Safety

Dulera (Mometasone Furoate and Formoterol Fumarate Dihydrate) Inhalation Aerosol

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

July 2016

Summary View

USE IN SPECIFIC POPULATIONS

PLLR Conversion:

Pregnancy
Risk Summary
  • There are no randomized clinical studies of DULERA, mometasone furoate, or formoterol fumarate in pregnant women. There are clinical considerations with the use of DULERA in pregnant women. Animal reproduction studies with DULERA are not available; however, studies are available with its individual components, mometasone furoate and formoterol fumarate. In animal reproduction studies, subcutaneous administration of mometasone furoate to pregnant mice, rats, or rabbits caused increased fetal malformations and decreased fetal survival and growth following administration of doses that produced exposures approximately 1/3 to 8 times the maximum recommended human dose (MRHD) on a mcg/m2 or AUC basis. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 1200 to 49,000 times the MRHD on a mg/m2 or AUC basis. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 500 times the MRHD.
  • The estimated background 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 embryo/fetal risk
  • In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.
Labor or delivery
  • There are no adequate and well-controlled human studies that have studied the effects of DULERA during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of DULERA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
Data
Animal Data
Mometasone Furoate
  • In an embryofetal development study with pregnant mice dosed throughout the period of organogenesis, mometasone furoate produced cleft palate at an exposure approximately one-third of the MRHD (on a mcg/m2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at an exposure approximately equivalent to the MRHD (on a mcg/m2 basis with a maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with a dose that produced an exposure approximately one-tenth of the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 20 mcg/kg and above).
  • In an embryofetal development study with pregnant rats dosed throughout the period of organogenesis, mometasone furoate produced fetal umbilical hernia at exposures approximately 6 times the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at exposures approximately 3 times the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 300 mcg/kg and above). In another reproductive toxicity study, pregnant rats were dosed with mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at an exposure that was approximately 8 times the MRHD (on an area under the curve (AUC) basis with a maternal subcutaneous dose of 15 mcg/kg). There were no findings with an exposure approximately 4 times the MRHD (on an AUC basis with a maternal subcutaneous dose of 7.5 mcg/kg).
  • Embryofetal development studies were conducted with pregnant rabbits dosed with mometasone furoate by either the topical dermal route or oral route throughout the period of organogenesis. In the study using the topical dermal route, mometasone furoate caused multiple malformations in fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at an exposure approximately 3 times the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 150 mcg/kg and above). In the study using the oral route, mometasone furoate caused increased fetal resorptions and cleft palate and/or head malformations (hydrocephaly and domed head) at an exposure approximately 1/2 of the MRHD (on AUC basis with a maternal oral dose of 700 mcg/kg). At an exposure approximately 2 times the MRHD (on an AUC basis with a maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No effects were observed at an exposure approximately 1/10 of the MRHD (on an AUC basis with a maternal oral dose of 140 mcg/kg).
Formoterol Fumarate
  • In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species. However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 80 times the MRHD (on a mcg/m2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 2400 times the MRHD (on a mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). In a pre- and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 2400 times the MRHD (on a mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). However, no effects were observed in this study at an exposure approximately 80 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 200 mcg/kg).
  • In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species. Umbilical hernia, a malformation, was observed in rat fetuses at exposures approximately 1200 times the MRHD (on a mcg/m2 basis with maternal oral doses of 3000 mcg/kg/day and above). Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 6100 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 15,000 mcg/kg/day). In another study with rats, no teratogenic effects were observed with exposures up to approximately 500 times the MRHD (on a mcg/m2 basis with a maternal inhalation dose of 1200 mcg/kg/day).
  • Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 49,000 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed with exposures up to approximately 3000 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 3500 mcg/kg).
Lactation
Risk Summary
  • There are no available data on the presence of DULERA, mometasone furoate, or formoterol fumarate in human milk, the effects on the breastfed child, or the effects on milk production. Other inhaled corticosteroids, similar to mometasone furoate, are present in human milk. Formoterol fumarate is present in rat milk; however, due to species specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DULERA and any potential adverse effects on the breastfed infant from DULERA or from the underlying maternal condition.

PATIENT COUNSELING INFORMATION

Instructions for Use

Patients should be instructed regarding the following:

  • Read the Medication Guide before use and follow the Instructions for Use carefully.
  • Patients should be reminded to:
    • Remove the cap from the mouthpiece of the actuator before use.
    • Not remove the canister from the actuator.
    • Not wash inhaler in water. The mouthpiece should be cleaned using a dry wipe after every 7 days of use.

MEDICATION GUIDE

How should I use DULERA?

  • DO NOT remove the canister from the actuator because:
    • You may not receive the correct amount of medication.
    • The dose counter may not function properly.
    • Reinsertion may cause the dose counter to count down by 1 and may discharge a puff.

 

April 2014

Summary View

17 PATIENT COUNSELLING INFORMATION

17.6 Instructions for Use

Patients should be instructed regarding the following:

  • Read the Medication Guide before use and follow the Instructions for Use carefully. 

Patients should be reminded to:

  • Remove the cap from the mouthpiece of the actuator before use. 
  • Not remove the canister from the actuator.
  • Not wash inhaler in water. The mouthpiece should be cleaned using a dry wipe after every 7 days of use.

MEDICATION GUIDE

How Should I Use DULERA?

DO NOT remove the canister from the actuator because:

  • You may not receive the correct amount of medication.
  • The dose counter may not function properly.
  • Reinsertion may cause the dose counter to count down by 1 and may discharge a puff.

Patient Instructions For Use

You should not remove the canister from the actuator because:

  • You may not receive the correct amount of medication.
  • The dose counter may not function properly.
  • Reinsertion may cause the counter to count down by 1 and may discharge a puff. 

 

July 2013

Summary View

WARNINGS AND PRECAUTIONS

Coexisting Conditions
  • DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, ….

ADVERSE REACTIONS

DRUG INTERACTIONS

Halogenated Hydrocarbons
  • There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.
Postmarketing Experience
  • cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia

 

 

January 2013

Summary View

MEDICATION GUIDE

How Should I Use Dulera?
  • Remove the cap from the mouthpiece of the actuator before using DULERA.

 

 

August 2012

Summary View

ADVERSE REACTIONS

Postmarketing Experience
  • angioedema

 

Page Last Updated: 08/15/2016
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