ALBUTEROL SULFATE (Page 3 of 5)

Pregnancy Teratogenic Effects

Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg of isoproterenol (positive control).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at 50 mg/kg dose (approximately 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

In an inhalation reproduction study in SPRAGUE-DAWLEY rats, the albuterol sulfate/HFA-134a formulation did not exhibit any teratogenic effects at 10.5 mg/kg (approximately 70 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

There are no adequate and well-controlled studies of Albuterol sulfate inhalation aerosol or albuterol sulfate in pregnant women. Albuterol sulfate inhalation aerosol 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 reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, 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 inhalation aerosol 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 pulmonary edema, have been reported during or following treatment of premature labor with beta₂ -agonists, including albuterol.

Nursing Mothers

Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of Albuterol sulfate inhalation aerosol are excreted in human milk.

Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of Albuterol sulfate inhalation aerosol by nursing mothers, 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. Caution should be exercised when albuterol sulfate is administered to a nursing woman.

Pediatrics

The safety and effectiveness of Albuterol sulfate inhalation aerosol in pediatric patients below the age of 4 years have not been established.

Geriatrics

Albuterol sulfate inhalation aerosol has not been studied in a geriatric population. As with other beta₂ -agonists, special caution should be observed when using Albuterol sulfate inhalation aerosol in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug.

ADVERSE REACTIONS

Adverse reaction information concerning Albuterol sulfate inhalation aerosol is derived from a 12‑week, double-blind, double-dummy study which compared Albuterol sulfate inhalation aerosol, a CFC 11/12 propelled albuterol inhaler, and an HFA-134a placebo inhaler in 565 asthmatic patients. The following table lists the incidence of all adverse events (whether considered by the investigator drug related or unrelated to drug) from this study which occurred at a rate of 3% or greater in the Albuterol sulfate inhalation aerosol treatment group and more frequently in the Albuterol sulfate inhalation aerosol treatment group than in the placebo group. Overall, the incidence and nature of the adverse reactions reported for Albuterol sulfate inhalation aerosol and a CFC 11/12 propelled albuterol inhaler were comparable.

Adverse Experience Incidences (% of patients) in a Large 12-week Clinical Trial^*

* This table includes all adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of at least 3.0% in the Albuterol sulfate inhalation aerosol group and more frequently in the Albuterol sulfate inhalation aerosol group than in the HFA-134a placebo inhaler group.
Body System/ Adverse Event (Preferred Term)		Albuterol Sulfate Inhalation Aerosol (N=193)	CFC 11/12 Propelled Albuterol Inhaler (N=186)	HFA-134a Placebo Inhaler (N=186)
Application Site Disorders	Inhalation Site Sensation	6	9	2
	Inhalation Taste Sensation	4	3	3
Body as a Whole	Allergic Reaction/Symptoms	6	4	<1
	Back Pain	4	2	3
	Fever	6	2	5
Central and Peripheral Nervous System	Tremor	7	8	2
Gastrointestinal System	Nausea	10	9	5
	Vomiting	7	2	3
Heart Rate and Rhythm Disorder	Tachycardia	7	2	<1
Psychiatric Disorders	Nervousness	7	9	3
Respiratory System Disorders	Respiratory Disorder (unspecified)	6	4	5
	Rhinitis	16	22	14
	Upper Resp Tract Infection	21	20	18
Urinary System Disorder	Urinary Tract Infection	3	4	2

Adverse events reported by less than 3% of the patients receiving Albuterol sulfate inhalation aerosol, and by a greater proportion of Albuterol sulfate inhalation aerosol patients than placebo patients, which have the potential to be related to Albuterol sulfate inhalation aerosol include: dysphonia, increased sweating, dry mouth, chest pain, edema, rigors, ataxia, leg cramps, hyperkinesia, eructation, flatulence, tinnitus, diabetes mellitus, anxiety, depression, somnolence, rash. Palpitation and dizziness have also been observed with Albuterol sulfate inhalation aerosol.

Adverse events reported in a 4-week pediatric clinical trial comparing Albuterol sulfate inhalation aerosol and a CFC 11/12 propelled albuterol inhaler occurred at a low incidence rate and were similar to those seen in the adult trials.

In small, cumulative dose studies, tremor, nervousness, and headache appeared to be dose related.

Rare cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema have been reported after the use of inhaled albuterol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, insomnia, headache, metabolic acidosis, and drying or irritation of the oropharynx.

To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch