VENTOLIN HFA (Page 2 of 5)

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of albuterol sulfate. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to albuterol or a combination of these factors.

Cases of paradoxical bronchospasm, hoarseness, arrhythmias (including atrial fibrillation, supraventricular tachycardia), and hypersensitivity reactions (including urticaria, angioedema, rash) have been reported after the use of VENTOLIN HFA.

In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypokalemia, hypertension, peripheral vasodilatation, angina, tremor, central nervous system stimulation, hyperactivity, sleeplessness, headache, muscle cramps, drying or irritation of the oropharynx, and metabolic acidosis.

7 DRUG INTERACTIONS

Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

7.1 Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as VENTOLIN HFA, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.2 Non–Potassium-Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non‑potassium-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 VENTOLIN HFA with non–potassium-sparing diuretics.

7.3 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 relevance of these findings for patients with obstructive airway disease who are receiving inhaled 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.

7.4 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

VENTOLIN HFA 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with VENTOLIN HFA or albuterol sulfate in pregnant women. 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. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. VENTOLIN HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking VENTOLIN HFA.

In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at exposures less than the maximum recommended human daily inhalation dose (MRHDID) for adults on a mg/m2 basis and in 10 of 108 (9.3%) fetuses at approximately 8 times the MRHDID. Similar effects were not observed at approximately one eleventh of the MRHDID. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

In a rabbit reproduction study, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 680 times the MRHDID.

In another rabbit study, an albuterol sulfate/HFA-134a formulation administered by inhalation produced enlargement of the frontal portion of the fetal fontanelles at approximately one third of the MRHDID.

Nonteratogenic Effects: 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.

8.2 Labor and Delivery

There are no well-controlled human trials that have investigated effects of VENTOLIN HFA on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

8.3 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 VENTOLIN HFA 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 VENTOLIN HFA 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 VENTOLIN HFA is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of VENTOLIN HFA in children aged 4 years and older have been established based upon two 12-week clinical trials in subjects aged 12 years and older with asthma and one 2-week clinical trial in subjects aged 4 to 11 years with asthma [see Adverse Reactions (6.1), Clinical Studies (14.1)]. The safety and effectiveness of VENTOLIN HFA in children younger than 4 years have not been established. Three trials have been conducted to evaluate the safety and efficacy of VENTOLIN HFA in subjects younger than 4 years and the findings are described below.

Two 4-week randomized, double-blind, placebo-controlled trials were conducted in 163 pediatric subjects aged from birth to 48 months with symptoms of bronchospasm associated with obstructive airway disease (presenting symptoms included: wheeze, cough, dyspnea, or chest tightness). VENTOLIN HFA or placebo HFA was delivered with either an AeroChamber Plus® Valved Holding Chamber or an Optichamber® Valved Holding Chamber with mask 3 times daily. In one trial, VENTOLIN HFA 90 mcg (n = 26), VENTOLIN HFA 180 mcg (n = 25), and placebo HFA (n = 26) were administered to children aged between 24 and 48 months. In the second trial, VENTOLIN HFA 90 mcg (n = 29), VENTOLIN HFA 180 mcg (n = 29), and placebo HFA (n = 28) were administered to children aged between birth and 24 months. Over the 4-week treatment period, there were no treatment differences in asthma symptom scores between the groups receiving VENTOLIN HFA 90 mcg, VENTOLIN HFA 180 mcg, and placebo in either trial.

In a third trial, VENTOLIN HFA was evaluated in 87 pediatric subjects younger than 24 months for the treatment of acute wheezing. VENTOLIN HFA was delivered with an AeroChamber Plus Valved Holding Chamber in this trial. There were no significant differences in asthma symptom scores and mean change from baseline in an asthma symptom score between VENTOLIN HFA 180 mcg and VENTOLIN HFA 360 mcg.

In vitro dose characterization studies were performed to evaluate the delivery of VENTOLIN HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers with masks (small and medium size). The in vitro study data when simulating patient breathing suggest that the dose of VENTOLIN HFA presented for inhalation via a valved holding chamber with mask will be comparable to the dose delivered in adults without a spacer and mask per kilogram of body weight (Table 2). However, clinical trials in children younger than 4 years described above suggest that either the optimal dose of VENTOLIN HFA has not been defined in this age-group or VENTOLIN HFA is not effective in this age-group. The safety and effectiveness of VENTOLIN HFA administered with or without a spacer device in children younger than 4 years have not been demonstrated.

Table 2. In Vitro Medication Delivery through AeroChamber Plus® Valved Holding Chamber with a Mask

Age

Mask

Flow Rate (L/min)

Holding Time (seconds)

Mean Medication Delivery through AeroChamber Plus (mcg/actuation)

Body Weight 50th Percentile (kg)a

Medication Delivered per Actuation (mcg/kg)b

6 to 12 Months

Small

4.9

0

2

5

10

18.2

19.8

13.8

15.4

7.5-9.9

1.8-2.4

2.0-2.6

1.4-1.8

1.6-2.1

2 to 5 Years

Small

8.0

0

2

5

10

17.8

16.0

16.3

18.3

12.3-18.0

1.0-1.4

0.9-1.3

0.9-1.3

1.0-1.5

2 to 5 Years

Medium

8.0

0

2

5

10

21.1

15.3

18.3

18.2

12.3-18.0

1.2-1.7

0.8-1.2

1.0-1.5

1.0-1.5

>5 Years

Medium

12.0

0

2

5

10

26.8

20.9

19.6

20.3

18.0

1.5

1.2

1.1

1.1

a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50 th percentile weight for boys and girls at the ages indicated.
b A single inhalation of VENTOLIN HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 90 mcg, or 1.3 mcg/kg.

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