Zafirlukast symptoms and conditions

From the FDA's "Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR)"

6/12/2009

Neuropsychiatric events have been reported in some patients taking montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo and Zyflo CR). FDA has requested that manufacturers include a precaution in the drug prescribing information (drug labeling).

Montelukast is used to treat asthma, and the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose), and to prevent exercise-induced asthma. Zafirlukast and zileuton are used to treat asthma.

The reported neuropsychiatric events include postmarket cases of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor.

This information reflects FDA’s current analysis of available data concerning this drug.

Advice to patients and healthcare professionals:

Patients and healthcare professionals should be aware of the potential for neuropsychiatric events with these medications.

Patients should talk with their healthcare providers if these events occur.

Healthcare professionals should consider discontinuing these medications if patients develop neuropsychiatric symptoms.

Background

In April 2009, FDA completed its review of neuropsychiatric events, (mood and behavioral changes) possibly related to drugs that act through the leukotriene pathway (montelukast, zafirlukast, zileuton). As part of its review, FDA reviewed post-marketing reports and also requested that manufacturers submit all available clinical trial data for these products.

The post-market reports of patients on these medications included cases of neuropsychiatric events. Some reports included clinical details consistent with a drug-induced effect. In the clinical trial data submitted by manufacturers, neuropsychiatric events were not commonly observed. However, the available data were limited because the trials were not designed to look for neuropsychiatric events. Sleep disorders (primarily insomnia) were reported more frequently with all three products compared to placebo.

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On January 13, 2009, the FDA released a Follow-up to their March 27, 2008, Communication about the Ongoing Safety Review of Montelukast (Singulair). Included in this update is the following information:

"Post-marketing reports of neuropsychiatric events associated with montelukast, zafirlukast and zileuton have been reported to FDA’s Adverse Event Reporting System (AERS). Most of the reports of neuropsychiatric events are associated with montelukast, currently the most commonly prescribed drug that acts through the leukotriene pathway. The clinical details of some reports involving montelukast are consistent with a drug-induced effect. Because of the paucity of reports involving zafirlukast and zileuton, assessment of a drug–induced effect with these is limited. Accordingly, at this time, patients and prescribers should monitor for the possibility of neuropsychiatric events associated with these agents."

To clear up any misunderstanding about the FDA Singulair investigation.
FROM THE FDA STATEMENT ABOUT THE SINGULAIR INVESTIGATION

"FDA has not yet reached a definitive conclusion regarding the clinical trial data on mood and behavioral adverse events associated with montelukast, zafirlukast, and zileuton."

"although (the clinical trial) data do not suggest that montelukast, zafirlukast, or zileuton are associated with suicide or suicidal behavior, these clinical trials were not designed specifically to examine neuropsychiatric events. As a result, some events may not have been reported."

The FDA is continuing to investigate a link between Singulair and suicide .
They stated that they have not "closed the book on suicidality". Any news reports stating there is no conclusive link are incorrect.

Post-marketing reports of neuropsychiatric events associated with montelukast, zafirlukast and zileuton have been reported to FDA’s Adverse Event Reporting System (AERS). Most of the reports of neuropsychiatric events are associated with montelukast, currently the most commonly prescribed drug that acts through the leukotriene pathway. The clinical details of some reports involving montelukast are consistent with a drug-induced effect. Because of the paucity of reports involving zafirlukast and zileuton, assessment of a drug–induced effect with these is limited. Accordingly, at this time, patients and prescribes should monitor for the possibility of neuropsychiatric events associated with these agents..........................................This is the small print that is missing from some news reports

I was shocked last night on the news, when they reported that "there is no link between Singulair and suicide". I guess Merck is going to stick their heads in the sand, and let children continue to be harmed by a drug that I feel should never be prescribed to a child in the first place. I'm shocked at how young some of these children are! It makes me sad that Dr.'s, the FDA, and Merck will continue to put profit before the safety of the people being prescribed this drug and having terrible side effects from it...and most Dr.s are not fully aware of!!!!

I was reading some research from the 90's where one researcher called montelukast an inverse agonist. So then, I looked for any thing more current on that subject. It would seem that genetic variation is again involved.

1: J Pharmacol Exp Ther. 2004 Apr;309(1):102-8. Epub 2004 Jan 12. Links
Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1.Dupré DJ, Le Gouill C, Gingras D, Rola-Pleszczynski M, Stanková J.
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4 Canada.

Cysteinyl leukotrienes (CysLTs) are associated with several inflammatory processes, including asthma. Due to this association, considerable effort has been invested in the development of antagonists to the CysLT receptors (CysLT(1)R). Many of these molecules have been shown to specifically interact with CysLT(1)R, but little is known about their impact on the conformation of the receptor and its activity. We were especially interested in possible inverse agonist activity of the antagonists. Using a constitutively active mutant (N106A) of the human CysLT(1)R and the wild-type (WT) receptor coexpressed with the G(alphaq) subunit of the trimeric G protein, we were able to address this issue with ligands commonly used in therapy. We demonstrated that some of these molecules are inverse agonists, whereas others act as partial agonists. In cells expressing the CysLT(1)R mutant N106A exposed to Montelukast, Zafirlukast, or 3- phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), the basal inositol phosphate production was reduced by 53 +/- 6, 44 +/- 3, and 54 +/- 4%, respectively. On the other hand, 6(R)-(4-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (BayU9773) and 1- -phenyl ethanone] (LY171883) acted as partial agonists and alpha-pentyl-3- benzyl alcohol (REV 5901) as a neutral antagonist. However, in cells expressing CysLT(1)R and G(alphaq), all antagonists used had inverse agonist activity. The decrease in basal inositol phosphate production by ligands with inverse agonist activity could be inhibited by a more neutral antagonist, confirming the specificity of the reaction. We demonstrate here that Montelukast, MK571, and Zafirlukast can act as inverse agonists on the human CysLT(1) receptor.

PMID: 14718577

I am a 57 year old man, who has been suffering from asthma several years. This spring my doctor put me on Singulair as an additional medicine to my cortisone-inhalator. after one month I feel symptoms of depression an mood-changing, severe ups and downs.
AND - as an additional symptom i have partially lost my feeling in some fingertips, and now parts of my left thumb and even a feeling of "cold2, mostly in my left hand.
anyone who share that symptom?
M.

If anyone has any access to databases that can describe the history of drug licensing in other countries and whether Merck had to amend product statements, this is worth investigating. I do know that montelukast was at least not initially licensed for seasonal allergies in the United Kingdom when the FDA granted approval in the US. As of 2006, seasonal allergies were not on the approved listed in the UK.

More to add to the files:

Safety of leukotriene antagonists
United Kingdom — The Medicines Control Agency
has published a review of adverse drug reactions to
a new class of asthma drugs, leukotriene antagonists.
Zafirlukast and moltelukast, competitive cysteinyl
leukotriene type-1 receptor antagonists, were
both marketed for the first time in 1998.
Cysteinyl leukotrienes are inflammatory mediators
and potent constrictors of bronchial smooth muscle
that attract human eosinophils and cause airway
oedema, mucus hypersecretion and reduced
mucociliary clearance. By blocking this action, leukotriene
antagonists can improve respiratory function
and lessen symptoms in patients with asthma.
The pharmacological action of leukotrienes is quite
complex and varying side effects have been
reported. Zafirlukast inhibits the hepatic cytochrome
P4502C9, and interacts with warfarin, theophyllin,
terfenadine, acetylsalicylic acid and erythromycin.
Montelukast is metabolized by hepatic cytochrome
P450CYP3A4 and co-administration of such drugs
as phenytoin, phenobarbitone and rifampicin, which
induce this enzyme, result in a marked reduction in
plasma levels.
Side-effects identified during clinical trials were
headache, abdominal pain, nausea, diarrhoea,
gastro-enteritis, influenza, pharyngitis, sinusitis,
cough, nasal congestion, dizziness, fatigue and insomnia.
Since marketing of montelukast, 173 reports
of 317 suspected adverse drug reactions
have been received in the United Kingdom. These
include oedema (50), psychiatric reactions, including
including agitation/restlessness (15), allergy, including
anaphylaxis, angioedema and urticaria (10), chest
pain (7), tremor (5), mouth dryness (5), vertigo (4)
and arthralgia (3).
Reference: Current Problems in Pharmacovigilance,
Volume 24, August 1998.
https://www.who.ch/druginformation/vol12/12-4.pdf

From a UK Yellow Card Report.

Montelukast

The product information for montelukast has been amended to include the following ADRs: Reaction No. of UK Yellow Card reports

Nausea 63 Diarrhoea 54 Rashes 52 Insomnia 44 Dizziness 42 Fatigue 37 Vomiting 24 Pruritus 24 Arthralgia 20 Urticaria 19 Malaise 18 Dyspepsia 13 Myalgia 12 Dry mouth 9 Anaphylaxis 4 Angioedema3

In addition, the following suspected ADRs have been reported and are still being evaluated: psychiatric disorders (63) ; also nightmares (13), sedation (13), palpitations (12), tremor (10) and increased sweating (10).
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Zafirlukast The most frequently reported ADRs under the Yellow Card Scheme for zafirlukast have been rashes (7), headache (7), abdominal pain (6), nausea (6) and pruritus (5). All of these are included in the product information which has also been updated to include the following ADRs that have been identified from data other than UK Yellow Card reports: urticaria, angioedema, blistering, bruising, bleeding disorders, including menorrhagia (rare), thrombocytopenia and agranulocytosis (both very rare). Churg-Strauss syndrome Churg-Strauss syndrome (CSS) is a rare syndrome characterised by a history of asthma, and often rhinitis and sinusitis, with systemic vasculitis and eosinophilia. There has been a recent increase in the number of reports of CSS associated with the use of anti-asthma drugs, particularly the leukotriene receptor antagonists. The MHRA/CSM have received 63 reports of CSS through the Yellow Card Scheme since 1963, 59 since the beginning of 1998; Of these, 90% were associated with drugs used to treat asthma (mainly leukotriene receptor antagonists). In many, but not all cases there was documented evidence of a reduction or withdrawal of oral corticosteroid therapy prior to the onset of the reaction. There are clear warnings regarding the possible association with CSS in the product information for montelukast and zafirlukast. Prescribers should be aware of the possibility that, although rare, CSS may be the underlying cause of asthma in their patients. In patients prescribed a leukotriene receptor antagonist prescribers should be alert to the development of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications and/or peripheral neuropathy. The identification of new and suspected ADRs emphasises the important role of the Yellow Card Scheme in helping to ensure the safe use of medicines. The safety profile of leukotriene receptor antagonists remains under close review. Please continue to report all suspected ADRs to montelukast (Singulairt) and zafirlukast (Accolatet) through the Yellow Card Scheme.1. MHRA/CSM Current Problems in Pharmacovigilance 1998; 24:14.
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http://64.233.169.104/search?q=cache:3fU602hhlG8J:www.mhra.gov.uk/home/groups/pl-p/documents/publication/con2023236.pdf+montelukast+ADR&hl=en&ct=clnk&cd=10&gl=us

From Canada:

Leukotriene receptor antagonists: suspected adverse reactions

The cysteinyl leukotrienes are inflammatory mediators that bind to cysteinyl leukotriene receptors found in the human airway and cause a number of airway actions including bronchoconstriction, mucous secretion, vascular permeability and eosinophil recruitment.1 Zafirlukast (Accolate®) and montelukast sodium (Singulair®), marketed in Canada since November 1997 and August 1998 respectively, are competitive cysteinyl leukotriene receptor antagonists. Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in patients 12 years of age and older.2 Montelukast is indicated for the prophylaxis and chronic treatment of asthma, the treatment of asthma in ASA-sensitive patients and the prevention of exercise-induced bronchoconstriction in pediatric patients 6-14 years of age and adults 15 years of age and older.1

As of June 1, 1999, the CADRMP has received 41 reports of suspected adverse drug reactions associated with the use of zafirlukast and 22 associated with the use of montelukast. This article will discuss a serious and rare adverse reaction associated with the use of these agents, drug-drug interactions and unexpected adverse reactions that have been reported to the CADRMP.

http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v9n4_e.html

Conditions are discussed in the article.