Montelukast’s Underrecognized Adverse Drug Events


The US Food and Drug Administration (FDA) first alerted healthcare professionals (HCPs) about a possible association between the use of leukotriene inhibitors and neuropsychiatric events in 2008 and added information to product labels in 2009. The reported events included agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor. While the precaution was extended to all agents in this class (montelukast [Singulair®], zafirlukast [Accolate®], and zileuton [Zyflo®]), particular concern has been raised about montelukast due to its widespread use in both adult and pediatric patients for multiple indications. Montelukast is approved for the chronic treatment of asthma, acute prevention of exercise-induced bronchial constriction, and relief of both perennial and seasonal allergic rhinitis symptoms. Singulair is approved in adults and children 6 months of age and older. Continued concerns about suicidality and neuropsychiatric events with montelukast were again raised at a recent FDA Pediatric Advisory Committee (PAC) meeting in September 2014. Medscape spoke with Sally Seymour, MD, and Erika Torjusen, MD, MHS, both at the Center for Drug Evaluation and Research in the Division of Pulmonary, Allergy, and Rheumatology at the FDA, about the advisory committee meeting, concerns with these agents, and the implications for HCPs.

Medscape: Can you briefly review the concerns presented at the advisory committee meeting about these agents?

Dr Seymour: On September 23, 2014, montelukast [Singulair] was discussed at the PAC meeting as part of a routine pediatric safety review conducted after a drug has new pediatric labeling.

During the open public hearing, a parent who represented numerous groups wanted to raise awareness of the potential for neuropsychiatric events with montelukast. The speaker stated that, despite the FDA’s communication efforts and information in the product label, many physicians are not aware or do not communicate the risk for neuropsychiatric events to patients.

As part of the discussion, the committee reviewed the current montelukast labeling regarding the risk for neuropsychiatric events. Members wanted HCPs to be cognizant of the association with neuropsychiatric events and consider discontinuing montelukast if they occur. The PAC recommended a communication directed at HCPs to raise awareness of the association of neuropsychiatric events. This Medscape interview is a result of the committee’s recommendations.

Medscape: In addition, the committee heard about the available objective data regarding montelukast and neuropsychiatric events. Could you summarize those data? What do we know about these adverse events, what they look like, how acutely they occur, and the populations in which they occur?

Dr Seymour: At the PAC meeting, we briefly summarized the FDA’s previous review of this safety issue. In 2008-2009, we reviewed available data (postmarketing and clinical trial data) to evaluate the risk for neuropsychiatric events with leukotriene modifiers: montelukast, zileuton, and zafirlukast. During this review of spontaneous postmarketing reports, we noted a variety of neurologic or psychiatric adverse events associated with use of these products. Reports included: 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), and tremor. Some of these reports appeared to be consistent with a drug-induced effect. Events were noted in both adults and children, and the onset of events varied.

Based upon these data, the FDA required the manufacturers to add information to the product labels. All of these labels now have a warning/precaution about the risk for neuropsychiatric events.

Medscape: This was a pediatric advisory committee meeting. Were all of these events reported in children, or are adults also experiencing these adverse events?

Dr Seymour: We have reports of children and adults experiencing these types of events. We especially want to reach out to HCPs taking care of children because montelukast is approved for children down to 6 months of age, and detecting these events in children may be more challenging. Small children can’t report side effects, and young children or teenagers may experience changes in behavior or mood that can be mistakenly attributed to a normal phase of development. Therefore, parents and practitioners need an increased level of awareness about the risks of montelukast in these age groups.

Medscape: Are these adverse events reversible with drug discontinuation, and is there a time frame in which they are likely to occur?

Dr Torjusen: The most common adverse events are typically not serious. These events are generally reversible with cessation of therapy. In terms of timing, we have reports following initiation of montelukast and after chronic use.

Medscape: You noted that the committee made a determination that more outreach and strengthening of prescriber warnings was warranted. Were there any other committee recommendations? For example, will there be any requirement to manufacturers to conduct any further studies?

Dr Torjusen: Based on the testimony provided during the open public hearing, the PAC recommended potential strategies for increasing awareness of the neuropsychiatric events that may occur with montelukast. Possibilities raised by the committee included labeling changes, education of providers, and consideration for further studies. The PAC recommendations can be found on our website.

Dr Seymour: When the FDA completed its initial review in 2009 and required the companies to update the product labeling, we did not require clinical trials to further evaluate this issue. Because this is a known safety issue, the FDA does not think that changes to the prescriber information or clinical studies are warranted at this time. The PAC noted that the patient labeling was clear.

Medscape: Given that this is a class-wide concern, should all leukotriene inhibitors be avoided in patients who experience these symptoms in response to one agent? Or is it worth a clinician trying another drug in the same class if it was felt it was really indicated?

Dr Torjusen: Based on the data available, this does appear to be a class effect and is the reason the labeling change was applied to all of the drugs in the class of leukotriene inhibitors. Therefore, if a patient experiences neuropsychiatric symptoms while on one leukotriene inhibitor, we would recommend that they avoid other drugs in the class.

Medscape: Why do you think this now 5-year-old safety issue is not well known by prescribers?

Dr Torjusen: That is a good question. It is possible that awareness of the association between montelukast and neuropsychiatric events has faded. HCPs are inundated with new products and new safety information, and keeping up with all of this can be a challenge. In addition, the types of events experienced are highly variable. Detecting these events in children and young adults can be particularly challenging. Young children may be less able to articulate these experiences, and parents may unknowingly attribute symptoms to be part of developmental changes. Therefore, reminders of important safety concerns may be necessary at times for both patients and providers.

Medscape: What are the key take-home messages for clinicians who are prescribing this class of drugs?

Dr Torjusen: The key take-home message is for HCPs to be aware of the risk for neuropsychiatric events with the use of montelukast. Providers should inform their patients and families that these types of side effects are a possibility with these medications, and they should follow up with their patients after initiation of therapy.

Patients should also notify their HCPs if side effects occur, and HCPs should consider discontinuing therapy if patients develop neuropsychiatric symptoms.

Medscape: Are there resources for patient education that clinicians can and should use?

Dr Torjusen: Certainly, clinicians can always refer to the product label for montelukast [Singulair], which provides safety information for the product. In addition, the patient prescribing information provides useful information on the product, including side effects.

Information about the FDA’s review of the safety issue can be found on the FDA website.

Serious adverse events should also be reported to the FDA MedWatch or by calling the FDA at 1-800-FDA-1088. Patients and HCPs who want more information about specific products can go to the FDA website or contact the FDA [1-888-INFO-FDA].

Fetal Exposure to Montelukast and Congenital Anomalies: A Population Based Study in Denmark


Abstract

Background

The objective was to study pregnancy outcomes between groups of Danish women, with pregnancy ending between 1998 and 2009, according to their exposure to montelukast.

Methods

Cross‐sectional observational study in Danish women, selecting live births and stillbirths (Birth Registry) and spontaneous abortions and induced terminations (Patient Registry). Montelukast exposure was obtained from the Prescription Registry (ATC code R03DC03). Exposure period was from 3 months before the last menstrual period until the end of the first trimester. Four groups were studied: (1) women with prescription for montelukast, (2) women with prescription for montelukast and other anti‐asthmatic medications, (3) women with prescription for other anti‐asthmatic medications, (4) women without prescription for any anti‐asthmatic medications.

Results

A total of 754,300 singleton pregnancies (> 12 weeks) were identified: 401 pregnancies in group 1, 426 pregnancies in group 2, 24878 in group 3 and 728,595 in group 4. Risk of preterm birth, maternal preeclampsia and gestational diabetes was increased for pregnancies exposed to montelukast. No significant differences were found for the risk of major congenital anomalies (CA). Adjusted odds ratio for CA was 1.4 (95% CI 0.9–2.3) for the group 1 and 1.0 (95% CI 0.6–1.8) for group 2.

Conclusion

Pregnant women with prescriptions for montelukast had a higher risk of preterm birth and maternal complications. These risks are known to be associated with maternal asthma, no increased risk of CA was found. Further analysis including more exposed pregnancies will be needed to determine the risk of specific CA.

Asthma Medication Recall Alert: Montelukast Tablets From Camber Pharmaceuticals for Incorrect Drug in Bottle


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The Asthma and Allergy Foundation of America is sharing this press release from the U.S. Food and Drug Administration (FDA) to bring you the latest recall news quickly.


 

The U.S. Food and Drug Administration is warning consumers and health care professionals about a voluntary recall of one lot of Montelukast Sodium Tablets – lot number MON17384, expiration 12/31/2019 – by Camber Pharmaceuticals, Inc., Piscataway, N.J. Sealed bottles labeled as montelukast sodium tablets, 10 milligram, 30-count bottle from Camber were found to instead contain 90 tablets of Losartan Potassium Tablets, 50 mg.

This tablet mix-up may pose a safety risk as taking losartan tablets when not prescribed has the potential to cause renal dysfunction, elevated potassium levels and low blood pressure. This risk is especially high for pregnant women taking the allergy and asthma medication montelukast because losartan, which is indicated to treat high blood pressure, could harm or kill the fetus. The FDA recommends that consumers who have this recalled product should contact their health care provider or pharmacist immediately.

This recall is not related to the recent valsartan recalls that were due to an impurity, N-nitrosodimethylamine (NDMA).

“We want to ensure that patients who take montelukast are aware of this recall due to the serious risks associated with taking losartan in its place,” said Donald D. Ashley J.D., director of the office of compliance in the FDA’s center for drug evaluation and research. “Patients who take prescription drugs expect and deserve to have the medication their doctor prescribed.”

Montelukast is used to prevent wheezing, difficulty breathing, chest tightness and coughing caused by asthma. It is also used to prevent bronchospasm (breathing difficulties) during exercise and to treat the symptoms of seasonal and perennial allergic rhinitis. Montelukast is in a class of medications called leukotriene receptor antagonists (LTRAs) which work by blocking the action of substances in the body that cause the symptoms of asthma and allergic rhinitis.

Losartan is often used alone or in combination with other medications to treat high blood pressure. Losartan is also used to decrease the risk of stroke in people who have high blood pressure and a heart condition called left ventricular hypertrophy (enlargement of the walls of the left side of the heart).

Patients should contact their health care provider or pharmacist to determine if their medicine has been recalled. Patients should also look at the drug name and company name on the label of their prescription bottle. If the information is not on the bottle, patients should contact the pharmacy that dispensed the medicine.

Montelukast sodium tablets are beige, rounded square-shaped, film coated tablets that are imprinted with “I” on one side and “114” on the reverse. Losartan tablets are white and oval-shaped with the letter “I” imprinted on one side and the number “5” imprinted on the reverse.

Recalled lots of montelukast sodium tablets, USP 10mg have the following information:

  • Label: Montelukast Sodium Tablets 10 mg 30 ct
  • Lot number: MON17384
  • Expiration date: 12/31/2019
  • NDC: 31722-726-30

To date, Camber has not received adverse event reports associated with this recall. The FDA encourages health care professionals and consumers to report adverse events to the FDA’s MedWatch Adverse Event Reporting program:

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Montelukast Tied to Psychiatric Adverse Events in Kids, Adults


The asthma medication montelukast (Singulair, Merck) is linked to increased reports of depression and nightmares in adults and children, as well as aggression in children, according to a review of voluntary adverse event reports published online September 20 in Pharmacology Research & Perspectives.

“Because of the high incidence of neuropsychiatric symptoms — especially nightmares — after using montelukast in both children and adults, the clinician should discuss the possibility of these adverse events with the patient and parents,” first author Meindina Haarman, MSc, from University Medical Center Groningen, The Netherlands, said in a news release.

Haarman and colleagues say this is the first study to analyze reports of adverse drug reactions related to montelukast in both children and adults.

Montelukast is used in maintenance therapy for adults and children with asthma and allergic rhinitis. Commonly reported adverse reactions include upper airway infection, fever, rash, nausea, vomiting, diarrhea, and elevated liver enzymes.

Sleep disorders and psychiatric symptoms have also been reported. In 2009, the US Food and Drug Administration mandated that the drug label of montelukast and other drugs in this class list neuropsychiatric symptoms such as depression and suicidality as possible adverse reactions.

Montelukast has also been linked to allergic granulomatous angiitis, also called Churg-Strauss syndrome, a rare autoimmune condition that causes inflammation of small and medium-sized blood vessels in people with airway allergies. The condition can affect various organs, especially the lungs and digestive tract, and can be life-threatening in some cases.

To better characterize the safety profile of montelukast in regular clinic use, the researchers conducted a retrospective study of all adverse drug reactions in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the World Health Organization (WHO) Global database (VigiBase®) up to 2016.

Overall, there were 331 montelukast-related adverse drug reactions in the Dutch database and 17,723 in the WHO database. Slightly less than one third of the reports in each database involved patients younger than 19 years (32.3% and 32.4%, respectively).

In the analysis, the researchers used the reporting odds ratio (ROR), which provides an estimate of whether an adverse event is disproportionately reported for a certain drug compared with all other drugs. Notably, ROR cannot say anything about causality.

Depression was the most frequently reported adverse reaction overall in the global WHO database (ROR, 6.93; 95% confidence interval [CI], 6.5 – 7.4). Among children only, the most commonly reported ADR was aggression (ROR, 29.77; 95% CI, 27.5 – 32.2).

In the Dutch database, headache was the most frequently reported adverse reaction overall in both adults (ROR, 2.26; 95% CI, 1.61 – 3.19), and children (ROR, 3.18; 95% CI, 2.66 – 3.70).

Other commonly reported adverse reactions in both the Dutch and WHO databases included nightmares in both children and adults. In the WHO database, suicidal ideation was also commonly reported.

Eight patients also reported allergic granulomatous angiitis to the Dutch database, whereas the WHO database had 563 reports of the condition. All patients survived.

The authors noted that the relationship between montelukast and allergic granulomatous angiitis is unclear. Some studies have suggested that the two are not connected, whereas others have suggested a causal relationship. More research is needed to clarify this relationship, they write.

“However, it has been reported that the symptoms of allergic granulomatous angiitis disappeared in some patients after withdrawing montelukast. This can be seen regarded as an argument for a causal relationship,” the authors write.

Until more data are available, “patients treated with montelukast should be followed to detect signs and symptoms of allergic granulomatous angiitis,” they advise.

They also note that the relationship between Montelukast and depression remains unclear. Asthma has been linked to increased depression and lower quality of life, so reports of depression may actually reflect symptoms of the underlying disease and not an adverse reaction to the drug.

“Further research is required to reveal the mechanism for the higher incidence of neuropsychiatric symptoms in patients using montelukast in comparison with other medications,” they conclude.

The authors mention several study limitations. Both databases relied on voluntary reporting of symptoms, which could have lead to underreporting. Also, the study cannot prove montelukast causes these adverse reactions.

First Generic Versions of Singulair Approved .


Generic versions of montelukast (marketed as Singulair) have received FDA approval, the agency announced.

The orally administered leukotriene receptor antagonist is used to control symptoms of asthma and allergies, although the FDA warns that montelukast should not be used for relief of sudden asthma attacks. The agency also urges patients to contact clinicians immediately if mood or behavioral changes occur with the drug.

Source: FDA news