EDITORIAL ESPANOL:

====================

Hola amigos del DERMA-CYBER, el MONTELUKAST SÓDICO, antagonista selectivo de los leucotrienos, ha salido al mercado en Venezuela, año 1998, también con el nombre de SINGULAIR. El motivo de la revisión es que el producto está siendo utilizado en algunas enfermedades de la piel: dermatitis atópica, dishidrosis y psoriasis, aunque no hay estudios al respecto. En las listas Americanas se oye con frecuencia hablar de este tema, de modo que ahora tendremos la oportunidad de probar este prometedor producto.

Cuando este producto salió al mercado se promociono que su uso por tres meses (3) seguidos provocaba una curación o remisión TOTAL del asma, el tiempo se encargó de demostrar que no era cierto eso. Su efectividad según estudios es del 32% en general.

La FDA EL 4 DICIEMBRE de 1.998 alerta sobre la producción de síndrome de Churg Strauss con el uso de este medicamento (19, 20)

Saludos,,,

Dr. José Lapenta.

 EDITORIAL ENGLISH:

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Hello friends of the DERMA-CYBER, the selective SODIUM, antagonist of the leukotrienes MONTELUKAST, it has left to the market in Venezuela, also with the name of SINGULAIR. The reason of the revision is that the product is being used in some illnesses of the skin: atopic dermatitis, dyshidrosis and psoriasis, although there are not studies in this respect. In the American lists it is frequently heard speak of this topic, so that now we will have the opportunity to prove this promising product. 

When this product came on the market, it was promoted that its use for three (3) consecutive months would cause a TOTAL cure or remission of asthma. Time proved that this was not true. Its effectiveness according to studies is 32% in general.

The FDA on DECEMBER 4, 1.998, it alerts on the production of Churg-Strauss syndrome with the use of this medication (19, 20) 

Greetings,,,

Dr. José Lapenta,

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DERMAGIC/EXPRESS(31)

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INHIBIDORES DE LOS LEUCOTRIENOS (II)

LEUKOTRIENE ANTAGONIST (II) Montelukast ================================================================

1.) Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma.

2.) Determination of montelukast sodium in human plasma by column-switching high-performance liquid chromatography with fluorescence detection.

3.) Montelukast.

4.) Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction [see comments]

5.) A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma Study Group.

6.) Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized,`double-blind trial. Montelukast Clinical Research Study Group.

7.) Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Montelukast Asthma Study Group.

8.) Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group.

9.) Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers.

10.) Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile.

11.) Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval.

12.) Hepatic microsomal metabolism of montelukast, a potent

leukotriene D4 receptor antagonist, in humans.

13.) Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled

corticosteroids.

14.) Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma.

15.) Pharmacokinetics, bioavailability, and safety of montelukast

sodium (MK-0476) in healthy males and females.

- Montelukast en la Web -

16.) WAM: Study Shows Children With Asthma Prefer Singulair To Cromolyn

17.) SINGULAIR® (Montelukast Sodium), the product 

18.) Patient Education Monograph for Montelukast Sodium (Oral )

19.) Singulair Safety Information Revised To Include Reports Of Inflammatory Condition.

20.) SINGULAIR® (Montelukast Sodium), the Food and Drug Administration.

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1.) Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma.

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J Pediatr 1998 Sep;133(3):424-8 (ISSN: 0022-3476)

Kemp JP; Dockhorn RJ; Shapiro GG; Nguyen HH; Reiss TF; Seidenberg BC; Knorr B 

Allergy and Asthma Medical Group and Research Center, San Diego, California, USA.

OBJECTIVE: To determine whether montelukast, a leukotriene receptor antagonist, attenuates

exercise-induced bronchoconstriction (EIB) in 6- to 14-year-old children with asthma. STUDY

DESIGN: Double-blind, multicenter, 2-period crossover study. Children (n = 27) with forced

expiratory volume in 1 second (FEV1) > or =70% of the predicted value and a fall in FEV1 > or

=20% after exercise on 2 occasions. Patients received montelukast (5-mg chewable tablet) or

placebo once daily in the evening for 2 days in crossover fashion (at least 4 days between treatment

periods). Standardized exercise challenges were performed 20 to 24 hours after the last dose in

each period. End points included area above the postexercise percent fall in FEV1 versus time

curve (AAC0-60 min), maximum percent fall in FEV1 from pre-exercise baseline, and time to

recovery of FEV1 to within 5% of pre-exercise baseline. RESULTS: Montelukast significantly

reduced AAC0-60 min (265 vs 590% x min for montelukast and placebo, respectively, P < or =

.05; approximately 59% protection relative to placebo) and the maximum percent fall (18% vs 26%

for montelukast and placebo, respectively, P < or = .05). Montelukast treatment resulted in a

shorter time to recovery (18 vs 28 minutes for montelukast and placebo, respectively, P = .079).

CONCLUSIONS: Montelukast attenuates EIB at the end of the dosing interval in 6- to

14-year-old children with asthma. 

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2.) Determination of montelukast sodium in human plasma by column-switching high-performance liquid chromatography with fluorescence detection.

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J Chromatogr B Biomed Sci Appl 1998 Aug 25;713(2):409-14 (ISSN: 1387-2273)

Ochiai H; Uchiyama N; Takano T; Hara K; Kamei T 

Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Saitama,

Japan.

MK-0476 (montelukast sodium) is a potent and selective cysteinyl leukotriene receptor antagonist

that is being investigated in the treatment of asthma. A simple and sensitive method for the

determination of MK-0476 in human plasma was developed using column-switching

high-performance liquid chromatography (HPLC) with fluorescence detection. A plasma sample

was injected directly onto the HPLC system consisting of a pre-column (Capcell pak MF) and an

analytical column (Capcell pak C18) which were connected with a six-port switching valve. The

column eluate was monitored with a fluorescence detector (excitation at 350 nm; emission at 400

nm). The calibration curve was linear in a concentration range of 1-500 ng ml(-1) for MK-0476 in

human plasma. The intra-day coefficients of variation of all concentrations within the range was less

than 9.2%, and the intra-day accuracy values were between 97.2 and 114.6%. This method was

used to measure the plasma concentration of MK-0476 following oral administration of the drug in

humans. 

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3.) Montelukast.

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Drugs 1998 Aug;56(2):251-6; discussion 257 (ISSN: 0012-6667)

Markham A; Faulds D 

Adis International Limited, Auckland, New Zealand. demail@adis.co.nz.

Montelukast is a selective antagonist of the leukotriene D4 (LTD4) receptor. In patients with

asthma, montelukast 5 to 250 mg/day attenuated LTD4-induced bronchoconstriction and, at a

dosage of 10 mg, significantly reduced early and late airway response to allergen (dust mite extract)

relative to placebo. In studies evaluating the effects of various dosages of montelukast on

exercise-induced bronchoconstriction the optimal dose of the drug was found to be 10 mg.

Montelukast 10 mg/day controlled asthma significantly more effectively than placebo in a 3-month

randomised double-blind study. In a 9-month open extension of this trial, during which patients were

randomised to treatment with montelukast 10 mg/day or beclomethasone (approximately 400

micrograms/day), daytime symptom score and beta-agonist use decreased to a similar extent in

each group. In a further study, treatment with montelukast 10 mg/day permitted clinically

significant tapering of corticosteroid dosage in patients with stable asthma. Montelukast (5

mg/day) has also demonstrated efficacy in childhood asthma. The tolerability profile of

montelukast was similar to that of placebo in placebo-controlled clinical trials in adults and

children; the most common adverse event was headache. 

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4.) Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction [see comments]

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N Engl J Med 1998 Jul 16;339(3):147-52 (ISSN: 0028-4793)

Leff JA; Busse WW; Pearlman D; Bronsky EA; Kemp J; Hendeles L; Dockhorn R; Kundu S;

Zhang J; Seidenberg BC; Reiss TF 

Department of Pulmonary-Immunology, Merck Research Laboratories, Rahway, NJ 07065-0914,

USA.

BACKGROUND: Patients with mild asthma frequently have only exercise-induced

bronchoconstriction, a symptom of inadequate control of asthma. We evaluated the ability of

montelukast, a leukotriene-receptor antagonist, to protect such patients against exercise-induced

bronchoconstriction. METHODS: We randomly assigned 110 patients (age, 15 to 45 years) with

mild asthma and a decrease in the forced expiratory volume in one second (FEV1) of at least 20

percent after exercise on two occasions during a placebo run-in period to receive 10 mg of

montelukast (54 patients) or placebo (56 patients) once daily at bedtime for 12 weeks in a

double-blind study. Treatment was followed by a two-week, single-blind washout period during

which all patients received placebo. Exercise challenges were performed at base line; 20 to 24

hours after dosing at weeks 4, 8, and 12; and at the end of the washout period. The primary end

point was the area under the curve for FEV1 (expressed as the percent change from base-line

values) in the first 60 minutes after exercise. This measure summarized the extent and duration of

bronchoconstriction after exercise. RESULTS: At 12 weeks, montelukast therapy offered

significantly greater protection against exercise-induced bronchoconstriction than placebo therapy

(expressed as the percentage of inhibition of the end points), as evidenced by the improvement in

the area under the FEV1 curve (degree of inhibition, 47.4 percent; P=0.002). Montelukast

therapy was also associated with a significant improvement in the maximal decrease in FEV1 after

exercise (P=0.003) and the time from the maximal decrease in FEV1 to the return of lung function

to within 5 percent of pre-exercise values (P=0.04). The differences between groups in the various

measures of lung function were similar at 4, 8, and 12 weeks; there was no evidence of rebound

worsening of lung function in the montelukast group after the washout period. After 12 weeks of

treatment, patients in the montelukast group were more likely to rate their asthma control as better

and less likely to require rescue therapy with a beta-agonist during or after exercise challenge. The

rates of adverse events were similar in the two groups. CONCLUSIONS: As compared with

placebo, once-daily treatment with montelukast provided significant protection against

exercise-induced asthma over a 12-week period. Tolerance to the medication and rebound

worsening of lung function after discontinuation of treatment were not seen.

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5.) A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma Study Group.

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J Allergy Clin Immunol 1998 Jul;102(1):50-6 (ISSN: 0091-6749)

Altman LC; Munk Z; Seltzer J; Noonan N; Shingo S; Zhang J; Reiss TF 

University of Washington, Seattle, USA.

BACKGROUND: The cysteinyl leukotrienes are important mediators of bronchial asthma. The

clinical effect of montelukast, a potent cysteinyl leukotriene-receptor antagonist, was investigated

in a randomized, placebo-controlled, multicenter, parallel-group, dose-ranging study. METHODS:

After a 3-week, single-blind, placebo run-in period, 343 asthmatic patients (FEV1 40% to 80% of

the predicted value with an improvement in FEV1 of at least 15% [absolute value] after receiving

inhaled beta-agonists on at least two occasions) were randomly assigned to one of six treatment

groups: placebo; 10, 100, or 200 mg once daily montelukast in the evening; or 10 or 50 mg twice

daily montelukast for a 6-week, double-blind treatment period followed by a 1-week placebo

washout period. All patients used inhaled, short-acting beta-agonists as needed. RESULTS: All

montelukast doses caused similar and significant differences compared with placebo in asthma

control endpoints. The least-square mean difference between pooled montelukast groups and

placebo in the percentage change from baseline in morning FEV1 (10.30%; 95% CI: 5.56 to

15.04), as-needed beta-agonist use (-0.98 puffs; 95% CI: -1.53 to -0.44), morning peak

expiratory flow rate (18.80 L/min; 95% CI: 8.62 to 28.98), physicians' and patients' global

evaluations, and asthma-specific quality-of-life scores were all significant (p or = 0.050). The

incidence of adverse experiences was not dose related and was similar between placebo and

montelukast treatment. CONCLUSION: Montelukast caused a significant improvement in

chronic asthma at an oral, once daily evening dose as low as 10 mg. 

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6.) Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized,`double-blind trial. Montelukast Clinical Research Study Group.

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Arch Intern Med 1998 Jun 8;158(11):1213-20 (ISSN: 0003-9926)

Reiss TF; Chervinsky P; Dockhorn RJ; Shingo S; Seidenberg B; Edwards TB 

Department of Pulmonary/Immunology, Merck Research Laboratories, Rahway, NJ 07065, USA.

OBJECTIVES: To determine the clinical effect of oral montelukast sodium, a leukotriene receptor

antagonist, in asthmatic patients aged 15 years or more. DESIGN: Randomized, multicenter,

double-blind, placebo-controlled, parallel-group study. A 2-week, single-blind, placebo run-in

period was followed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg,

or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period.

SETTING/PATIENTS: Fifty clinical centers randomly allocated 681 patients with chronic, stable

asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1

second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory

volume in 1 second (absolute value) after inhaled beta-agonist administration, a minimal predefined

level of daytime asthma symptoms, and inhaled beta-agonist use. Twenty-three percent of the

patients used concomitant inhaled corticosteroids. PRIMARY END POINTS: Forced expiratory

volume in 1 second and daytime asthma symptoms. RESULTS: Montelukast improved airway

obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate)

and patient-reported end points (daytime asthma symptoms, "as-needed" beta-agonist use,

nocturnal awakenings) (P .001 compared with placebo). Montelukast provided near-maximal

effect in these end points within the first day of treatment. Tolerance and rebound worsening of

asthma did not occur. Montelukast improved outcome end points, including asthma exacerbations,

asthma control days (P .001 compared with placebo), and decreased peripheral blood eosinophil

counts (P .001 compared with placebo). The incidence of adverse events and discontinuations from

therapy were similar in the montelukast and placebo groups. CONCLUSIONS: Montelukast,

compared with placebo, significantly improved asthma control during a 12-week treatment period.

Montelukast was generally well tolerated, with an adverse event profile comparable with that of

placebo. 

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7.) Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Montelukast Asthma Study Group.

=========================================================================

Eur Respir J 1998 Jun;11(6):1232-9 (ISSN: 0903-1936)

Noonan MJ; Chervinsky P; Brandon M; Zhang J; Kundu S; McBurney J; Reiss TF 

Allergy Associates, PC Research, Portland, Oregon, USA.

The leukotrienes are known to be important mediators of bronchial asthma. The ability of

montelukast, a potent and selective CysLT1 leukotriene receptor antagonist, to cause a

dose-related improvement in chronic asthma was investigated in a placebo-controlled, multicentre,

parallel-group study. After a two week placebo run-in period, chronic asthmatic patients with a

forced expiratory volume in one second (FEV1) 40-80% predicted with > or = 15% increase

(absolute value) after beta2-agonist were randomly assigned to one of four treatment groups

(placebo or montelukast 2, 10, or 50 mg once daily in the evening) for a three week, double-blind

treatment period. For patient-reported end-points (daytime symptom score, use of as needed

inhaled beta2 agonist, asthma-specific quality of life) and frequency of asthma exacerbations,

montelukast 10 and 50 mg caused similar responses, superior to 2 mg and significantly (p<0.05;

linear trend test) different from placebo. All three doses caused improvements in FEV1 and morning

and evening peak expiratory flow rate (PEFR) that were significantly (p<0.05) different from

placebo. Differences (least square mean) between the pooled 10 and 50 mg montelukast

treatment groups and placebo were: 7.1% change from baseline in FEV1, 19.23 L x min(-1) in

morning PEFR, -0.29 in daytime asthma symptom score (absolute value), and -0.82 in

beta2-agonist use (puff x day(-1)). The incidence of adverse experiences was neither dose-related

nor different between montelukast and placebo treatments. We conclude that montelukast

causes a dose-related improvement in patient-reported asthma end-points over the range 2-50 mg.

Montelukast causes benefit to chronic asthmatic patients by improving asthma control end-points. 

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8.) Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group.

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JAMA 1998 Apr 15;279(15):1181-6 (ISSN: 0098-7484)

Knorr B; Matz J; Bernstein JA; Nguyen H; Seidenberg BC; Reiss TF; Becker A

Department of Pulmonary-Immunology, Merck Research Laboratories, Rahway, NJ 07065, USA.

CONTEXT: Leukotrienes are important mediators of asthma by causing bronchoconstriction,

mucous secretion, and increased vascular permeability. Studies using compounds that block

leukotrienes have demonstrated improvement in asthma control in adults and adolescents, but

children younger than 12 years, for whom asthma is the most common chronic disease, have not

been studied. OBJECTIVE: To determine the clinical effect of montelukast, a leukotriene receptor

antagonist, in 6- to 14-year-old children with asthma. DESIGN: Eight-week, multicenter,

randomized, double-blind study. SETTING: Forty-seven outpatient centers at private practices and

academic medical centers in the United States and Canada. PATIENTS: A total of 336 children

with forced expiratory volume in 1 second (FEV1) between 50% to 85% of the predicted value, at

least 15% reversibility after inhaled beta-agonist administration, a minimal predefined level of

daytime asthma symptoms, and daily beta-agonist use. Concomitant inhaled corticosteroids at a

constant daily dose were used by 39% of patients receiving montelukast and 33% receiving

placebo. INTERVENTION: After a 2-week placebo run-in period, patients received either

montelukast (5-mg chewable tablet) or matching-image placebo once daily at bed-time for 8

weeks. MAIN OUTCOME MEASURE: Morning FEV1 percent change from baseline.

RESULTS: Mean morning FEV1 increased from 1.85 L to 2.01 L in the montelukast group and

from 1.85 L to 1.93 L in the placebo group. This represents an 8.23% (95% confidence interval

[CI], 6.33% to 10.13%) increase from baseline in the montelukast group and a 3.58% (95% CI,

1.29% to 5.87%) increase from baseline in the placebo group (P .001 for montelukast vs

placebo). CONCLUSION: Montelukast improves morning FEV1 in 6- to 14-year-old children

with chronic asthma. 

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9.) Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers.

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Biopharm Drug Dispos 1997 Dec;18(9):769-77 (ISSN: 0142-2782)

Zhao JJ; Rogers JD; Holland SD; Larson P; Amin RD; Haesen R; Freeman A; Seiberling M; Merz

M; Cheng H 

Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast

sodium (MK-0476), 10 mg d-1 in healthy young subjects (N = 12), (ii) evaluate the

pharmacokinetics of montelukast in healthy elderly subjects (N = 12), and (iii) compare the

pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects.

Following oral administration of montelukast sodium, 10 mg d-1 (the therapeutic regimen for

montelukast sodium) for 7 d, there was little difference in the plasma concentration-time profiles of

montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma

concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL-1 on days 3-7,

indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio

was 1.14, indicating that this dose regimen results in a 14% accumulation of montelukast. In

elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (Vss),

plasma terminal half-life (t1/2), and mean residence time in the body (MRTIV) following a 7 mg

intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30.8 mL

min-1, 9.7 L, 6.7 h, and 5.4 h, respectively. Following a 10 mg oral dose, the bioavailability of

montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in

healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC0--

infinity, Cmax, tmax, and t1/2, and the mean plasma concentration-time profile of montelukast in

the elderly, were generally similar to those in young subjects, indicating that age has little or no effect

on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age. 

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10.) Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile.

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Drug Metab Dispos 1997 Nov;25(11):1282-7 (ISSN: 0090-9556)

Balani SK; Xu X; Pratha V; Koss MA; Amin RD; Dufresne C; Miller RR; Arison BH; Doss GA;

Chiba M; Freeman A; Holland SD; Schwartz JI; Lasseter KC; Gertz BJ; Isenberg JI; Rogers JD;

Lin JH; Baillie TA 

Department of Drug Metabolism, Merck Research Laboratories; 

Montelukast sodium [1- [(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-

ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]meth yl cyclopropylacetic acid

sodium salt] (MK-476, Singulair) is a potent and selective antagonist of the cysteinyl leukotriene

(Cys-LT1) receptor and is under investigation for the treatment of bronchial asthma. To assess the

metabolism and excretion of montelukast, six healthy subjects received single oral doses of 102

mg of [14C]montelukast, and the urine and feces were collected. Most of the radioactivity was

recovered in feces, with /=0.2% appearing in urine. Based on these results and the reported

modestly high oral bioavailability of montelukast, it could be concluded that a major part of the

radioactivity was excreted via bile. A second clinical study was conducted to identify biliary

metabolites of montelukast. The bile was aspirated using a modified procedure involving a

nasogastric tube placed fluoroscopically near the ampulla of Vater, after an oral dose of 54.8 mg of

[14C]montelukast. This technique appears to be a new application for drug metabolism studies.

The study was conducted with fasted and nonfasted subjects, with the bile being aspirated

continuously under suction over periods of 2-8 hr and 8-12 hr after the dose, respectively. Two

hours before the end of the collection procedure, cholecystokinin carboxyl-terminal octapeptide

was administered iv to stimulate gallbladder contraction. Plasma samples also were collected

periodically over 10 hr. Due to the nature of the collection procedure and the limited sampling time,

recovery of radioactivity in bile was incomplete and varied from 3 to 20% of the dose.

Radiochromatographic and LC-MS/MS analyses of bile showed the presence of one major and

several minor metabolites, along with small amounts of unchanged parent drug. The minor

metabolites were identified, by LC-MS/MS comparison with synthetic standards or by NMR, as

acyl glucuronide (M1), sulfoxide (M2), 25-hydroxy (a phenol, M3), 21-hydroxy (diastereomers of

a benzylic alcohol, M5a and M5b), and 36-hydroxy (diastereomers of a methyl alcohol, M6a and

M6b) analogs of montelukast. The major metabolite was characterized as a dicarboxylic acid

(M4), a product of further oxidation of the hydroxymethyl metabolite M6. Chiral LC-MS/MS

analyses of M4 revealed that this diacid, like M5 and M6, was formed in both diastereomeric

forms. The levels of metabolites in the systemic circulation were low in the fed as well as fasted

subjects, with 2% of the circulating radioactivity being due to metabolites M5a, M5b, M6a, and

M6b. Overall, this bile aspiration technique, which is less invasive than either T-tube drainage or

fine-needle percutaneous puncture, provided a convenient and expedient means of identifying the

biliary metabolites of montelukast, relatively free of contributions from colonic microflora. 

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11.) Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval.

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Clin Pharmacol Ther 1997 Nov;62(5):556-61 (ISSN: 0009-9236)

Bronsky EA; Kemp JP; Zhang J; Guerreiro D; Reiss TF 

AAAA Medical Research Group, Salt Lake City, USA.

The dose-related protective effects of montelukast, a potent and selective cysteinyl

leukotriene-receptor antagonist, against exercise-induced bronchoconstriction were investigated in a

five-period, randomized, incomplete-block, crossover study with montelukast (0.4, 2, 10, 50 mg)

and placebo. The study subjects were 27 nonsmoking, healthy stable patients with asthma (mean

forced expiratory volume in 1 second [FEV1], 82.0% predicted) who demonstrated a or = 20%

decrease in FEV1 while beta-agonist was withheld for 6 hours before treadmill exercise. The

standard exercise challenge was performed 20 to 24 hours, and again 32 to 36 hours, after the

second of two once-daily doses. The effect of oral montelukast on exercise was measured by the

area above the postexercise percentage decrease in FEV1 versus time curve from 0 to 60 minutes

[AUC(0-60)], the maximal percentage decrease in FEV1 after exercise, and time after maximal

decrease to recovery of FEV1 to within 5% of the preexercise baseline. Twenty to 24 hours after

administration, montelukast caused dose-related protection, while providing similar protection

against exercise-induced bronchoconstriction at the two highest doses. The AUC(0-60) values

(mean +/- SD) were 637 +/- 898, 715 +/- 870, 988 +/- 1147, and 927 +/- 968 min. % for 50, 10,

2, and 0.4 mg montelukast, respectively, and 1193 +/- 1097 min. % for placebo (p = 0.003). No

important clinical effect was present 36 hours after dosing. Montelukast was generally well

tolerated at all dose levels. In conclusion, montelukast caused dose-related protection against

exercise-induced bronchoconstriction at the end of a once-daily dosing interval. Protection against

exercise-induced bronchoconstriction can be used to determine appropriate dose selection. 

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12.) Hepatic microsomal metabolism of montelukast, a potent

leukotriene D4 receptor antagonist, in humans.

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Drug Metab Dispos 1997 Sep;25(9):1022-31 (ISSN: 0090-9556)

Chiba M; Xu X; Nishime JA; Balani SK; Lin JH 

Department of Drug Metabolism I, Merck Research Laboratories, West Point, PA 19486, USA.

Montelukast (L-706,631, MK-0476, SINGULAIR), a potent and selective leukotriene D4

(CysLT1) receptor antagonist, is currently under development for the treatment of asthma. In vitro

studies were conducted using human liver microsomes to evaluate: 1) the difference in the metabolic

kinetics of montelukast between adult and pediatric subjects; 2) the relative contribution of

flavin-containing monooxygenase and cytochrome P450 (P450) to the sulfoxidation; and 3) the

P450 isoforms responsible for montelukast oxidation. No statistically significant difference was

observed in the in vitro kinetics for acyl glucuronidation and oxidative metabolism between the two

age groups. Results from studies on heat inactivation of flavin-containing monooxygenase and

immunochemical inhibition by an anti-rat NADPH P450 reductase antibody on montelukast

oxidation indicated that all oxidative metabolism of montelukast-including diastereomeric

sulfoxidations, as well as 21- and methyl-hydroxylations-are catalyzed exclusively by P450. Five in

vitro approaches have been used to identify the P450 isoforms responsible for the human liver

microsomal oxidation of montelukast. The experimental results consistently indicated that

CYP3A4 catalyzes sulfoxidation and 21-hydroxylation, whereas CYP2C9 selectively mediates

methyl-hydroxylation. 

=========================================================================

13.) Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled

corticosteroids.

=========================================================================

Thorax 1997 Jan;52(1):45-8 (ISSN: 0040-6376)

Reiss TF; Sorkness CA; Stricker W; Botto A; Busse WW; Kundu S; Zhang J 

Department of Pulmonary Immunology, Merck Research Laboratories, Rahway, New Jersey

07065, USA.

BACKGROUND: Cysteinyl leukotriene release in association with airway inflammation is a feature

of clinical asthma. The acute effects of montelukast (MK-0476), a potent, orally administered,

specific cysteinyl leukotriene receptor antagonist, on airways obstruction was assessed in patients

with mild to moderately severe asthma. METHODS: Twenty two asthmatic subjects were

randomised to receive montelukast, 100 mg or 250 mg, or placebo in a double blind, three

period, crossover trial. Ten of the patients were using concomitant inhaled corticosteroids.

RESULTS: Montelukast increased the forced expiratory volume in one second (FEV1) from

predose baseline values compared with placebo, the percentage point differences between

montelukast and placebo being 8.6% (95% CI 3.6 to 13.6) and 8.5% (95% CI 3.5 to 13.5) for

the 100 mg and 250 mg doses, respectively. CONCLUSION: Single oral doses of montelukast

100 mg and 250 mg produced significant increases in FEV1 irrespective of the concurrent use of

inhaled corticosteroids in asthmatic subjects with airflow limitation. 

=========================================================================

14.) Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma.

=========================================================================

Clin Pharmacol Ther 1997 Jan;61(1):83-92 (ISSN: 0009-9236)

De Lepeleire I; Reiss TF; Rochette F; Botto A; Zhang J; Kundu S; Decramer M 

Merck Research Laboratories, Brussels.

Montelukast, a new specific oral cysteinyl LT3-receptor antagonist was evaluated for its activity in

attenuating inhaled leukotriene D4 (LTD4) bronchoconstriction in patients with asthma. In two

double-blind, placebo-controlled, randomized crossover studies, patients with mild asthma (forced

expiratory volume in 1 second [FEV1] or = 70%) were studied. In trial A, LTD4 challenge began 4

hours (peak plasma concentration) after a single dose of placebo or 5, 20, 100, and 250 mg

montelukast. In trial B, and LTD4 challenge was started 20 hours after administration of placebo,

40 mg montelukast, or 200 mg montelukast. During each challenge, twofold increasing

concentrations of LTD4 were inhaled until specific airways conductance (sGaw) decreased by at

least 50% (PC50) or the highest concentration of LTD4 was inhaled. In trial A with all doses and in

trial B with the 200 mg dose, bronchoconstriction was attenuated (50% fall in sGaw was not

observed) up to the highest dose of LTD4 administered. In trial B, during the 40 mg period, only

two of six patients exhibited a 50% fall in sGaw; PC50 ratios (montelukast 40 mg/placebo) were

18 and 45 in these two patients. These results indicate that montelukast is a highly potent and

long-lasting antagonist of LTD4-induced bronchoconstriction in patients with asthma. 

=========================================================================

15.) Pharmacokinetics, bioavailability, and safety of montelukast

sodium (MK-0476) in healthy males and females.

=========================================================================

Pharm Res 1996 Mar;13(3):445-8 (ISSN: 0724-8741)

Cheng H; Leff JA; Amin R; Gertz BJ; De Smet M; Noonan N; Rogers JD; Malbecq W; Meisner

D; Somers G 

Merck Research Laboratories, Department of Drug Metabolism, West Point, Pennsylvania 19486,

USA.

PURPOSE. The safety, tolerability, and pharmacokinetics of intravenous *i.v.) montelukast

sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males

and healthy females were studied. METHODS. This was a two-part study. Part I was a four-period

study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as

15-minute constant-rate i.v. infusions (Periods 1-3), followed by a 10-mg oral tablet dose of

montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females

of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively)

or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of

montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC.

RESULTS. In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg,

the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity

(AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume

of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body

(MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and

remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg

tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax

occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of

montelukast sodium averaged 2441 ng.hr/ml, 385 ng/ml. 3.7 hr, 4.9 hr, 3.4 hr, and 66%,

respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the

values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively.

Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent

t1/2, MAT and F were 2270 ng.hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively.

These parameter values were similar to or slightly smaller than those in healthy males receiving the

same i.v. and oral doses. CONCLUSIONS. The disposition kinetics of montelukast sodium were

linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this

study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral

dose are well tolerated. 

=========================================================================

16.) WAM: Study Shows Children With Asthma Prefer Singulair To Cromolyn

=========================================================================

BARCELONA, SPAIN -- Dec. 11, 1998 -- Four out of five children with

asthma preferred the oral therapy Merck & Co.’s Singulair™ (montelukast)

over inhaled cromolyn, resulting in twice as good compliance with treatment,

according to a new study presented at the World Asthma Meeting here this

week.

A study of 296 children (mean age 8.8 years) with mild-to-moderate asthma

found that more than 82 percent preferred Singulair to inhaled cromolyn. The

children were randomised to one-month treatment periods with Singulair (5mg

chewable tablet, once daily at bedtime) followed by cromolyn sodium (1.6mg

given by a metered dose inhaler four times daily), or cromolyn followed by

Singulair.

The children had baseline FEV values of 74 percent of predicted, with an

average treatment dose of 2.7 puffs of beta-agonist daily. Using questionnaires,

researchers determined which treatment the children and their parents

preferred.

The research demonstrated that the parents of the children in the study also

preferred Singulair by a wide margin. An overwhelming 87 percent of the

parents preferred Singulair, compared to about 12 percent who preferred

cromolyn.

Previous research has shown that as many as half of parents of children with

asthma do not give asthma treatment reliably, even if their children’s symptoms

are frequent.

The preference for Singulair by both the children and their parents was

reflected in improved compliance with this therapy, an essential ingredient to

controlling asthma symptoms and the inflammation underlying the disease.

Researchers reported that nearly twice as many children (78 percent) on

Singulair were highly compliant (on more than 95 percent of days) compared to

cromolyn (43 percent). This improved compliance was associated with far

fewer children taking Singulair (one percent) dropping out of the study due to

worsening asthma compared with those on cromolyn (five percent). Singulair

was well tolerated throughout the study.

A survey of 4,000 school children in England and Wales -- 19 percent of

whom had asthma – revealed that nearly a third of those with asthma

sometimes forgot and 15 percent always forgot to take their preventer inhaler

medication. Other studies on compliance have confirmed these disturbing

findings, revealing that 30 to 70 percent of patients with asthma -- both adults

and children -- fail to comply with their prescribed treatment regimen.

The strong preference by both children and their parents for Singulair reflects

several of the new medicine’s advantages, including the fact that Singulair is

available as a cherry-flavoured, chewable tablet. The vast majority of asthma

drugs, both symptom-relievers and anti-inflammatory agents, are formulated as

inhaled therapies.

In addition to the child-friendly formulation, Singulair is prescribed once-daily,

in contrast to most other asthma therapies that need to be taken two or more

times each day. Previous research on patient compliance has shown that the

number of times a medication has to be taken each day appears to directly

affect patient compliance. These studies have confirmed that patients find it

difficult to take medicine four times a day, the frequency recommended for

inhaled cromolyn as prescribed in this study.

==========================================================================

17.) SINGULAIR® (Montelukast Sodium), the product 

=========================================================================

1.) DESCRIPTION:

------------

Montelukast sodium, the active ingredient in SINGULAIR*, is a selective and orally active

leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.

Montelukast sodium is described chemically as

[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-

methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.

The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18. 

2.) CLINICAL PHARMACOLOGY:

-------------------------

Mechanism of Action 

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism

and are released from various cells, including mast cells and eosinophils. These eicosanoids

bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Cysteinyl

leukotrienes and leukotriene receptor occupation have been correlated with the

pathophysiology of asthma, including airway edema, smooth muscle contraction, and altered

cellular activity associated with the inflammatory process, which contribute to the signs and

symptoms of asthma.

Montelukast is an orally active compound that binds with high affinity and selectivity to the

CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as

the prostanoid, cholinergic, or ß-adrenergic receptor). Montelukast inhibits physiologic actions

of LTD4 at the CysLT1 receptor without any agonist activity.

3.) DOSAGE AND ADMINISTRATION:

-----------------------------

General Information:

Adolescents and Adults 15 Years of Age and Older

The dosage for adolescents and adults 15 years of age and older is one 10-mg tablet daily to

be taken in the evening.

Pediatric Patients 6 to 14 Years of Age

The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily to be

taken in the evening. No dosage adjustment within this age group is necessary. Safety and

effectiveness in pediatric patients younger than 6 years of age have not been established.

The safety and efficacy of SINGULAIR was demonstrated in clinical trials where it was

administered in the evening without regard to the time of food ingestion. There have been no

clinical trials evaluating the relative efficacy of morning versus evening dosing.

4.) OVERDOSAGE:

---------------

No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice

(approximately 2000 times the maximum recommended daily oral dose in adults and

2400 times the maximum recommended daily oral dose in children, on a mg/m2 basis) and

rats (approximately 4100 times the maximum recommended daily oral dose in adults and

4800 times the maximum recommended daily oral dose in children, on a mg/m2 basis).

No specific information is available on the treatment of overdosage with SINGULAIR. In

chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to

patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for

approximately a week without clinically important adverse experiences. In the event of

overdose, it is reasonable to employ the usual supportive measures; e.g., remove

unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute

supportive therapy, if required.

It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

5.) ADVERSE REACTIONS:

---------------------

Adolescents and Adults 15 Years of Age and Older

SINGULAIR has been evaluated for safety in approximately 2600 adolescent and adult

patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the

following adverse experiences reported with SINGULAIR occurred in greater than or equal to

1% of patients and at an incidence greater than that in patients treated with placebo, regardless of causality assessment:

"The following adverse reactions have been reported in post-marketing use: hypersensitivity

reactions, including anaphylaxis, angioedema, pruritus, and urticaria"

"Additionally, the following have been reported: allergic reactions including swelling of the

face, lips, tongue, and/or throat, which may cause difficulty in breathing or swallowing; hives,

and itching." 

6.) PRECAUTIONS:

-----------------

SINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks,

including status asthmaticus.

Patients should be advised to have appropriate rescue medication available. Therapy with

SINGULAIR can be continued during acute exacerbations of asthma.

While the dose of inhaled corticosteroid may be reduced gradually under medical

supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.

SINGULAIR should not be used as monotherapy for the treatment and management of

exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise

should continue to use their usual regimen of inhaled ß-agonists as prophylaxis and have

available for rescue a short-acting inhaled ß-agonist.

==========================================================================

18.) Patient Education Monograph for Montelukast Sodium (Oral )

==========================================================================

IMPORTANT NOTE: 

THE FOLLOWING INFORMATION IS INTENDED TO SUPPLEMENT, NOT

SUBSTITUTE FOR, THE EXPERTISE AND JUDGMENT OF YOUR PHYSICIAN,

PHARMACIST OR OTHER HEALTHCARE PROFESSIONAL. IT SHOULD NOT BE

CONSTRUED TO INDICATE THAT USE OF THE DRUG IS SAFE, APPROPRIATE,

OR EFFECTIVE FOR YOU. CONSULT YOUR HEALTHCARE PROFESSIONAL

BEFORE USING THIS DRUG. 

USES: 

This medication is used to control chronic asthma, helping to decrease the number of asthma

attacks. 

HOW TO USE THIS MEDICATION: 

--------------------------

Take this medicine by mouth as directed, generally one tablet (10mg) daily in the evening with

or without food. Keep taking this medicine every day, even during asthma attacks and

periods when you have no asthma symptoms. This drug does not relieve acute asthma

attacks. Use your prescribed acute asthma attack medicines (and pre-exercise medicines for

exercise-related asthma) as directed. Consult your doctor or pharmacist for specific advice

on your drug therapy. Do not decrease or stop any asthma medicine unless instructed to do

so by your doctor. Report promptly to your doctor or pharmacist any worsening of asthma

symptoms, if your short-acting inhaler use increases or if use exceeds the 24 hour maximum

prescribed by your doctor. 

SIDE EFFECTS: 

------------

Unusual weakness, stomach upset, diarrhea, dizziness, cough, headache or mouth pain may

occur. If these effects persist or worsen, notify your doctor promptly. Unlikely but report

promptly stomach pain, fever, persistent sore throat or earache, muscle aches, rash,

yellowing eyes and skin or numbness/tingling of hands or feet. 

PRECAUTIONS: 

-----------

Before using this drug, tell your doctor your medical history, including any allergies (especially

drug allergies) or liver disease. Tell your doctor if you are pregnant before using this

medication. It is not known whether this drug is excreted into breast milk. Consult your

doctor before breast-feeding. 

DRUG INTERACTIONS: 

-----------------

Tell your doctor of all nonprescription and prescription medication you may use, especially

rifamycin antibiotics (e.g., rifampin), certain anti-seizure drugs (e.g., phenytoin, phenobarbital,

carbamazepine) or other drugs for asthma. 

NOTES: 

------

Do not share this medication with others. Medical tests will be performed to monitor for

effectiveness and possible side effects of this drug. 

MISSED DOSE: 

-----------

If you miss a dose, use it as soon as you remember. If it is near the time of the next dose,

skip the missed dose and resume your usual dosing schedule. Do not "double-up" the dose to

catch up. 

STORAGE: 

-------

Store at room temperature between 59 and 86 degrees F 

(15-30 degrees C) away from light and moisture. 

==========================================================================

19.) Singulair Safety Information Revised To Include Reports Of Inflammatory Condition

==========================================================================

WEST POINT, PA – Dec. 4, 1998 -- Merck & Co., Inc. has begun informing

healthcare professionals about new safety information, revising the current

precautionary language in the prescribing information for Singulair(R)

(montelukast sodium). 

Singulair is a member of the class of asthma medicines called leukotriene

antagonists, used for the chronic treatment of asthma. The information is also

being communicated in a letter to physicians and pharmacists throughout the

United States.

The company has become aware of rare case reports in which patients who

were receiving Singulair were reported to have an inflammatory condition

associated with an increase in eosinophils, one of the types of cells in the blood.

This was sometimes associated with additional features consistent with

Churg-Strauss syndrome (CSS), a condition which is often treated with oral or

intravenous corticosteroids.

Most of these patients had severe asthma and were receiving multiple asthma

medications, often including systemic corticosteroids. In a number of the

reported cases, it appears that the symptoms of this syndrome were present

before therapy with Singulair was started. In most, but not all, of these cases,

clinical features associated with CSS occurred or worsened during

corticosteroid reduction. Singulair has not been shown to cause this condition.

CSS is a rare but serious condition involving inflammation of blood vessels that

affects a small subset of asthmatic patients. CSS may lead to neurological,

pulmonary or cardiac complications. Common symptoms include a combination

of a flu-like illness, rash, pins and needles or numbness of arms and legs and

severe sinusitis.

The Precautions and Adverse Reactions sections of the physician's prescribing

information, as well as the Patient Product Information (PPI), have been

revised to alert physicians to the signs and symptoms of this

condition.

The revisions to the prescribing information are being made voluntarily, based

on reports received during the marketed use of Singulair since its approval and

its use by more than 600,000 patients world-wide.

Singulair is a once-a-day pill used for the prevention and chronic treatment of

asthma in adults and children aged six years and older. It was approved for use

in the U.S. in February 1998. Singulair should not be used for the immediate

relief of asthma attacks. Patients should always have appropriate rescue

medication available and continue to take their other asthma medications unless

instructed otherwise by their doctor.

In clinical studies, side effects reported with Singulair were usually mild and

generally did not require patients to stop taking Singulair. Side effects seen in

adults and children during the clinical trials were similar for the groups treated

with Singulair and for those treated with placebo. The most commonly reported

side effects in adults for both placebo and Singulair were headache, influenza

and abdominal pain. There was no increase in side effects with extended

treatment and no clinically meaningful drug interactions. 

=========================================================================

20.) SINGULAIR® (Montelukast Sodium), the Food and Drug Administration

Source: December 4, 1998 -- MedWatch Program 

=========================================================================

Food and Drug Administration

============================

This is the retyped text of a letter from Merck & Co., Inc.

Contact the company for a copy of any referenced enclosures.

December, 1998

Dear Healthcare Professional:

Merck & Co., Inc., would like to bring to your attention recent changes

to the current Physician's Circular and Patient Product Information for

SINGULAIR (Montelukast Sodium) Tablets concerning the

description of eosinophilic conditions. SINGULAIR is a selective

leukotriene (LTD4) receptor antagonist that was approved by the FDA

in February 1998 for the prophylaxis and chronic treatment of asthma

in adults and pediatric patients 6 years of age and older.

As part of our customary postmarketing surveillance, we have become

aware of case reports in which patients who were receiving

SINGULAIR presented with eosinophilic conditions sometimes

consistent with the Churg-Strauss syndrome (CSS). Patients presenting

with these conditions had significant asthma histories and were receiving

multiple asthma medications, often including systemic corticosteroids.

On review some of these cases had features consistent with these

conditions present prior to initiation of therapy with SINGULAIR. In

most but not all of these cases clinical features associated with CSS

occurred or worsened during corticosteroid reduction. A causal

association between SINGULAIR and these underlying conditions has

not been established.

In order to communicate this important information to health care

professionals, the PRECAUTIONS and ADVERSE REACTIONS

sections of the Product Circular for SINGULAIR have been revised to

include the following:

PRECAUTIONS

Eosinophilic Conditions: In rare cases, patients 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 events usually, but not always,

have been 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. A causal association between SINGULAIR

and these underlying conditions has not been established (see

ADVERSE REACTIONS).

ADVERSE REACTIONS

In rare cases, patients 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 events usually,

but not always, have been 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. A causal association

between SINGULAIR and these underlying conditions has not been

established (see PRECAUTIONS, Eosinophilic Conditions). 

These changes to the Physician's Circular and Patient Product

Information are being made voluntarily, based on reports received

during marketed use of SINGULAIR since its approval and its use by

over 600,000 patients worldwide.

In order to communicate this information to patients, similar changes in

laymen's terms have been incorporated into the Patient Product

Information for SINGULAIR.

At Merck, our primary concern remains the safety and well-being of

the patients who use our products. You can assist us in this regard by

reporting all adverse events involving patients on SINGULAIR to the

Merck National Service Center at 1-800-672-6372 or to the FDA

MedWatch program by phone at 1-800-FDA-1088, by FAX at

1-800-FDA-0178, or by mail at MedWatch, HF-2, 5600 Fishers

Lane, Rockville, MD 20857.

Please take the time to read the revised Physician's Circular and Patient

Product Information for SINGULAIR which are enclosed. Questions

from health care professionals may be directed to the Merck National

Service Center. Thank you very much for your time and attention to this

matter.

======================================================================

DATA-MÉDICOS/DERMAGIC-EXPRESS No (31) 22/01/99 DR. JOSE LAPENTA R. 

======================================================================