Fluticasone Propionate and Salmeterol DISKUS (Page 7 of 13)

8.2 Lactation

Risk Summary

There are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fluticasone Propionate/Salmeterol DISKUS and any potential adverse effects on the breastfed child from Fluticasone Propionate/Salmeterol DISKUS or from the underlying maternal condition.

Data

Animal Data: Subcutaneous administration of tritiated fluticasone propionate at a dose of 10 mcg/kg/day to lactating rats resulted in measurable levels in milk. Oral administration of salmeterol at a dose of 10,000 mcg/kg/day to lactating rats resulted in measurable levels in milk.

8.4 Pediatric Use

Use of fluticasone propionate/salmeterol DISKUS 100/50 mcg in patients aged 4 to 11 years is supported by extrapolation of efficacy data from older subjects and by safety and efficacy data from a trial of fluticasone propionate/salmeterol DISKUS 100/50 mcg in children with asthma aged 4 to 11 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)]. The safety and effectiveness of fluticasone propionate/salmeterol DISKUS in children with asthma younger than 4 years have not been established.

ICS, including fluticasone propionate, a component of Fluticasone Propionate/Salmeterol DISKUS, may cause a reduction in growth velocity in children and adolescents [see Warnings and Precautions (5.14)]. The growth of pediatric patients receiving orally inhaled corticosteroids, including Fluticasone Propionate/Salmeterol DISKUS, should be monitored.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S. in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3^rd percentile = 3.8 cm/year, 50^th percentile = 5.4 cm/year, and 97^th percentile = 7.0 cm/year; girls – 3^rd percentile = 4.2 cm/year, 50^th percentile = 5.7 cm/year, and 97^th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain.

If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including Fluticasone Propionate/Salmeterol DISKUS, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2.1)].

8.5 Geriatric Use

Clinical trials of fluticasone propionate/salmeterol DISKUS for asthma did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects with asthma respond differently than younger subjects.

Of the total number of subjects in clinical trials receiving fluticasone propionate/salmeterol DISKUS for COPD, 1,621 were aged 65 years and older and 379 were aged 75 years and older. Subjects with COPD aged 65 years and older had a higher incidence of serious adverse events compared with subjects younger than 65 years. Although the distribution of adverse events was similar in the 2 age groups, subjects older than 65 years experienced more severe events. In two 1-year trials, the excess risk of pneumonia that was seen in subjects treated with fluticasone propionate/salmeterol DISKUS compared with those treated with salmeterol was greater in subjects older than 65 years than in subjects younger than 65 years [see Adverse Reactions (6.2)]. As with other products containing beta₂ -agonists, special caution should be observed when using Fluticasone Propionate/Salmeterol DISKUS in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta₂ -agonists. Based on available data for fluticasone propionate/salmeterol DISKUS or its active components, no adjustment of dosage of Fluticasone Propionate/Salmeterol DISKUS in geriatric patients is warranted.

No relationship between fluticasone propionate systemic exposure and age was observed in 57 subjects with COPD (aged 40 to 82 years) given 250 or 500 mcg twice daily.

8.6 Hepatic Impairment

Formal pharmacokinetic studies using fluticasone propionate/salmeterol DISKUS have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

8.7 Renal Impairment

Formal pharmacokinetic studies using fluticasone propionate/salmeterol DISKUS have not been conducted in patients with renal impairment.

10 OVERDOSAGE

No human overdosage data has been reported for fluticasone propionate/salmeterol DISKUS.

Fluticasone Propionate/Salmeterol DISKUS contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to Fluticasone Propionate/Salmeterol DISKUS. Treatment of overdosage consists of discontinuation of Fluticasone Propionate/Salmeterol DISKUS together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

10.1 Fluticasone Propionate

Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.8)]. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

10.2 Salmeterol

The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias.

As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of salmeterol.