effect was seen in cultured human peripheral lymphocytes in vitro oin the in vivo mouse micronucleus test.
Fertility and reproductive performance were unaffected in male and female rats at subcutaneousdoses up to 50 mcg/kg (approximately equivalent to the MRHDID for adults on a mcg/m2basis).
Salmeterol:
In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1400 mcg/kg andabove (approximately 240 times the MRHDID on a mcg/m2basis) caused a dose-related increasein the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of theuterus, and ovarian cysts. No tumors were seen at 200 mcg/kg (approximately 35 times theMRHDID on a mcg/m2basis).
In a 24 month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterolcaused a dose related increase in the incidence of mesovarian leiomyomas and ovarian cysts atdoses of 680 mcg/kg and above (approximately 240 times the MRHDID on a mcg/m2basis). Notumors were seen at 210 mcg/kg (approximately 75 times the MRHDID on a mcg/m2basis).
These findings in rodents are similar to those reported previously for other beta adrenergicagonist drugs. The relevance of these findings to human use is unknown.
Salmeterol produced no detectable or reproducible increases in microbial and mammalian genemutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in arat micronucleus test.
Fertility and reproductive performance were unaffected in male and female rats at oral doses upto 2000 mcg/kg (approximately 690 times the MRHDID for adults on a mcg/m2basis).
13.2 Animal Toxicology and/or Pharmacology
Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated theoccurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardialnecrosis) when beta-agonists and methylxanthines are administered concurrently. The clinicalrelevance of these findings is unknown.
14 CLINICAL STUDIES
The safety and efficacy of fluticasone propionate and salmeterol inhalation powder [AIRDUORESPICLICK, hereafter referred to as fluticasone propionate/salmeterol multidose dry powderinhaler (MDPI)] were eva luated in 3004 patients with asthma. The development programincluded 2 confirmatory trials of 12 weeks duration, a 26 week safety trial and three doserangingtrials. The efficacy of AirDuo Digihaler is based primarily on the dose-ranging trials andthe confirmatory trials described below.
14.1 Dose-Ranging Studies in Patients with AsthmaSix doses of fluticasone propionate ranging from 16 mcg to 434 mcg (expressed as metereddoses) administered twice daily via MDPI were eva luated in 2 randomized, double-blind,placebo-controlled 12 week trials in patients with asthma.
Trial 201 was conducted in patients whose asthma was uncontrolled at baseline and hadbeen treated by short-acting beta2-agonist alone or in combination with non-corticosteroidasthma medication. Low dose inhaled corticosteroids (ICS)-treated patients may havebeen included after a minimum of 2 weeks washout. This trial contained an open-labelactive comparator fluticasone propionate inhalation powder 100 mcg administered twicedaily.
Trial 202 was conducted in patients whose asthma was uncontrolled at baseline and hadbeen treated with high dose ICS with or without a LABA. This study contained an openlabelactive comparator fluticasone propionate inhalation powder 250 mcg twice |
