ALBUTEROL SULFATE- albuterol sulfate syrup

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

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Active ingredient:
ALBUTEROL SULFATE (UNII: 021SEF3731) (ALBUTEROL - UNII:QF8SVZ843E)
Available from:
QUAGEN PHARMACEUTICALS LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Albuterol Sulfate Syrup is indicated for the relief of bronchospasm in adults and children 2 years of age and older with reversible obstructive airway disease. Albuterol Sulfate Syrup is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.
Product summary:
Albuterol Sulfate Syrup, 2 mg/5 mL, a clear, yellow liquid with a strawberry flavor, contains 2 mg of albuterol (present as the sulfate) per 5 mL in bottles of 16 fluid ounces (one pint) (NDC 70752-102-12). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Authorization status:
Abbreviated New Drug Application
Authorization number:
70752-102-12

ALBUTEROL SULFATE- albuterol sulfate syrup

QUAGEN PHARMACEUTICALS LLC

----------

Albuterol Sulfate Syrup, 2 mg/5 mL

Rx only

DESCRIPTION

Albuterol Sulfate Syrup contains albuterol sulfate, USP, the racemic form of albuterol and a relatively

selective beta -adrenergic bronchodilator. Albuterol sulfate has the chemical name α -[(tert-

butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt) and the following chemical

structure:

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

alcohol, in chloroform, and in ether per USP definition.

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

Albuterol Sulfate Syrup for oral administration contains 2 mg of albuterol as 2.4 mg of albuterol sulfate

in each teaspoonful (5 mL). Albuterol Sulfate Syrup also contains the inactive ingredients Citric Acid,

FD&C Yellow No. 6, Hypromellose, Purified Water, Sodium Benzoate, Sodium Citrate, Sorbitol

Solution and Strawberry Flavor. The pH of the syrup is 3.5 to 4.5.

CLINICAL PHARMACOLOGY

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, data indicate that there

is a population of beta -receptors in the human heart existing in a concentration between 10% and 50%.

The precise function of these receptors has not been established (see WARNINGS).

The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part

attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme

that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate

(cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle

and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast

cells.

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.

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.

Preclinical

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood

brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma

concentrations. In structures outside the brain barrier (pineal and pituitary glands), albuterol

concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac

arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and

methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Pharmacokinetics

Albuterol is rapidly absorbed after oral administration of 10 mL of albuterol sulfate syrup (4 mg of

albuterol) in normal volunteers. Maximum plasma concentrations of about 18 ng/mL of albuterol are

achieved within 2 hours, and the drug is eliminated with a half-life of about 5 hours.

In other studies, the analysis of urine samples of patients given 8 mg of tritiated albuterol orally showed

that 76% of the dose was excreted over three days, with the majority of the dose being excreted within

the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite. Feces collected

over this period contained 4% of the administered dose.

Clinical Trials

In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as

measured by maximum midexpiratory flow rate (MMEF) and forced expiratory volume in 1 second

(FEV ), was within 30 minutes after a dose of albuterol sulfate syrup, with peak improvement occurring

between 2 and 3 hours. In a controlled clinical trial involving 55 children, clinically significant

improvement (defined as maintaining a 15% or more increase in FEV and a 20% or more increase in

MMEF over baseline values) continued to be recorded up to 6 hours. No decrease in the effectiveness

was reported in one uncontrolled study of 32 children who took albuterol sulfate syrup for a 3-month

period.

INDICATIONS AND USAGE

Albuterol Sulfate Syrup is indicated for the relief of bronchospasm in adults and children 2 years of age

and older with reversible obstructive airway disease.

CONTRAINDICATIONS

Albuterol Sulfate Syrup is contraindicated in patients with a history of hypersensitivity to albuterol or

any of its components.

WARNINGS

Cardiovascular Effects

Albuterol Sulfate Syrup, like all other beta-adrenergic agonists, can produce a clinically significant

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

Although such effects are uncommon after administration of albuterol sulfate syrup at recommended

doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported

to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the

QTc interval, and ST segment depression. The clinical significance of these findings is unknown.

Therefore, Albuterol Sulfate Syrup, like all sympathomimetic amines, should be used with caution in

patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and

hypertension.

Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If

the patient needs more doses of albuterol sulfate syrup than usual, this may be a marker of

destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special

consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

Paradoxical Bronchospasm

Albuterol Sulfate Syrup can produce paradoxical bronchospasm, which may be life threatening. If

paradoxical bronchospasm occurs, albuterol sulfate syrup should be discontinued immediately and

alternative therapy instituted.

Use of Anti-Inflammatory Agents

The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many

patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids.

Immediate Hypersensitivity Reactions

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

rare cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema. Albuterol, like

other beta-adrenergic agonists, can produce a significant cardiovascular effect in some patients, as

measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the

administration of albuterol sulfate in children.

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. Clinically significant changes in systolic and

diastolic blood pressure have been seen in individual patients and could be expected to occur in some

patients after use of any beta-adrenergic bronchodilator.

Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and

ketoacidosis. As with other beta-agonists, 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.

Information for Patients

The action of albuterol sulfate syrup may last up to 6 hours or longer. Albuterol Sulfate Syrup should

not be taken more frequently than recommended. Do not increase the dose or frequency of albuterol

sulfate syrup without consulting your physician. If you find that treatment with albuterol sulfate syrup

becomes less effective for symptomatic relief, your symptoms get worse, and/or you need to take the

product more frequently than usual, you should seek medical attention immediately. While you are taking

albuterol sulfate syrup, other asthma medications and inhaled drugs should be taken only as directed by

your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, and tremor or

nervousness. If you are pregnant or nursing, contact your physician about use of albuterol sulfate syrup.

Effective and safe use of albuterol sulfate syrup includes an understanding of the way that it should be

administered.

Drug Interactions

The concomitant use of albuterol sulfate syrup and other oral sympathomimetic agents is not

recommended since such combined use may lead to deleterious cardiovascular effects. This

recommendation does not preclude the judicious use of an aerosol bronchodilator of the adrenergic

stimulant type in patients receiving albuterol sulfate syrup. Such concomitant use, however, should be

individualized and not given on a routine basis. If regular coadministration is required, then alternative

therapy should be considered.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Albuterol should be administered

with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic

antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on

the vascular system may be potentiated.

Beta-Blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-

agonists, such as albuterol sulfate syrup, but may produce severe bronchospasm in asthmatic patients.

Therefore, patients with asthma should not normally be treated with beta-blockers. However, under

certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable

alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting,

cardioselective beta-blockers could be considered, although they should be administered with caution.

Diuretics: The ECG changes and/or hypokalemia that may result from the administration of

nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-

agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical

significance of these effects is not known, caution is advised in the coadministration of beta-agonists

with nonpotassium-sparing diuretics.

Digoxin: Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose

intravenous and oral administration of albuterol, respectively, to normal volunteers who had received

digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway

disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would

be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving

digoxin and albuterol.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in

the incidence of benign leiomyomas of the mesovarium at dietary doses of 2.0, 10, and 50 mg/kg

(approximately 1/2, 2, and 10 times, respectively, the maximum recommended daily oral dose for adults

and children, on a mg/m basis). In another study this effect was blocked by the coadministration of

propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice albuterol

sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 60

times the maximum recommended daily oral dose for adults and children on a mg/m basis). In a 22-

month study in the Golden hamster albuterol sulfate showed no evidence of tumorigenicity at dietary

doses of up to 50 mg/kg (approximately 8 times the maximum recommended daily oral dose for adults

and children on a mg/m basis).

Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester

strains S. typhimurium TA1537, TA1538, and TA98 or E. coli WP2, WP2uvrA, and WP67. No forward

mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S.

cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E.

coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a

human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal

doses of up to 200 mg/kg.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg

(approximately 15 times the maximum recommended daily oral dose for adults on a mg/m basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses

of 0.025, 0.25, and 2.5 mg/kg (approximately 3/1000, 3/100, and 3/10, respectively, the maximum

recommended daily oral dose for adults on a mg/m basis), 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. The drug did not induce cleft

palate formation at the lowest dose, 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses

from females treated with 2.5 mg/kg of isoproterenol (positive control) subcutaneously (approximately

3/10 times the maximum recommended daily oral dose for adults on a mg/m basis).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when

albuterol was administered orally at a 50 mg/kg dose (approximately 25 times the maximum

recommended daily oral dose for adults on a mg/m basis).

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.

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.

Use in Labor and Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of albuterol sulfate

syrup for relief of bronchospasm during labor should be restricted to those patients in whom the

benefits clearly outweigh the risk.

Tocolysis: Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio

when albuterol is administered for tocolysis has not been established. Serious adverse reactions,

including maternal pulmonary edema, have been reported during or following treatment of premature

labor with beta -agonists, including albuterol.

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

Safety and effectiveness in children below 2 years of age have not been established.

ADVERSE REACTIONS

In clinical trials, the most frequent adverse reactions to albuterol sulfate syrup in adults and older

children were:

Percent Incidence of Adverse Reactions in Adults

and

Children (6-14 Years of Age)

Reaction

Percent Incidence

Central nervous system

Tremor

Nervousness

Shakiness

Headache

Dizziness

Hyperactivity

Excitement

Sleeplessness

Disturbed sleep

<1%

Irritable behavior

<1%

Dilated pupils

<1%

Weakness

<1%

Cardiovascular

Tachycardia

Palpitations

<1%

Sweating

<1%

Chest pain

<1%

Ear, nose, and throat

Epistaxis

Gastrointestinal

Increased appetite

Epigastric pain

<1%

Stomachache

<1%

Musculoskeletal

Muscle spasm

<1%

Respiratory

Cough

<1%

In clinical trials, the following adverse reactions to albuterol sulfate syrup were noted more frequently

in young children 2 to 6 years of age than in older children and adults:

Percent Incidence of Adverse Reactions Noted

More

Frequently in Children 2 to 6 Years of Age Than in

Older

Children and Adults

Reaction

Percent Incidence

Central nervous system

Excitement

Nervousness

Hyperkinesia

Sleeplessness

Emotional lability

Fatigue

Cardiovascular

Tachycardia

Pallor

Gastrointestinal

Gastrointestinal

symptoms

Loss of Appetite

Ophthalmologic

Conjunctivitis

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

(including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the

use of albuterol sulfate syrup.

In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as

hypertension, angina, vomiting, vertigo, central nervous system stimulation, unusual taste, and drying or

irritation of the oropharynx.

The reactions are generally transient in nature, and it is usually not necessary to discontinue treatment

with albuterol sulfate syrup. In selected cases, however, dosage may be reduced temporarily; after the

reaction has subsided, dosage should be increased in small increments to the optimal dosage.

OVERDOSAGE

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or

occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g.,

seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute,

arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise,

and sleeplessness. Hypokalemia may also occur. As with all sympathomimetic medications, cardiac

arrest and even death may be associated with abuse of albuterol sulfate syrup. Treatment consists of

discontinuation of albuterol sulfate syrup together with appropriate symptomatic therapy. The judicious

use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication

can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for

overdosage of albuterol sulfate syrup.

The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 240

times the maximum recommended daily oral dose for adults and children on a mg/m basis). In mature

rats the subcutaneous (sc) median lethal dose of albuterol sulfate is approximately 450 mg/kg

(approximately 110 times the maximum recommended daily oral dose for adults and children on a mg/m

basis). In small young rats the oral median lethal dose is approximately 2000 mg/kg (approximately 480

times the maximum recommended daily oral dose for adults and children on a mg/m basis).

DOSAGE AND ADMINISTRATION

The following dosages of albuterol sulfate syrup are expressed in terms of albuterol base.

Usual Dosage

Adults and Children Over 14 Years of Age: The usual starting dosage for adults and children over 14

years of age is 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day.

Children Over 6 Years to 14 Years of Age: The usual starting dosage for children over 6 years to 14

years of age is 2 mg (1 teaspoonful) three or four times a day.

Children 2 to 5 Years of Age: Dosing in children 2 to 5 years of age should be initiated at 0.1 mg/kg of

body weight three times a day. This starting dosage should not exceed 2 mg (1 teaspoonful) three times

a day.

Dosage Adjustment

Adults and Children Over 14 Years of Age: For adults and children over 14 years of age, a dosage

above 4 mg four times a day should be used only when the patient fails to respond. If a favorable

response does not occur with the 4-mg initial dosage, it should be cautiously increased stepwise up to a

maximum of 8 mg four times a day as tolerated.

Children Over 6 Years to 14 Years of Age Who Fail to Respond to the Initial Starting Dosage of 2 mg

Four Times a Day: For children over 6 years to 14 years of age who fail to respond to the initial

starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to

exceed 24 mg/day (given in divided doses).

Children 2 to 5 Years of Age Who Do Not Respond Satisfactorily to the Initial Dosage: For children from

2 to 5 years of age who do not respond satisfactorily to the initial starting dosage, the dosage may be

increased stepwise to 0.2 mg/kg of body weight three times a day, but not to exceed a maximum of 4 mg

(2 teaspoonfuls) given three times a day.

Elderly Patients and Those Sensitive to Beta-adrenergic Stimulators: The initial dosage should be

restricted to 2 mg three or four times a day and individually adjusted thereafter.

HOW SUPPLIED

Albuterol Sulfate Syrup, 2 mg/5 mL, a clear, yellow liquid with a strawberry flavor, contains 2 mg of

albuterol (present as the sulfate) per 5 mL in bottles of 16 fluid ounces (one pint) (NDC 70752-102-12).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as

required).

Manufactured by:

Quagen Pharmaceuticals LLC

West Caldwell, NJ 07006

52004

Rev. 09/19

PRINCIPAL DISPLAY PANEL

NDC 70752-102-12

Albuterol

Sulfate Syrup

2 mg/5 mL

16 fl. oz. (473 mL)

Rx only

ALBUTEROL SULFATE

albuterol sulfate syrup

Product Information

QUAGEN PHARMACEUTICALS LLC

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:70 752-10 2

Route of Administration

ORAL

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 mg in 5 mL

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

WATER (UNII: 0 59 QF0 KO0 R)

SO DIUM BENZO ATE (UNII: OJ245FE5EU)

TRISO DIUM CITRATE DIHYDRATE (UNII: B22547B9 5K)

SO RBITO L (UNII: 50 6 T6 0 A25R)

Product Characteristics

Color

S core

S hap e

S iz e

Flavor

STRAWBERRY

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:70 752-10 2-12

473 mL in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA21219 7

0 9 /0 6 /20 19

Labeler -

QUAGEN PHARMACEUT ICALS LLC (073645339)

Registrant -

QUAGEN PHARMACEUT ICALS LLC (073645339)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

QUAGEN PHARMACEUTICALS LLC

0 8 0 28 1331

MANUFACTURE(70 752-10 2) , PACK(70 752-10 2)

Revised: 9/2019

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