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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
SINGULAIR (NDA-020829)
(MONTELUKAST SODIUM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/22/2021 (SUPPL-74)
4 Contraindications
(Additions and/or revisions underlined)
SINGULAIR is contraindicated in patients with hypersensitivity to any of its components.
5 Warnings and Precautions
5.6 Risk in Patients with Phenylketonuria(Subsection title revised; Additions and/or revisions underlined)
SINGULAIR contains aspartame, a source of phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria (PKU). Each 4 mg and 5 mg chewable tablet contains 0.674 mg and 0.842 mg of phenylalanine, respectively. Before prescribing SINGULAIR to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including SINGULAIR.
6 Adverse Reactions
(Additions and/or revisions underlined)
The following clinically significant adverse reactions are described elsewhere in the labeling:
Neuropsychiatric Events [see Warnings and Precautions (5.1)]
(Extensive changes; please refer to label)
(Additions and/or revisions underlined)
…
Patients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These reactions have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see Warnings and Precautions (5.5)].
7 Drug Interactions
(Additions and/or revisions underlined)
No dose adjustment is needed when SINGULAIR is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, fexofenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3)].
8 Use in Specific Populations
8.2 Lactation(Additions and/or revisions underlined)
Risk Summary
A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly [see Use in Specific Populations (8.4)] or through breast milk, do not suggest a significant risk of adverse reactions from exposure to SINGULAIR. The effects of the drug on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SINGULAIR and any potential adverse reactions on the breastfed infant from SINGULAIR or from the underlying maternal condition.
(Additions and/or revisions underlined)
Safety and effectiveness of SINGULAIR for asthma have been established in pediatric patients 6 to 14 years of age. Use of SINGULAIR for this indication is supported by evidence from well-controlled studies. Safety and efficacy data in this age group are similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Specific Populations (12.3), and Clinical Studies (14.1, 14.2)].
The effectiveness of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 6 months to 14 years of age have been established and is supported by extrapolation from the demonstrated effectiveness in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.
The safety of SINGULAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see Adverse Reactions (6.1)]. Effectiveness of SINGULAIR in this age group is extrapolated from the demonstrated effectiveness in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Effectiveness in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.
The safety of SINGULAIR 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with SINGULAIR, in a 6-week, double-blind, placebo-controlled study [see Adverse Reactions (6.1)]. Effectiveness of SINGULAIR in this age group is extrapolated from the demonstrated effectiveness in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment.
…
(Subsection title revised)
(Subsection title revised)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
…
Inform phenylketonuric patients that the 4-mg and 5-mg chewable tablets contain phenylalanine (a source of aspartame) [see Warnings and Precautions (5.6)].
04/29/2020 (SUPPL-73)
Boxed Warning
(newly added section)
WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS
Serious neuropsychiatric (NP) events have been reported with the use of SINGULAIR. The types of events reported were highly variable, and included, but were not limited to, agitation, aggression, depression, sleep disturbances, suicidal thoughts and behavior (including suicide). The mechanisms underlying NP events associated with SINGULAIR use are currently not well understood.
Because of the risk of NP events, the benefits of SINGULAIR may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve use of SINGULAIR for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. In patients with asthma or exercise-induced bronchoconstriction, consider the benefits and risks before prescribing SINGULAIR.
Discuss the benefits and risks of SINGULAIR with patients and caregivers when prescribing SINGULAIR. Advise patients and/or caregivers to be alert for changes in behavior or new NP symptoms when taking SINGULAIR. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue SINGULAIR and contact a healthcare provider immediately.
5 Warnings and Precautions
5.1 Neuropsychiatric Events(additions underlined)
Serious neuropsychiatric (NP) events have been reported with use of SINGULAIR. These postmarketing reports have been highly variable and included, but were not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behavior (including suicide), tic, and tremor. NP events have been reported in adult, adolescent, and pediatric patients with and without a previous history of psychiatric disorder. NP events have been reported mostly during SINGULAIR treatment, but some were reported after SINGULAIR discontinuation. Animal studies showed that montelukast distributes into the brain in rats; however, the mechanisms underlying SINGULAIR- associated NP events are currently not well understood. Based upon the available data, it is difficult to identify risk factors for or quantify the risk of NP events with SINGULAIR use.
Because of the risk of NP events, the benefits of SINGULAIR may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve use of SINGULAIR for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. In patients with asthma or exercise- induced bronchoconstriction, consider the benefits and risks before prescribing SINGULAIR.
Discuss the benefits and risks of SINGULAIR use with patients and caregivers when prescribing SINGULAIR. Advise patients and/or caregivers to be alert for changes in behavior or for new NP symptoms when taking SINGULAIR. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue SINGULAIR and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping SINGULAIR therapy; however, in some cases symptoms persisted after discontinuation of SINGULAIR. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with SINGULAIR if such events occur.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(newly added, please refer to label for complete information)
(additions underlined)
…
Advise patients about the potential risk for serious neuropsychiatric symptoms and behavioral changes with SINGULAIR use.
Discuss the benefits and risks of SINGULAIR with patients when prescribing or continuing treatment with SINGULAIR.
Advise patients to monitor for changes in behavior or neuropsychiatric symptoms in patients taking SINGULAIR.
Instruct patients to discontinue SINGULAIR and contact a healthcare provider immediately if changes in behavior or thinking that are not typical for the patient occur, or if the patient develops suicidal ideation or suicidal behavior.
…
08/09/2019 (SUPPL-72)
5 Warnings and Precautions
5.4 Neuropsychiatric Events
(Additions and/or revisions are underlined)
Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include, but are not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive- compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor. The clinical details of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect.
Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur.
6 Adverse Reactions
6.2 Post-Marketing Experience
(Additions and/or revisions are underlined)
The following adverse reactions have been identified during post-approval use of SINGULAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia.
Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.
Psychiatric disorders: including, but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(Additions and/or revisions are underlined)
What are the possible side effects of SINGULAIR? SINGULAIR may cause serious side effects.
Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking SINGULAIR:
depression • stuttering
12/21/2018 (SUPPL-70)
5 Warnings and Precautions
5.3 Neuropsychiatric Events(Additions and/or revisions are underlined)
Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include, but are not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms…
6 Adverse Reactions
6.2 Post-Marketing Experience(Additions and/or revisions are underlined)
Psychiatric disorders: including, but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects. In animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background 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
Poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age.
Data
Human Data
Published data from prospective and retrospective cohort studies have not identified an association with SINGULAIR use during pregnancy and major birth defects. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.
Animal Data
In embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days 6 to 17 in rats and 6 to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to 400 and 300 mg/kg/day in rats and rabbits, respectively (approximately 100 and 110 times the AUC in humans at the MRHDOD, respectively).(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly or through breast milk, do not suggest a significant risk of adverse events from exposure to SINGULAIR. The effects of the drug on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SINGULAIR and any potential adverse effects on the breastfed infant from SINGULAIR or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(Additions and/or revisions are underlined)
What are the possible side effects of SINGULAIR? SINGULAIR may cause serious side effects.
obsessive-compulsive symptoms
12/21/2018 (SUPPL-71)
5 Warnings and Precautions
5.3 Neuropsychiatric Events(Additions and/or revisions are underlined)
Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include, but are not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms…
6 Adverse Reactions
6.2 Post-Marketing Experience(Additions and/or revisions are underlined)
Psychiatric disorders: including, but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects. In animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background 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
Poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age.
Data
Human Data
Published data from prospective and retrospective cohort studies have not identified an association with SINGULAIR use during pregnancy and major birth defects. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.
Animal Data
In embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days 6 to 17 in rats and 6 to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to 400 and 300 mg/kg/day in rats and rabbits, respectively (approximately 100 and 110 times the AUC in humans at the MRHDOD, respectively).
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly or through breast milk, do not suggest a significant risk of adverse events from exposure to SINGULAIR. The effects of the drug on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SINGULAIR and any potential adverse effects on the breastfed infant from SINGULAIR or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(Additions and/or revisions are underlined)
What are the possible side effects of SINGULAIR? SINGULAIR may cause serious side effects.
obsessive-compulsive symptoms
12/13/2016 (SUPPL-69)
5 Warnings and Precautions
5.4 Neuropsychiatric Events(addition underlined)
Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor. The clinical details of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect.
Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur.
6 Adverse Reactions
6.2 Post-Marketing Experience(addition underlined)
Psychiatric disorders: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 Patient Counceling Information(additions underlined)
What are the possible side effects of SINGULAIR?
SINGULAIR may cause serious side effects.
• Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking SINGULAIR:
• hallucinations (seeing or hearing things that are not really there)
• uncontrolled muscle movements