Wixela Inhub - Use fluticasone propionate and salmeterol

The use of Wixela™ Inhub™ is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions (5.2)].
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients [see Warnings and Precautions (5.11), Adverse Reactions (6.3), Description (11)].

risk summary

There are insufficient data on the use of fluticasone propionate and salmeterol inhalation powder or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women. There are clinical considerations with the use of fluticasone propionate and salmeterol inhalation powder in pregnant women (see Clinical Considerations). In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m2 basis (see Data). However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m2 basis (see Data). Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 50 times the MRHDID on an AUC basis. These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures. No such effects occurred at an oral salmeterol dose approximately 20 times the MRHDID (see Data).

The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

clinical considerations

Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma.

labor & delivery

There are no human studies evaluating the effects of fluticasone propionate and salmeterol inhalation powder during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of Wixela™ Inhub™ during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

data

human data

fluticasone propionate

Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

animal data

fluticasone propionate & salmeterol

In an embryofetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,000; 30/0; 10/100; 30/1,000; and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Omphalocele, increased embryofetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses in the presence of maternal toxicity when combining fluticasone propionate at a dose approximately equivalent to the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and salmeterol at a dose approximately 970 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed when combining fluticasone propionate at a dose approximately 0.3 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and salmeterol at a dose approximately 100 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1,000 mcg/kg/day).

In an embryofetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,400; 40/0; 10/200; 40/1,400; or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 0.7 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 490 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.2 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 70 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1,400 mcg/kg).

fluticasone propionate

In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat NOAEL was observed at approximately 0.3 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.2 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.07 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.25 times the MRHDID (on a mcg/m2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.05 times the MRHDID (on a mcg/m2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.012 times the MRHDID and higher (on a mcg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.08 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.002 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.5 times the MRHDID (on a mcg/m² basis with maternal subcutaneous doses up to 50 mcg/kg/day).

salmeterol

In 3 embryofetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. In pregnant Dutch rabbits administered salmeterol doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1,000 mcg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 600 mcg/kg/day). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,000 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 10,000 mcg/kg/day).

In 2 embryofetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. Salmeterol produced no maternal toxicity or embryofetal effects at doses up to 973 times the MRHDID (on a mcg/m² basis at maternal oral doses up to 10,000 mcg/kg/day).

In a peri- and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 973 times the MRHDID (on a mcg/m² basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors.

Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.

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 Wixela™ Inhub™ and any potential adverse effects on the breastfed child from Wixela™ Inhub™ 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.

Use of fluticasone propionate and salmeterol inhalation powder 100 mcg/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 and salmeterol inhalation powder 100 mcg/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 and salmeterol inhalation powder in children with asthma younger than 4 years have not been established.

ICS, including fluticasone propionate, a component of Wixela™ Inhub™, 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 Wixela™ Inhub™, 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 Wixela™ Inhub™, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2.1)].

Clinical trials of fluticasone propionate and salmeterol inhalation powder 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 and salmeterol inhalation powder 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 and salmeterol inhalation powder 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 Wixela™ Inhub™ in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta₂-agonists. Based on available data for fluticasone propionate and salmeterol inhalation powder or its active components, no adjustment of dosage of Wixela™ Inhub™ 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.

Formal pharmacokinetic studies using fluticasone propionate and salmeterol inhalation powder 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.

Formal pharmacokinetic studies using fluticasone propionate and salmeterol inhalation powder have not been conducted in patients with renal impairment.