Drug Safety-related Labeling Changes (SrLC)

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DULERA (NDA-022518)

(FORMOTEROL FUMARATE; MOMETASONE FUROATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/12/2019 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

Local Effects

Additions and/or revisions underlined:

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with DULERA. If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with DULERA therapy, but at times therapy with DULERA may need to be interrupted. To reduce the risk of oropharyngeal candidiasis, after dosing with DULERA, advise patients to rinse their mouth with water and spit out the contents without swallowing.

6 Adverse Reactions

Clinical Trials Experience

Newly added heading to existing text:

Adult and Adolescent Patients Aged 12 Years and Older

Newly added subsection:

Pediatric Patients Aged 5 to Less Than 12 Years

The safety data for pediatric patients aged 5 to less than 12 years are primarily based on a clinical trial of 24 weeks treatment duration with a 2-week safety follow-up. A total of 181 patients with asthma (92 male and 89 female) who were receiving any ICS/LABA therapy at trial entry were randomized to either DULERA 50 mcg/5 mcg (n=91) or mometasone furoate MDI 50 mcg (n=90), administered as 2 inhalations twice daily. The mean age was 9.1 years, 22.1% were between the ages of 5 to 7, and more than half (53.6%) of the population was non-Caucasian, with 38.7% of the total population reporting at least two races (i.e., multiracial). Common treatment-emergent adverse events that occurred in patients treated with DULERA with an incidence of >3% and more frequently than patients treated with mometasone furoate alone included influenza, upper respiratory tract infection, and headache.

8 Use in Specific Populations

Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of DULERA have been established in patients 12 years of age and older in 3 clinical trials up to 52 weeks in duration. In the 3 clinical trials, 101 patients 12 to 17 years of age were treated with DULERA. Patients in this age-group demonstrated efficacy results similar to those observed in patients 18 years of age and older. There were no obvious differences in the type or frequency of adverse reactions reported in this age group compared to patients 18 years of age and older. Similar efficacy and safety results were observed in an additional 22 patients 12 to 17 years of age who were treated with DULERA in another clinical trial.

The safety and effectiveness of DULERA 50 mcg/5 mcg, two inhalations twice daily, have been established in patients with asthma aged 5 to less than 12 years in clinical trials up to 24 weeks of treatment duration. Patients in this age group demonstrated efficacy and safety results similar to those observed in patients aged 12 years and older who were treated with DULERA.

The safety and effectiveness of DULERA have not been established in children younger than 5 years of age.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Not for Acute Symptoms

DULERA is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose. Treat acute symptoms with an inhaled, short-acting, beta2-agonist (the health care provider should prescribe the patient with such medication and instruct the patient in how it should be used).

Instruct patients to seek medical attention immediately if they experience any of the following:

·         If their symptoms worsen

·         Significant decrease in lung function as outlined by the physician

·         If they need more inhalations of a short-acting beta2-agonist than usual

Advise patients not to increase the dose or frequency of DULERA. Do not exceed the daily dosage of DULERA of two inhalations twice daily. If they miss a dose, instruct patients to take their next dose at the same time they normally do. DULERA provides bronchodilation for up to 12 hours.

Instruct patients not to stop or reduce DULERA therapy without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists

When patients are prescribed DULERA, other long-acting beta2-agonists should not be used.

Risks Associated With Corticosteroid Therapy

Local Effects: Advise patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with DULERA therapy, but at times therapy with DULERA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.

Immunosuppression: Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: Advise patients that DULERA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, instruct patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Instruct patients to taper slowly from systemic corticosteroids if transferring  to  DULERA.

Reduction in Bone Mineral Density: Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk and that they should be monitored and, where appropriate, be treated for this condition. 

Reduced Growth Velocity: Inform patients that orally inhaled corticosteroids, a component of DULERA, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route.

Glaucoma and Cataracts: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (glaucoma or cataracts); consider regular eye examinations.

Risks Associated With Beta-Agonist Therapy

Inform patients that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness.

Instructions for Use

Instruct patients regarding the following:

·         Read the Patient Information before use and follow the Instructions for Use carefully.

·         Remind patients to:

o   Remove the cap from the mouthpiece of the actuator before use.

o   After dosing, rinse their mouth with water without swallowing and spit out after breathing in the medicine. This will help reduce the risk of oropharyngeal candidiasis.

03/23/2018 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Additions and/or revisions underlined:

… (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin …

7 Drug Interactions

7.1 Inhibitors of Cytochrome P450 3A4

Additions and/or revisions underlined:

… Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate and potentially increase the risk for systemic corticosteroid side effects. Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir … telithromycin. Consider the benefit of coadministration versus the potential risk of systemic corticosteroid effects, in which case patients should be monitored for systemic corticosteroid side effects.

03/23/2018 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Glaucoma and Cataracts

Additions and/or revisions underlined:

… including mometasone furoate, a component of DULERA. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term.

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information:

Eye disorders: vision blurred

12/20/2017 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, and Death

(Extensive changes; please refer to labeling)

6 Adverse Reactions

(Additions and/or revisions are underlined)

LABA use may result in the following:

• Serious asthma-related events – hospitalizations, intubations, and death.

• Cardiovascular and central nervous system effects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Serious Asthma-Related Events

Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization, or asthma-related death. Available data show that when ICS and LABA are used together, such as with DULERA, there is not a significant increase in risk of these events.

 

07/12/2016 (SUPPL-19)

Approved Drug Label (PDF)

8 Use in Specific Populations

Lactation (PLLR Conversion)

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.

Pregnancy (PLLR Conversion)

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).

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - 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.

PCI - 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.