Salbutamol / Beclomethasone dipropionate

Pregnancy

[Salbutamol] Inhaled salbutamol widely used; uncontrolled asthma risk > drug risk. [Beclomethasone dipropionate] 8.1 Pregnancy Risk Summary There are no adequate and well‑controlled studies with QVAR REDIHALER or beclomethasone dipropionate in pregnant women. There are clinical considerations with the use of inhaled corticosteroids (ICS), including beclomethasone dipropionate, in pregnant women [see Clinical Considerations] . Also, no published studies, including studies of large birth registries, have to date related the use of ICS to any increases in congenital malformations or other adverse perinatal outcomes. Thus, available human data do not establish the presence or absence of drug‑associated risk to the fetus. In animal reproduction studies, beclomethasone dipropionate resulted in adverse developmental effects in mice and rabbits at subcutaneous doses equal to or greater than approximately 0.75 times the maximum recommended human daily inhalation dose (MRHDID) in adults (0.64 mg/day) [see Data] . In rats exposed to beclomethasone dipropionate by inhalation, dose‑related gross injury to the fetal adrenal glands was observed at doses greater than 180 times the MRHDID, but there was no evidence of external or skeletal malformations or embryolethality at inhalation doses of up to 440 times the MRHDID. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the US general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2‑4% and 15‑20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk The risk of complications to the mother and developing fetus from inadequate control of asthma must be balanced against the risks from exposure to beclomethasone dipropionate. In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age for the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted to maintain optimal control. Labor or Delivery There are no specific human data regarding any adverse effects of inhaled beclomethasone dipropionate on labor and delivery. Data Animal Data In an embryofetal development study in pregnant rats, beclomethasone dipropionate administration during organogenesis from gestation days 6 to 15 at inhaled doses 180 times the MRHDID in adults and higher (on a mg/m 2 basis at maternal doses of 11.5 and 28.3 mg/kg/day) produced dose‑dependent gross injury (characterized by red foci) of the adrenal glands in fetuses. There were no findings in the adrenal glands of rat fetuses at an inhaled dose that was 40 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 2.4 mg/kg/day). There was no evidence of external or skeletal malformations or embryolethality in rat at inhaled doses up to 440 times the MRHDID (on a mg/m 2 basis at maternal doses up to 28.3 mg/kg/day). In an embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 18 at subcutaneous doses equal to and greater than 0.75 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 0.1 mg/kg/day and higher) produced adverse developmental effects (increased incidence of cleft palate). A no-effect dose in mice was not identified. In a second embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 13 at subcutaneous doses equal to and greater than 2.3 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.3 mg/kg/day) produced embryolethal effects (increased fetal resorptions) and decreased pup survival. In an embryofetal development study in pregnant rabbits, beclomethasone dipropionate administration during organogenesis from gestation days 7 to 16 at subcutaneous doses equal to and greater than 0.75 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 0.025 mg/kg/day and higher) produced external and skeletal malformations and embryolethal effects (increased fetal resorptions). There were no effects in fetuses of pregnant rabbits administered a subcutaneous dose 0.2 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.006 mg/kg/day). 8.2 Lactation Risk Summary There are no data available on the presence of beclomethasone dipropionate in human milk, the effects on the breastfed child, or the effects on milk production. However, other inhaled corticosteroids have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QVAR REDIHALER and any potential adverse effects on the breastfed child from beclomethasone dipropionate or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Impairment of fertility was observed in rats and dogs at oral doses of beclomethasone dipropionate corresponding to 250 and 25 times the MRHDID for adults on a mg/m 2 basis, respectively. [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of QVAR REDIHALER for the maintenance treatment of asthma as prophylactic therapy have been established in pediatric patients aged 4 years and older. Use of QVAR REDIHALER for this indication is supported by evidence from adequate and well-controlled studies. Five-hundred and one children between the ages of 4 and 11 were treated with at least one dose of QVAR REDIHALER or QVAR MDI in one 12‑week clinical trial. The safety and effectiveness of QVAR REDIHALER in children below 4 years of age have not been established. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. A 12‑month, randomized, controlled clinical trial evaluated the effects of QVAR MDI versus beclomethasone dipropionate in a CFC propellant‑based formulation (CFC‑BDP) on growth in children age 5 to 11. A total of 520 patients were enrolled, of whom 394 received QVAR MDI (100 to 400 mcg/day ex‑valve) and 126 received CFC‑BDP (200 to 800 mcg/day ex‑valve). Similar control of asthma was noted in each treatment arm. When comparing results at month 12 to baseline, the mean growth velocity in children treated with QVAR MDI was approximately 0.5 cm/year less than that noted with children treated with CFC‑BDP via large‑volume spacer. The long‑term effects of the reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch‑up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of children and adolescents receiving orally inhaled corticosteroids, including QVAR REDIHALER, should be monitored routinely (e.g., via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including QVAR REDIHALER, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration ( 2.2 )] . 8.5 Geriatric Use Clinical studies of QVAR REDIHALER did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Lactation

[From component Beclomethasone Dipropionate /Clioquinol] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well‑controlled studies with QVAR REDIHALER or beclomethasone dipropionate in pregnant women. There are clinical considerations with the use of inhaled corticosteroids (ICS), including beclomethasone dipropionate, in pregnant women [see Clinical Considerations] . Also, no published studies, including studies of large birth registries, have to date related the use of ICS to any increases in congenital malformations or other adverse perinatal outcomes. Thus, available human data do not establish the presence or absence of drug‑associated risk to the fetus. In animal reproduction studies, beclomethasone dipropionate resulted in adverse developmental effects in mice and rabbits at subcutaneous doses equal to or greater than approximately 0.75 times the maximum recommended human daily inhalation dose (MRHDID) in adults (0.64 mg/day) [see Data] . In rats exposed to beclomethasone dipropionate by inhalation, dose‑related gross injury to the fetal adrenal glands was observed at doses greater than 180 times the MRHDID, but there was no evidence of external or skeletal malformations or embryolethality at inhalation doses of up to 440 times the MRHDID. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the US general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2‑4% and 15‑20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk The risk of complications to the mother and developing fetus from inadequate control of asthma must be balanced against the risks from exposure to beclomethasone dipropionate. In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age for the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted to maintain optimal control. Labor or Delivery There are no specific human data regarding any adverse effects of inhaled beclomethasone dipropionate on labor and delivery. Data Animal Data In an embryofetal development study in pregnant rats, beclomethasone dipropionate administration during organogenesis from gestation days 6 to 15 at inhaled doses 180 times the MRHDID in adults and higher (on a mg/m 2 basis at maternal doses of 11.5 and 28.3 mg/kg/day) produced dose‑dependent gross injury (characterized by red foci) of the adrenal glands in fetuses. There were no findings in the adrenal glands of rat fetuses at an inhaled dose that was 40 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 2.4 mg/kg/day). There was no evidence of external or skeletal malformations or embryolethality in rat at inhaled doses up to 440 times the MRHDID (on a mg/m 2 basis at maternal doses up to 28.3 mg/kg/day). In an embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 18 at subcutaneous doses equal to and greater than 0.75 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 0.1 mg/kg/day and higher) produced adverse developmental effects (increased incidence of cleft palate). A no-effect dose in mice was not identified. In a second embryofetal development study in pregnant mice, beclomethasone dipropionate administration from gestation days 1 to 13 at subcutaneous doses equal to and greater than 2.3 times the MRHDID in adults (on a mg/m 2 basis at a maternal dose of 0.3 mg/kg/day) produced embryolethal effects (increased fetal resorptions) and decreased pup survival. In an embryofetal development study in pregnant rabbits, beclomethasone dipropionate administration during organogenesis from gestation days 7 to 16 at subcutaneous doses equal to and greater than 0.75 times the MRHDID in adults (on a mg/m 2 b