listed below. NDC 0781-7155-86 carton of 25 vials. NDC 0781-7155-64 carton of 30 vials. NDC 0781-7155-29 carton of 60 vials. PROTECT FROM LIGHT. Store in pouch until time of use. Store between 2° and 25° C (36° and 77° F).
Authorization status:
Abbreviated New Drug Application
Authorization number:
0781-7155-29, 0781-7155-64, 0781-7155-86

ALBUTEROL SULFATE- albuterol sulfate solution

Sandoz Inc.

----------

Albuterol Sulfate Inhalation Solution 0.083%

PRESCRIBING INFORMATION

FOR INHALATION USE ONLY-NOT FOR INJECTION.

DESCRIPTION

Albuterol sulfate inhalation solution is a relatively selective beta

-adrenergic bronchodilator (see

CLINICAL PHARMACOLOGY section below). Albuterol sulfate, the racemic form of albuterol, has

the chemical name α

-[( tert-Butylamino)methyl]-4-hydroxy- m-xylene-α,α'-diol sulfate (2:1) (salt), and

the following structural formula:

Albuterol sulfate has a molecular weight of 576.70 and the molecular formula (C

H

. Albuterol sulfate is a white or practically white powder, freely soluble in water and slightly

soluble in alcohol.

The World Health Organization recommended name for albuterol base is salbutamol.

Albuterol sulfate inhalation solution 0.083% requires no dilution before administration.

Each milliliter of albuterol sulfate inhalation solution 0.083% contains 0.83 mg of albuterol (as 1 mg of

albuterol sulfate) in an isotonic, sterile, aqueous solution containing sodium chloride; sulfuric acid is

used to adjust the pH to between 3 and 5. Albuterol sulfate inhalation solution 0.083% contains no

sulfiting agents or preservatives.

Albuterol sulfate inhalation solution is a clear, colorless to light yellow solution.

CLINICAL PHARMACOLOGY

The prime action of beta-adrenergic drugs is to stimulate adenyl cyclase, the enzyme which catalyzes

the formation of cyclic-3',5'-adenosine monophosphate (cyclic AMP) from adenosine triphosphate

(ATP). The cyclic AMP thus formed mediates the cellular responses. In vitro studies and in vivo

pharmacologic studies have demonstrated that albuterol has a preferential effect on beta

-adrenergic

receptors compared with isoproterenol. While it is recognized that beta

-adrenergic receptors are the

predominant receptors in bronchial smooth muscle, 10% to 50% of the beta-receptors in the human heart

may be beta

-receptors. The precise function of these receptors, however, is not yet established.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract

in the form of bronchial smooth muscle relaxation than isoproterenol at comparable doses while

producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have

shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant

(Potency expressed as albuterol, equivalent to 3 mg albuterol sulfate)

cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or

electrocardiographic changes.

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is

not a substrate for the cellular uptake processes for catecholamines nor for catechol-O-methyl

transferase.

Studies in asthmatic patients have shown that less than 20% of a single albuterol dose was absorbed

following IPPB (intermittent positive-pressure breathing) or nebulizer administration; the remaining

amount was recovered from the nebulizer and apparatus and expired air. Most of the absorbed dose was

recovered in the urine 24 hours after drug administration. Following a 3 mg dose of nebulized

albuterol, the maximum albuterol plasma level at 0.5 hour was 2.1 ng/mL (range 1.4 to 3.2 ng/mL). There

was a significant dose-related response in FEV

(forced expiratory volume in one second) and peak

flow rate. It has been demonstrated that following oral administration of 4 mg albuterol, the elimination

half-life was five to six hours.

Animal studies show that albuterol does not pass the blood-brain barrier. Recent studies in laboratory

animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death

(with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were

administered concurrently. The significance of these findings when applied to humans is currently

unknown.

In controlled clinical trials, most patients exhibited an onset of improvement in pulmonary function

within 5 minutes as determined by FEV

. FEV

measurements also showed that the maximum average

improvement in pulmonary function usually occurred at approximately 1 hour following inhalation of 2.5

mg of albuterol by compressor-nebulizer, and remained close to peak for 2 hours. Clinically significant

improvement in pulmonary function (defined as maintenance of a 15% or more increase in FEV

over

baseline values) continued for 3 to 4 hours in most patients and in some patients continued up to 6 hours.

In repetitive dose studies, continued effectiveness was demonstrated throughout the three-month period

of treatment in some patients.

Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant

improvement in either FEV

or PEFR within 2 to 20 minutes following single dose of albuterol

inhalation solution. An increase of 15% or more in baseline FEV

has been observed in children aged 5

to 11 years up to 6 hours after treatment with doses of 0.10 mg/kg or higher of albuterol inhalation

solution. Single doses of 3, 4, or 10 mg resulted in improvement in baseline PEFR that was comparable

to extent and duration to a 2 mg dose, but doses above 3 mg were associated with heart rate increases of

more than 10%.

INDICATIONS AND USAGE

Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 2 years of

age and older with reversible obstructive airway disease and acute attacks of bronchospasm.

CONTRAINDICATIONS

Albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to

any of its components.

WARNINGS

As with other inhaled beta-adrenergic agonists, albuterol sulfate inhalation solution can produce

paradoxical bronchospasm, which can be life threatening. If it occurs, the preparation should be

discontinued immediately and alternative therapy instituted.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs and

with the home use of nebulizers. It is, therefore, essential that the physician instruct the patient in the

need for further evaluation, if his/her asthma becomes worse. In individual patients, any beta

adrenergic agonist, including albuterol solution for inhalation, may have a clinically significant cardiac

effect.

Immediate hypersensitivity reactions may occur after administration of albuterol as demonstrated by rare

cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema.

PRECAUTIONS

General

Albuterol, as with all sympathomimetic amines, should be used with caution in patients with

cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension, in

patients with convulsive disorders, hyperthyroidism or diabetes mellitus and in patients who are

unusually responsive to sympathomimetic amines.

Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and

ketoacidosis. As with other beta-agonists, inhaled and intravenous albuterol may produce significant

hypokalemia in some patients, possibly through intracellular shunting, which has the potential to

produce adverse cardiovascular effects. The decrease is usually transient, not requiring

supplementation.

Repeated dosing with 0.15 mg/kg of albuterol inhalation solution in children aged 5 to 17 years who

were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum

potassium levels.

Information for Patients

The action of albuterol sulfate inhalation solution may last up to six hours, and therefore it should not

be used more frequently than recommended. Do not increase the dose or frequency of medication

without medical consultation. If symptoms get worse, medical consultation should be sought promptly.

While taking albuterol sulfate inhalation solution, other anti-asthma medicines should not be used unless

prescribed.

Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution

when mixed with other drugs in a nebulizer have not been established.

See illustrated " Patient's Instructions for Use."

Drug Interactions

Other sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with

albuterol.

Albuterol should be administered with extreme caution to patients being treated with monoamine

oxidase inhibitors or tricyclic antidepressants, since the action of albuterol on the vascular system may

be potentiated.

Beta-receptor blocking agents and albuterol inhibit the effect of each other.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of

the mesovarium in a 2-year study in the rat, at oral doses of 2, 10, and 50 mg/kg corresponding to 10, 50

and 250 times, respectively, the maximum nebulization dose for a 50 kg human. In another study, this

effect was blocked by the coadministration of propranolol. The relevance of these findings to humans is

not known. An 18-month study in mice and a lifetime study in hamsters revealed no evidence of

tumorigenicity. Studies with albuterol revealed no evidence of mutagenesis. Reproduction studies in

rats revealed no evidence of impaired fertility.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Albuterol has been shown to be teratogenic in mice when given subcutaneously in doses corresponding

to 1.25 times the human nebulization dose (based on a 50 kg human). There are no adequate and well-

controlled studies in pregnant women. Albuterol should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus. A reproduction study in CD-1 mice with albuterol (0.025,

0.25, and 2.5 mg/kg subcutaneously, corresponding to 0.125, 1.25 and 12.5 times the maximum human

nebulization dose, respectively) showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg

and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. None were observed at 0.025 mg/kg. Cleft palate also

occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoproterenol (positive control). A

reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg,

corresponding to 250 times the maximum nebulization dose for a 50 kg human.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb

defects, have been rarely reported in the offspring of patients being treated with albuterol. Some of the

mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can

be discerned, and a relationship between albuterol use and congenital anomalies has not been

established.

Labor and Delivery

Oral albuterol has been shown to delay preterm labor in some reports. There are presently no well-

controlled studies that demonstrate that it will stop preterm labor or prevent labor at term. Therefore,

cautious use of albuterol sulfate inhalation solution is required in pregnant patients when given for

relief of bronchospasm so as to avoid interference with uterine contractibility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity

shown for albuterol in some animal studies, a decision should be made whether to discontinue nursing

or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of albuterol sulfate inhalation solution have been established in children 2

years of age or older. Use of albuterol sulfate inhalation solution in these age groups is supported by

evidence from adequate and well-controlled studies of albuterol sulfate inhalation solution in adults; the

likelihood that the disease course, pathophysiology, and the drug's effect in pediatric and adult patients

are substantially similar; and published reports of trials in pediatric patients 3 years of age or older. The

recommended dose for the pediatric population is based upon three published dose comparison studies

of efficacy and safety in children aged 5 to 17 years, and on the safety profile in both adults and

pediatric patients at doses equal to or higher than the recommended doses. The safety and effectiveness

of albuterol sulfate inhalation solution in children below 2 years of age have not been established.

ADVERSE REACTIONS

Clinical Trial Experience

The results of clinical trials with albuterol sulfate inhalation solution in 135 patients showed the

following side effects which were considered probably or possibly drug related:

Central Nervous System: tremors (20%), dizziness (7%), nervousness (4%), headache (3%), insomnia

(1%).

Gastrointestinal: nausea (4%), dyspepsia (1%).

Ear, Nose and Throat: pharyngitis (<1%), nasal congestion (1%).

Cardiovascular: tachycardia (1%), hypertension (1%).

Respiratory: bronchospasm (8%), cough (4%), bronchitis (4%), wheezing (1%).

No clinically relevant laboratory abnormalities related to albuterol sulfate inhalation solution

administration were determined in these studies.

In comparing the adverse reactions reported for patients treated with albuterol sulfate inhalation

solution with those of patients treated with isoproterenol during clinical trials of three months, the

following moderate to severe reactions, as judged by the investigators, were reported. This table does

not include mild reactions.

Percent Incidence of Moderate to Severe Adverse Reactions

Reaction

Albuterol

N=65

Is oproterenol

N=65

Central Nervous System

Tremors

10.7%

13.8%

Headache

3.1%

1.5%

Insomnia

3.1%

1.5%

Cardiovas cular

Hypertension

3.1%

3.1%

Arrhythmias

Palpitation

Res piratory

Bronchospasm

15.4%

Cough

3.1%

Bronchitis

1.5%

Wheeze

1.5%

1.5%

Sputum Increase

1.5%

1.5%

Dyspnea

1.5%

1.5%

Gas trointes tinal

Nausea

3.1%

Dyspepsia

1.5%

Sys temic

Malaise

1.5%

Post-Marketing Experience

The finding of no arrhythmias and no palpitations after

albuterol administration in this clinical study should not

be interpreted as indicating that these adverse effects

cannot occur after the administration of inhaled

albuterol.

In most cases of bronchospasm, this term was generally

used to describe exacerbations in the underlying

pulmonary disease.

Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias

(including atrial fibrillations, supraventricular tachycardia, extrasystoles) and metabolic acidosis have

been reported after the use of albuterol sulfate inhalation solution. Because these reactions are reported

voluntarily from a population of uncertain size, it is not always possible to reliably estimate their

frequency or establish a causal relationship to drug exposure.

OVERDOSAGE

Manifestations of overdosage may include seizures, anginal pain, hypertension, hypokalemia,

tachycardia with rates up to 200 beats/min, and exaggeration of the pharmacological effects listed in

ADVERSE REACTIONS. In isolated cases in children 2 to 12 years of age, tachycardia with rates

>200 beats/min has been observed.

The oral LD

in rats and mice was greater than 2,000 mg/kg. The inhalational LD

could not be

determined.

There is insufficient evidence to determine if dialysis is beneficial for overdosage of albuterol

inhalation solution.

DOSAGE AND ADMINISTRATION

Adults and Children 2 to 12 Years of Age

The usual dosage for adults and for children weighing at least 15 kg is 2.5 mg of albuterol (one vial)

administered three to four times daily by nebulization. Children weighing < 15 kg who require < 2.5

mg/dose (i.e., less than a full vial) should use albuterol inhalation solution, 0.5% instead of albuterol

inhalation solution, 0.083%. More frequent administration or higher doses are not recommended. To

administer 2.5 mg of albuterol, administer the entire contents of one sterile unit dose vial (3 mL of

0.083% inhalation solution) by nebulization. The flow rate is regulated to suit the particular nebulizer

so that albuterol inhalation solution will be delivered over approximately 5 to 15 minutes.

The use of albuterol sulfate inhalation solution can be continued as medically indicated to control

recurring bouts of bronchospasm. During this time most patients gain optimum benefit from regular use

of the inhalation solution.

If a previously effective dosage regimen fails to provide the usual relief, medical advice should be

sought immediately, as this is often a sign of seriously worsening asthma which would require

reassessment of therapy.

HOW SUPPLIED

Unit-dose plastic vial containing Albuterol Sulfate Inhalation Solution 0.083%, 2.5 mg/3 mL

Equivalent to 0.5 mL albuterol (as the sulfate) 0.5% (2.5 mg albuterol) diluted to 3 mL. Supplied in

cartons as listed below.

NDC 0781-7155-86 carton of 25 vials.

NDC 0781-7155-64 carton of 30 vials.

NDC 0781-7155-29 carton of 60 vials.

Storage

PROTECT FROM LIGHT. Store in pouch until time of use. Store between 2° and 25° C (36° and 77°

(Potency expressed as albuterol, equivalent to 3 mg albuterol sulfate)

Rx only.

Manufactured by: The Ritedose

Corporation, Columbia, SC 29203 for

Sandoz Inc., Princeton, NJ 08540

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

RPIN0055

April 2014

Patient's Instructions for Use

Albuterol Sulfate Inhalation Solution 0.083% .

Note: This is a unit-dose vial. No dilution is required.

Read complete instructions carefully before using.

1. Remove the vial from the foil pouch.

2. Twist the cap completely off the vial and squeeze the contents into the nebulizer reservoir (Figure

3. Connect the nebulizer reservoir to the mouthpiece or face mask (Figure 2).

4. Connect the nebulizer to the compressor.

5. Sit in a comfortable, upright position; place the mouthpiece in your mouth (Figure 3) (or put on the

face mask); and turn on the compressor.

6. Breathe as calmly, deeply and evenly as possible until no more mist is formed in the nebulizer

chamber (about 5 to 15 minutes). At this point, the treatment is finished.

7. Clean the nebulizer (see manufacturer's instructions).

Note: Use only as directed by your physician. More frequent administration or higher doses are

not recommended.

Store Albuterol Sulfate Inhalation Solution 0.083%* between 2° and 25° C (36° and 77° F). Store

in pouch until time of use.

ADDITIONAL INSTRUCTIONS: ___________________________________________

________________________________________________________________________

Manufactured by: The Ritedose Corporation,

Columbia, SC 29203 for

Sandoz, Inc. Princeton, NJ 08540

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

RPIN0055

April 2014

PRINCIPAL DISPLAY PANEL - 30 Vial Carton

NDC 0781-7155-86

Albuterol Sulfate

Inhalation Solution, 0.083%*

2.5 mg / 3 mL*

*Potency expressed as albuterol, equivalent to 3 mg albuterol sulfate.

Each mL contains 1 mg albuterol sulfate, equivalent to 0.83 mg albuterol in an

aqueous solution containing sodium chloride and sulfuric acid to adjust pH

between 3 and 5. Contains no preservatives.

Please consult your physician before use. Do not exceed recommended dosage.

Usual Dosage: See package insert. Protect from light.

Store between 2° and 25° C (36° and 77° F). Discard if solution becomes

discolored.

(Note: Albuterol Sulfate Inhalation Solution is a clear, colorless to light yellow

solution).

Rx only

25 x 3 mL Sterile unit-Dose Vials

SANDOZ

(Potency expressed as albuterol, equivalent to 3 mg albuterol sulfate)

ALBUTEROL SULFATE

albuterol sulfate solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 78 1-7155

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ALBUTERO L SULFATE (UNII: 0 21SEF3731) (ALBUTEROL - UNII:QF8 SVZ8 43E)

ALBUTEROL

2.5 mg in 3 mL

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 78 1-7155-8 6

1 in 1 CARTON

0 8 /17/20 11

1

25 in 1 POUCH

1

3 mL in 1 AMPULE; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:0 78 1-7155-6 4

1 in 1 CARTON

0 8 /17/20 11

2

30 in 1 POUCH

2

3 mL in 1 AMPULE; Type 0 : No t a Co mbinatio n Pro duct

3

NDC:0 78 1-7155-29

2 in 1 CARTON

0 8 /17/20 11

Sandoz Inc.

3

30 in 1 POUCH

3

3 mL in 1 AMPULE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 778 39

0 8 /17/20 11

Labeler -

Sandoz Inc. (110342024)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

The Ritedo se Co rpo ratio n

8 3776 9 546

manufacture(0 78 1-7155) , label(0 78 1-7155) , pack(0 78 1-7155) , analysis(0 78 1-7155)

Revised: 12/2017

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