Admont

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Admont uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Admont reviews

1 INDICATIONS AND USAGE

Admont sodium tablets are a leukotriene receptor antagonist indicated for:

• Prophylaxis and chronic treatment of asthma in patients 2 years of age and older.
• Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2)
• Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 2 years of age and older (1.3).

1.1 Asthma

Admont sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older.

1.2 Exercise-Induced Bronchoconstriction

Admont sodium is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Admont tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

1.3 Allergic Rhinitis

Admont sodium is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 2 years of age and older.

2 DOSAGE AND ADMINISTRATION

Administration :

• Asthma ( 2.1 ): Once daily in the evening for patients 2 years and older.
• Acute prevention of EIB ( 2.2 ): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older.
• Seasonal allergic rhinitis ( 2.3 ): Once daily for patients 2 years and older.
• Perennial allergic rhinitis ( 2.3 ): Once daily for patients 2 years of age and older.

Dosage (by age)

• 15 years and older: one 10 mg tablet
• 6 to 14 years: one 5 mg chewable tablet
• 2 to 5 years: one 4 mg chewable tablet

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening ( 2.4 ).

2.1 Asthma

Admont sodium should be taken once daily in the evening. The following doses are recommended:

For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.

There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of Admont are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when Admont was administered in the evening without regard to time of food ingestion.

2.2 Exercise-Induced Bronchoconstriction in Patients 15 Years of Age and Older

For prevention of EIB, a single 10 mg dose of Admont should be taken at least 2 hours before exercise.

An additional dose of Admont should not be taken within 24 hours of a previous dose. Patients already taking Admont sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of Admont sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Admont tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Allergic Rhinitis

For allergic rhinitis, Admont sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when Admont was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.

The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.

The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.

2.4 Asthma and Allergic Rhinitis

Patients with both asthma and allergic rhinitis should take only one Admont sodium dose daily in the evening.

3 DOSAGE FORMS AND STRENGTHS

• Admont sodium tablets, 10 mg (montelukast) are beige colored, round, biconvex, film coated tablets with "SZ 344" debossed on one side and plain on other side.
• Admont sodium chewable tablets, 4 mg (montelukast) are pink colored, round, mottled and debossed “SZ 74” on one side and plain on the other side.
• Admont sodium chewable tablets, 5 mg (montelukast) are pink colored, round, mottled and debossed “SZ 76” on one side and plain on other side.

• Admont sodium film-coated tablets, 10 mg ( Admont)
• Admont sodium chewable tablets, 4 mg and 5 mg (montelukast)

4 CONTRAINDICATIONS

Hypersensitivity to any component of this product.

• Hypersensitivity to any component of this product ( 4 ).

5 WARNINGS AND PRECAUTIONS

• Do not prescribe Admont sodium to treat an acute asthma attack.
• Advise patients to have appropriate rescue medication available ( 5.1 ).
• Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute Admont sodium for inhaled or oral corticosteroids ( 5.2 ).
• Patients with known aspirin sensitivity should continue to avoid aspirin or non-steroidal anti-inflammatory agents while taking Admont sodium ( 5.3 ).
• Neuropsychiatric events have been reported with Admont sodium. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with Admont sodium if such events occur ( 5.4 and 6.2 ).
• Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy ( 5.5 and 6.2 ).
• Inform patients with phenylketonuria that the 4 mg and 5 mg chewable tablets contain phenylalanine ( 5.6 ).

5.1 Acute Asthma

Admont sodium 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 Admont sodium can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist.

5.2 Concomitant Corticosteroid Use

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Admont sodium should not be abruptly substituted for inhaled or oral corticosteroids.

5.3 Aspirin Sensitivity

Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Admont sodium. Although Admont sodium is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see CLINICAL STUDIES ].

5.4 Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Admont sodium. Post-marketing reports with Admont sodium use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Admont sodium appear consistent with a drug-induced effect.

Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Admont sodium if such events occur [see ADVERSE REACTIONS (6.2)].

5.5 Eosinophilic Conditions

Patients with asthma on therapy with Admont sodium 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 Admont sodium and these underlying conditions has not been established [see ADVERSE REACTIONS ].

5.6 Phenylketonuria

Phenylketonuric patients should be informed that the 4 mg and 5 mg chewable tablets contain phenylalanine (a component of aspartame), 0.48 mg and 0.60 mg per 4 mg and 5 mg chewable tablet, respectively.

6 ADVERSE REACTIONS

Most common adverse reactions : upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.

The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Adults and Adolescents 15 Years of Age and Older with Asthma

Admont sodium has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with Admont sodium occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

	Admont 10 mg/day (%) (n=1955)	Placebo (%) (n=1180)
Body As A Whole Pain, abdominal Asthenia/fatigue Fever Trauma	2.9 1.8 1.5 1	2.5 1.2 0.9 0.8
Digestive System Disorders Dyspepsia Pain, dental Gastroenteritis, infectious	2.1 1.7 1.5	1.1 1 0.5
Nervous System/Psychiatric Headache Dizziness	18.4 1.9	18.1 1.4
Respiratory System Disorders Influenza Cough Congestion, nasal	4.2 2.7 1.6	3.9 2.4 1.3
Skin/Skin Appendages Disorder Rash	1.6	1.2
Laboratory Adverse Experiences* ALT increased AST increased Pyuria	2.1 1.6 1	2 1.2 0.9

*Number of patients tested (montelukast sodium and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.

The frequency of less common adverse events was comparable between Admont sodium and placebo.

The safety profile of Admont sodium, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for Admont sodium.

Cumulatively, 569 patients were treated with Admont sodium for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.

Pediatric Patients 6 to 14 Years of Age with Asthma

Admont sodium has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with Admont sodium for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of Admont sodium in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving Admont sodium, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse events was comparable between Admont sodium and placebo. With prolonged treatment, the adverse experience profile did not significantly change.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Admont tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for Admont sodium. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving Admont sodium, the following events not previously observed with the use of Admont sodium in this age group occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.

Pediatric Patients 2 to 5 Years of Age with Asthma

Admont sodium has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with Admont sodium for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving Admont sodium, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.

Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis

Admont sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Admont sodium administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with Admont sodium with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving Admont sodium vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.

Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis

Admont sodium has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. Admont sodium administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency ≥2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.

Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis

Admont sodium has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received Admont sodium in two, 6-week, clinical studies. Admont sodium administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with Admont sodium with a frequency ≥1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.

Pediatric Patients 2 to 14 Years of Age with Perennial Allergic Rhinitis

The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Admont sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia.

Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.

Psychiatric disorders: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tremor [see WARNINGS AND PRECAUTIONS (5.4)].

Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures.

Cardiac disorders: palpitations.

Respiratory, thoracic and mediastinal disorders: epistaxis.

Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis, vomiting.

Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with Admont sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when Admont sodium was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.

Skin and subcutaneous tissue disorders: angioedema, bruising, erythema multiforme, erythema nodosum, pruritus, urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps.

General disorders and administration site conditions: edema.

Patients with asthma on therapy with Admont sodium 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 [see WARNINGS AND PRECAUTIONS (5.5)].

7 DRUG INTERACTIONS

No dose adjustment is needed when Admont sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see CLINICAL PHARMACOLOGY (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Admont sodium should be used during pregnancy only if clearly needed.

Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see NONCLINICAL TOXICOLOGY ].

During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with Admont sodium during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and Admont sodium has not been established.

8.3 Nursing Mothers

Studies in rats have shown that Admont is excreted in milk. It is not known if Admont is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Admont sodium is given to a nursing mother.

8.4 Pediatric Use

Safety and efficacy of Admont sodium have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Special Populations (12.3), AND CLINICAL STUDIES (14.1, 14.2)].

The efficacy of Admont sodium for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 2 to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.

The safety of Admont sodium chewable tablets, 4 mg in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see ADVERSE REACTIONS (6.1)]. Efficacy of Admont sodium in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.

The safety of Admont sodium chewable tablets, 4 mg and 5 mg in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see ADVERSE REACTIONS (6.1)].

The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 6 years with exercise-induced bronchoconstriction have not been established.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Admont tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Growth Rate in Pediatric Patients

A 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of Admont sodium on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included Admont 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between Admont sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the Admont sodium, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for Admont sodium minus placebo, beclomethasone minus placebo, and Admont sodium minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1.

FIGURE 1: Change in Height (cm) from Randomization Visit by Scheduled Week (Treatment Group Mean ± Standard Error* of the Mean)

^*The standard errors of the treatment group means in change in height are too small to be visible on the plot

8.5 Geriatric Use

Of the total number of subjects in clinical studies of Admont, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of Admont are similar in elderly and younger adults. The plasma half-life of Admont is slightly longer in the elderly. No dosage adjustment in the elderly is required.

8.6 Hepatic Insufficiency

No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency [see CLINICAL PHARMACOLOGY ].

8.7 Renal Insufficiency

No dosage adjustment is recommended in patients with renal insufficiency [see CLINICAL PHARMACOLOGY (12.3)].

10 OVERDOSAGE

No mortality occurred following single oral doses of Admont up to 5000 mg/kg in mice (estimated exposure was approximately 335 and 210 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).

No specific information is available on the treatment of overdosage with Admont sodium. In chronic asthma studies, Admont has been administered at doses up to 200 mg/day to adult 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.

There have been reports of acute overdosage in post-marketing experience and clinical studies with Admont sodium. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Admont sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.

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

11 DESCRIPTION

Admont sodium, the active ingredient in Admont sodium tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT₁ receptor.

Admont 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 molecular formula is C₃₅H₃₅ClNNaO₃S, and its molecular weight is 608.18. The structural formula is:

Admont sodium is a hygroscopic, optically active, white to off-white to light yellow powder. Admont sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.

Each 10 mg film-coated Admont sodium tablet contains 10.4 mg Admont sodium, which is equivalent to 10 mg of Admont. In addition Admont tablets contain the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red ferric oxide, titanium dioxide, and yellow ferric oxide.

Each 4 mg and 5 mg chewable Admont sodium tablet contains 4.2 and 5.2 mg Admont sodium, which are equivalent to 4 and 5 mg of Admont, respectively. Admont chewable tablets contain the following inactive ingredients: artificial cherry durarome flavor, aspartame, cherry flavor, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, and red ferric oxide.

The artificial cherry durarome flavor contain: artificial flavors, maltodextrin, red # 40, silicon dioxide, soy lecithin and sugar.

The cherry flavor contain: artificial flavors, benzyl alcohol, lactic acid, and maltodextrin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The cysteinyl leukotrienes are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT₁) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis.

Admont 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 β-adrenergic receptor). Admont inhibits physiologic actions of LTD₄ at the CysLT₁ receptor without any agonist activity.

12.2 Pharmacodynamics

Admont causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD₄ in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD₄-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), Admont sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of Admont sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Admont sodium, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received Admont sodium, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of Admont sodium. The relationship between these observations and the clinical benefits of Admont noted in the clinical trials is not known [see CLINICAL STUDIES (14)].

12.3 Pharmacokinetics

Absorption

Admont is rapidly absorbed following oral administration. After administration of the 10 mg film-coated tablet to fasted adults, the mean peak Admont plasma concentration (C_max) is achieved in 3 to 4 hours (T_max). The mean oral bioavailability is 64%. The oral bioavailability and C_max are not influenced by a standard meal in the morning.

For the 5 mg chewable tablet, the mean C_max is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.

For the 4 mg chewable tablet, the mean C_max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.

The 4 mg oral granule formulation is bioequivalent to the 4 mg chewable tablet when administered to adults in the fasted state.

The safety and efficacy of Admont sodium in patients with asthma were demonstrated in clinical trials in which the 10 mg film-coated tablet and 5 mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of Admont sodium in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablet and 4 mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and efficacy of Admont sodium in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10 mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.

The comparative pharmacokinetics of Admont when administered as two 5 mg chewable tablets versus one 10 mg film-coated tablet have not been evaluated.

Distribution

Admont is more than 99% bound to plasma proteins. The steady state volume of distribution of Admont averages 8 to 11 liters. Studies in rats with radiolabeled Admont indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.

Metabolism

Admont is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Admont are undetectable at steady state in adults and pediatric patients.

In vitro studies using human liver microsomes indicate that CYP3A4 and 2C9 are involved in the metabolism of Admont. Clinical studies investigating the effect of known inhibitors of CYP3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on Admont pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Admont do not inhibit CYP3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 [see DRUG INTERACTIONS (7) AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions (12.3)]. In vitro studies have shown that Admont is a potent inhibitor of CYP2C8; however, data from a clinical drug-drug interaction study involving Admont and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that Admont does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme [see DRUG INTERACTIONS (7) AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions (12.3)].

Elimination

The plasma clearance of Admont averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled Admont, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of Admont oral bioavailability, this indicates that Admont and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of Admont ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Admont are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10 mg Admont, there is little accumulation of the parent drug in plasma (14%).

Special Populations

Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of Admont resulting in 41% (90% CI=7%, 85%) higher mean Admont AUC following a single 10 mg dose. The elimination of Admont was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of Admont sodium in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Renal Insufficiency: Since Admont and its metabolites are not excreted in the urine, the pharmacokinetics of Admont were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Gender: The pharmacokinetics of Admont are similar in males and females.

Race: Pharmacokinetic differences due to race have not been studied.

Adolescents and Pediatric Patients: Pharmacokinetic studies evaluated the systemic exposure of the 4 mg chewable tablets in pediatric patients 2 to 5 years of age, the 5 mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10 mg film-coated tablets in young adults and adolescents ≥15 years of age.

The plasma concentration profile of Admont following administration of the 10 mg film-coated tablet is similar in adolescents ≥15 years of age and young adults. The 10 mg film-coated tablet is recommended for use in patients ≥15 years of age.

The mean systemic exposure of the 4 mg chewable tablet in pediatric patients 2 to 5 years of age and the 5 mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10 mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4 mg chewable tablet should be used in pediatric patients 2 to 5 years of age.

In children 6 to 11 months of age, the systemic exposure to Admont and the variability of plasma Admont concentrations were higher than those observed in adults. Based on population analyses, the mean AUC (4296 ng-hr/mL [range 1200 to 7153]) was 60% higher and the mean C_max (667 ng/mL [range 201 to 1058]) was 89% higher than those observed in adults (mean AUC 2689 ng-hr/mL [range 1521 to 4595]) and mean C_max (353 ng/mL [range 180 to 548]). The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3574 ng-hr/mL [range 2229 to 5408]) was 33% higher and the mean C_max (562 ng/mL [range 296 to 814]) was 60% higher than those observed in adults. Safety and tolerability of Admont in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above [see ADVERSE REACTIONS (6.1)]. The 4 mg oral granule formulation should be used for pediatric patients 12 to 23 months of age for the treatment of asthma, or for pediatric patients 6 to 23 months of age for the treatment of perennial allergic rhinitis. Since the 4 mg oral granule formulation is bioequivalent to the 4 mg chewable tablet, it can also be used as an alternative formulation to the 4 mg chewable tablet in pediatric patients 2 to 5 years of age.

Drug-Drug Interactions

Theophylline, Prednisone, and Prednisolone: Admont sodium has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of Admont did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.

Admont at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Admont at doses of ≥100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.

Oral Contraceptives, Terfenadine , Digoxin, and Warfarin: In drug interaction studies, the recommended clinical dose of Admont did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Admont at doses of ≥100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Admont at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30 mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).

Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants: Although additional specific interaction studies were not performed, Admont was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Cytochrome P450 (CYP) Enzyme Inducers: Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of Admont approximately 40% following a single 10 mg dose of Admont. No dosage adjustment for Admont sodium is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with Admont sodium.

Admont is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving Admont and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that Admont does not inhibit CYP2C8 in vivo. Therefore, Admont is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose.

Admont demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay.

In fertility studies in female rats, Admont produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg. No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Admont had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300 mg/kg/day in rats and rabbits, respectively. These doses were approximately 100 and 110 times the maximum recommended daily oral dose in adults, respectively, based on AUCs. Admont crosses the placenta following oral dosing in rats and rabbits [see USE IN SPECIFIC POPULATIONS (8.1)].

14 CLINICAL STUDIES

14.1 Asthma

Adults and Adolescents 15 Years of Age and Older with Asthma

Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to Admont doses above 10 mg once daily.

The efficacy of Admont sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with Admont, sodium 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV₁) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV₁ and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving Admont sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects.

The results of the U.S. trial on the primary endpoint, morning FEV₁, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 2. Compared with placebo, treatment with one Admont sodium 10 mg tablet daily in the evening resulted in a statistically significant increase in FEV₁ percent change from baseline (13%-change in the group treated with Admont sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV₁ for Admont sodium was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV₁ were similar.

FIGURE 2: FEV₁ Mean Percent Change from Baseline (U.S. Trial: Admont Sodium N=406; Placebo N=270) (ANOVA Model)

The effect of Admont sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2. Results on these endpoints were similar in the US study.

	Admont Sodium			Placebo
Endpoint	N	Baseline	Mean Change from Baseline	N	Baseline	Mean Change from Baseline
Daytime Asthma Symptoms (0 to 6 scale)	372	2.35	-0.49*	245	2.40	-0.26
β-agonist (puffs per day)	371	5.35	-1.65*	241	5.78	-0.42
AM PEFR (L/min)	372	339.57	25.03*	244	335.24	1.83
PM PEFR (L/min)	372	355.23	20.13*	244	354.02	-0.49
Nocturnal Awakenings (#/week)	285	5.46	-2.03*	195	5.57	-0.78

*p<0.001, compared with placebo

Both studies evaluated the effect of Admont sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on Admont sodium experienced asthma attacks compared with patients on placebo (27.3%, p< 0.001). In the US study, 7.8% of patients on Admont sodium and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p = 0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on Admont sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p< 0.001). In the US study, 6.9% of patients on Admont sodium and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p = 0.196).

Onset of Action and Maintenance of Effects

In each placebo-controlled trial in adults, the treatment effect of Admont sodium, measured by daily diary card parameters, including symptom scores, “as-needed” β-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of Admont sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma.

Pediatric Patients 6 to 14 Years of Age with Asthma

The efficacy of Admont sodium in pediatric patients 6 to 14 years of age was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336 patients (201 treated with Admont sodium and 135 treated with placebo) using an inhaled β-agonist on an “as-needed” basis. The patients had a mean baseline percent predicted FEV₁ of 72% (approximate range, 45 to 90%) and a mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. The median age was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5% Hispanic, and 2.7% other origins.

Compared with placebo, treatment with one 5 mg Admont sodium chewable tablet daily resulted in a significant improvement in mean morning FEV₁ percent change from baseline (8.7% in the group treated with Admont sodium vs. 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily “as-needed” inhaled β-agonist use (11.7% decrease from baseline in the group treated with Admont sodium vs. 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the Admont and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14.

Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months.

Pediatric Patients 2 to 5 Years of Age with Asthma

The efficacy of Admont sodium for the chronic treatment of asthma in pediatric patients 2 to 5 years of age was explored in a 12-week, placebo-controlled safety and tolerability study in 689 patients, 461 of whom were treated with Admont sodium. The median age was 4 years (range 2 to 6); 41.5% were females and 58.5% were males. The ethnic/racial distribution in this study was 56.5% Caucasian, 20.9% Hispanic, 14.4% other origins, and 8.3% Black.

While the primary objective was to determine the safety and tolerability of Admont sodium in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, β-agonist use, oral corticosteroid rescue, and the physician’s global evaluation. The findings of these exploratory efficacy evaluations, along with pharmacokinetics and extrapolation of efficacy data from older patients, support the overall conclusion that Admont sodium is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age.

Effects in Patients on Concomitant Inhaled Corticosteroids

Separate trials in adults evaluated the ability of Admont sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly.

One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV₁ of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The ethnic/racial distribution in this study was 92% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5 to 7 week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with Admont sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12 week active treatment period (p≤0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids.

In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of Admont sodium to beclomethasone resulted in statistically significant improvements in FEV₁ compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with Admont or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to Admont sodium alone or placebo alone as indicated by FEV₁, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” β-agonist requirements.

In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that Admont sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of Admont sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of Admont sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see WARNINGS AND PRECAUTIONS (5.3)].

14.2 Exercise-Induced Bronchoconstriction (EIB)

Exercise-Induced Bronchoconstriction (Adults and Adolescents 15 years of age and older)

The efficacy of Admont, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV₁ following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of Admont sodium 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies.

Time of exercise challenge following medication administration	Mean Maximum percent fall in FEV1 *		Treatment difference % for Admont sodium versus Placebo (95%CI)*
	Admont Sodium	Placebo
2 hours	13	22	-9 (-12, -5)
8.5 hours	12	17	-5 (-9, -2)
24 hours	10	14	-4 (-7, -1)

^*Least squares-mean

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Admont tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

The efficacy of Admont sodium for prevention of EIB in patients below 6 years of age has not been established.

Daily administration of Admont sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV₁ percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with Admont sodium, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV₁ and mean time to recovery to within 5% of the pre-exercise FEV₁. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Admont sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV₁ after exercise (i.e., ≥20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10-mg doses of Admont sodium.

In pediatric patients 6 to 14 years of age, using the 5 mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose).

14.3 Allergic Rhinitis

Seasonal Allergic Rhinitis

The efficacy of Admont sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with Admont sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry.

The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0 to 3 categorical scale.

Four of the five trials showed a significant reduction in daytime nasal symptoms scores with Admont sodium 10 mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received Admont sodium tablets, loratadine, and placebo are shown in TABLE 4. The remaining three trials that demonstrated efficacy showed similar results.

Treatment Group (N)	Baseline Mean Score	Mean Change from Baseline	Difference Between Treatment and Placebo (95% CI) Least-Squares Mean
Admont 10 mg (344)	2.09	-0.39	-0.13† (-0.21, -0.06)
Placebo (351)	2.10	-0.26	N.A.
Active Control‡ (Loratadine 10 mg) (599)	2.06	-0.46	-0.24† (-0.31, -0.17)

^*Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0 to 3 categorical scale.

^†Statistically different from placebo (p≤0.001).

^‡The study was not designed for statistical comparison between Admont sodium and the active control (loratadine).

Perennial Allergic Rhinitis

The efficacy of Admont sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received Admont sodium 10 mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled.

In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1% other origins. Admont sodium 10 mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 5); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing).

Treatment Group (N)	Baseline Mean Score	Mean Change from Baseline	Difference Between Treatment and Placebo (95% CI) Least-Squares Mean
Admont 10 mg (1000)	2.09	-0.42	-0.08† (-0.12, -0.04)
Placebo (980)	2.10	-0.35	N.A.

^*Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0 to 3 categorical scale.

^†Statistically different from placebo (p≤0.001).

The other 6-week study evaluated Admont 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120). The primary analysis compared the mean change from baseline in daytime nasal symptoms score for Admont sodium vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between Admont sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between Admont sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01).

16 HOW SUPPLIED/STORAGE AND HANDLING

Admont sodium tablets, 10 mg are beige colored, round, biconvex, film coated tablets with "SZ 344" debossed on one side and plain on other side. They are available as follows:

NDC 0781-5560-31, bottles of 30 tablets

NDC 0781-5560-92, bottles of 90 tablets

NDC 0781-5560-13, carton of 100 tablets (10 x 10 Unit-dose)

Admont sodium chewable tablets, 4 mg are pink colored, round, mottled, and debossed with “SZ 74” on one side and plain on the other side. They are available as follows:

NDC 0781-5554-31, bottles of 30 tablets

NDC 0781-5554-92, bottles of 90 tablets

NDC 0781-5554-05, bottles of 500 tablets

NDC 0781-5554-64, carton of 30 tablets (3 x 10 Unit-dose)

NDC 0781-5554-13, carton of 100 tablets (10 x 10 Unit-dose)

Admont sodium chewable tablets, 5 mg are pink colored, round, mottled, and debossed with “SZ 76” on one side and plain on other side. They are available as follows:

NDC 0781-5555-31, bottles of 30 tablets

NDC 0781-5555-92, bottles of 90 tablets

NDC 0781-5555-05, bottles of 500 tablets

NDC 0781-5555-64, carton of 30 tablets (3 x 10 Unit-dose)

NDC 0781-5555-13, carton of 100 tablets (10 x 10 Unit-dose)

Storage

Store at 20° to 25°C (68° to 77°F). Protect from moisture and light. Store in original package.

Storage for Bulk Bottles

Store at 20° to 25°C (68° to 77°F). Protect from moisture and light. Store in original package. When product container is subdivided, repackage into a well-closed, light-resistant container.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

17.1 Information for Patients

• Patients should be advised to take Admont sodium daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
• Patients should be advised that oral Admont sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of Admont sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
• Patients should be advised that, while using Admont, sodium medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
• Patients receiving Admont sodium should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
• Patients should be instructed to notify their physician if neuropsychiatric events occur while using Admont sodium.
• Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Admont sodium.
• Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame).

Patient Information

Admont Sodium Tablets

Read the Patient Information Leaflet that comes with Admont sodium before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is Admont sodium?

• Admont sodium is a prescription medicine that blocks substances in the body called leukotrienes. This may help to improve symptoms of asthma and allergic rhinitis. Admont sodium does not contain a steroid.

Admont sodium is used to:

• Prevent asthma attacks and for the long-term treatment of asthma in adults and children ages 2 years and older.
  

  Do not take Admont sodium if you need relief right away for a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks.
  

• Prevent exercise-induced asthma in people 15 years of age and older.
• Help control the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose). Admont sodium is used to treat:
  • outdoor allergies that happen part of the year (seasonal allergic rhinitis) in adults and children ages 2 years and older, and
  • indoor allergies that happen all year (perennial allergic rhinitis) in adults and children ages 2 years and older.

Who should not take Admont sodium?

Do not take Admont sodium if you are allergic to any of its ingredients.

See the end of this leaflet for a complete list of the ingredients in Admont sodium.

What should I tell my healthcare provider before taking Admont sodium?

Before taking Admont sodium, tell your healthcare provider if you:

• are allergic to aspirin
• have phenylketonuria. Admont sodium chewable tablets contain aspartame, a source of phenylalanine
• have any other medical conditions
• are pregnant or plan to become pregnant. If you are pregnant or plan to become pregnant, Admont sodium may not be right for you.
• are breast-feeding or plan to breast-feed. It is not known if Admont sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Admont sodium.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how Admont sodium works, or Admont sodium may affect how your other medicines work.

How should I take Admont sodium?

For anyone who takes Admont sodium:

• Take Admont sodium exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much Admont sodium to take, and when to take it.
• Do not stop taking Admont sodium or change when you take it without talking with your healthcare provider.
• You can take Admont sodium with food or without food.
• If you or your child misses a dose of Admont , sodium just take the next dose at your regular time. Do not take 2 doses at the same time.
• If you take too much Admont sodium call your doctor.

For adults and children 2 years of age and older with asthma:

• Take Admont sodium one time each day, in the evening. Continue to take Admont sodium every day for as long as your healthcare provider prescribes it, even if you have no asthma symptoms.
• Tell your healthcare provider right away if your asthma symptoms get worse, or if you need to use your rescue inhaler medicine more often for asthma attacks.
• Do not take Admont sodium if you need relief right away from a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks.
• Always have your rescue inhaler medicine with you for asthma attacks.
• Do not stop taking or lower the dose of your other asthma medicines unless your healthcare provider tells you to.

For patients 15 years of age and older for the prevention of exercise-induced asthma:

• Take Admont sodium at least 2 hours before exercise.
• Always have your rescue inhaler medicine with you for asthma attacks.
• If you take Admont sodium every day for chronic asthma or allergic rhinitis, do not take another dose to prevent exercise-induced asthma. Talk to your healthcare provider about your treatment for exercise-induced asthma.
• Do not take 2 doses of Admont within 24 hours (1 day).

For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 2 years of age and older with perennial allergic rhinitis:

• Take Admont sodium one time each day, at about the same time each day.

What is the dose of Admont sodium?

The dose of Admont sodium prescribed for your or your child's condition is based on age:

• 2 to 5 years: one 4 mg chewable tablet
• 6 to 14 years: one 5 mg chewable tablet.
• 15 years and older: one 10 mg tablet.

What should I avoid while taking Admont sodium?

If you have asthma and aspirin makes your asthma symptoms worse, continue to avoid taking aspirin or other medicines called non-steroidal anti-inflammatory drugs (NSAIDs) while taking Admont sodium.

What are the possible side effects of Admont sodium?

Admont sodium may cause serious side effects.

• Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking Admont sodium:
• agitation including aggressive behavior or hostility
• bad or vivid dreams
• depression
• disorientation (confusion)
• feeling anxious
• hallucinations (seeing or hearing things that are not really there)
• irritability
• restlessness
• sleep walking
• suicidal thoughts and actions (including suicide)
• tremor
• trouble sleeping
• Increase in certain white blood cells ( eosinophils ) and possible inflamed blood vessels throughout the body (systemic vasculitis ). Rarely, this can happen in people with asthma who take Admont sodium. This usually, but not always, happens in people who also take a steroid medicine by mouth that is being stopped or the dose is being lowered.
• Tell your healthcare provider right away if you get one or more of these symptoms:
  • a feeling of pins and needles or numbness of arms or legs
  • a flu-like illness
  • rash
  • severe inflammation (pain and swelling) of the sinuses (sinusitis)

The most common side effects with Admont sodium include:

• upper respiratory infection
• fever
• headache
• sore throat
• cough
• stomach pain
• diarrhea
• earache or ear infection
• flu
• runny nose
• sinus infection

Other side effects with Admont sodium include:

• increased bleeding tendency, low blood platelet count
• allergic reactions [including swelling of the face, lips, tongue, and/or throat (which may cause trouble breathing or swallowing), hives and itching]
• dizziness, drowsiness, pins and needles/numbness, seizures (convulsions or fits)
• palpitations
• nose bleed, stuffy nose
• diarrhea, heartburn, indigestion, inflammation of the pancreas, nausea, stomach or intestinal upset, vomiting
• hepatitis
• bruising, rash
• joint pain, muscle aches and muscle cramps
• tiredness, swelling

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Admont sodium. For more information ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Admont sodium?

• Store Admont sodium at 20° to 25°C (68° to 77°F).
• Keep Admont sodium in the container it comes in.
• Keep Admont sodium in a dry place and away from light.

General information about the safe and effective use of Admont sodium

Medicines are sometimes prescribed for purposes other than those mentioned in Patient Information Leaflets. Do not use Admont sodium for a condition for which it was not prescribed. Do not give Admont sodium to other people even if they have the same symptoms you have. It may harm them. Keep Admont sodium and all medicines out of the reach of children.

This leaflet summarizes information about Admont sodium. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Admont sodium that is written for health professionals. For more information, call Sandoz Inc. at 1-800-525-8747.

What are the ingredients in Admont sodium?

Active ingredient: Admont sodium

Inactive ingredients:

10 mg tablet: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red ferric oxide, titanium dioxide, and yellow ferric oxide.

4 mg and 5 mg chewable tablets: artificial cherry durarome flavor, aspartame, cherry flavor croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, and red ferric oxide.

The artificial cherry durarome flavor contain: artificial flavors, maltodextrin, red # 40, silicon dioxide, soy lecithin and sugar.

The cherry flavor contain: artificial flavors, benzyl alcohol, lactic acid, and maltodextrin.

Pediatric use information for patients ages 6 to 14 years of age for prevention of exercise-induced asthma is approved for Merck Sharp & Dohme Corp’s Admont tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Manufactured in India by Sandoz Private Ltd.

for Sandoz Inc., Princeton, NJ 08540

Rev. July 2012

Admont Sodium 10mg Tablet

Figure 1: Change in Height (cm) Structural Formula Figure 2

Admont pharmaceutical active ingredients containing related brand and generic drugs:

• Montelukast

Admont available forms, composition, doses:

• Tablets; Oral; Montelukast 10 mg

Admont destination | category:

• Human:
• Antiasthmatic and COPD preparations
• Antihistamines and antiallergics
• Leukotriene modifiers

Admont Anatomical Therapeutic Chemical codes:

• R03DC03 - Montelukast

Admont pharmaceutical companies:

• Adley Formulation

References

1. Dailymed."MONTELUKAST TABLET, FILM COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "montelukast". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
3. "montelukast". http://www.drugbank.ca/drugs/DB0047... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Admont?

Depending on the reaction of the Admont after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Admont not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Admont addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Admont, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Admont consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology