Zomont Theo

Montelukast:

• 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
• Zomont Theo (Montelukast) reviews

1 INDICATIONS AND USAGE

Zomont Theo sodium tablets are a leukotriene receptor antagonist indicated for:

• Prophylaxis and chronic treatment of asthma in patients 2 years of age and older (1.1).
• 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

Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) should be taken at least 2 hours before exercise.

An additional dose of Zomont Theo (Montelukast) should not be taken within 24 hours of a previous dose. Patients already taking Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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, Zomont Theo sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium dose daily in the evening.

3 DOSAGE FORMS AND STRENGTHS

• Zomont Theo (Montelukast) 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.
• Zomont Theo (Montelukast) sodium chewable tablets, 4 mg (montelukast) are pink colored, round, mottled and debossed “SZ 74” on one side and plain on the other side.
• Zomont Theo (Montelukast) sodium chewable tablets, 5 mg (montelukast) are pink colored, round, mottled and debossed “SZ 76” on one side and plain on other side.

• Zomont Theo (Montelukast) sodium film-coated tablets, 10 mg ( Zomont Theo (Montelukast))
• Zomont Theo (Montelukast) 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 Zomont Theo sodium to treat an acute asthma attack ( 5.1 ).
• Advise patients to have appropriate rescue medication available ( 5.1 ).
• Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium ( 5.3 ).
• Neuropsychiatric events have been reported with Zomont Theo (Montelukast) sodium. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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, Zomont Theo 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 Zomont Theo (Montelukast) sodium. Although Zomont Theo (Montelukast) 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 (14.1)].

5.4 Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Zomont Theo sodium. Post-marketing reports with Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium if such events occur [see ADVERSE REACTIONS (6.2)].

5.5 Eosinophilic Conditions

Patients with asthma on therapy with Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium and these underlying conditions has not been established [see ADVERSE REACTIONS (6.2)].

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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

*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 Zomont Theo (Montelukast) sodium and placebo.

The safety profile of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium.

Cumulatively, 569 patients were treated with Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) sodium has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with Zomont Theo (Montelukast) sodium for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving Zomont Theo (Montelukast) sodium, the following events not previously observed with the use of Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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. Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium in two, 6-week, clinical studies. Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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, Zomont Theo 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 (13.2)].

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and efficacy of Zomont Theo 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 (6.1), CLINICAL PHARMACOLOGY, Special Populations (12.3), AND CLINICAL STUDIES (14.1, 14.2)].

The efficacy of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium minus placebo, beclomethasone minus placebo, and Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast), 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 Zomont Theo (Montelukast) are similar in elderly and younger adults. The plasma half-life of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium. In chronic asthma studies, Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.

It is not known whether Zomont Theo (Montelukast) is removed by peritoneal dialysis or hemodialysis.

11 DESCRIPTION

Zomont Theo (Montelukast) sodium, the active ingredient in Zomont Theo (Montelukast) sodium tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT₁ receptor.

Zomont Theo (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 molecular formula is C₃₅H₃₅ClNNaO₃S, and its molecular weight is 608.18. The structural formula is:

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

Each 10 mg film-coated Zomont Theo (Montelukast) sodium tablet contains 10.4 mg Zomont Theo (Montelukast) sodium, which is equivalent to 10 mg of Zomont Theo (Montelukast). In addition Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium tablet contains 4.2 and 5.2 mg Zomont Theo (Montelukast) sodium, which are equivalent to 4 and 5 mg of Zomont Theo (Montelukast), respectively. Zomont Theo (Montelukast) 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.

Zomont Theo (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 β-adrenergic receptor). Zomont Theo (Montelukast) inhibits physiologic actions of LTD₄ at the CysLT₁ receptor without any agonist activity.

12.2 Pharmacodynamics

Zomont Theo (Montelukast) 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), Zomont Theo (Montelukast) sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of Zomont Theo (Montelukast) sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium. The relationship between these observations and the clinical benefits of Zomont Theo (Montelukast) noted in the clinical trials is not known [see CLINICAL STUDIES (14)].

12.3 Pharmacokinetics

Absorption

Zomont Theo (Montelukast) is rapidly absorbed following oral administration. After administration of the 10 mg film-coated tablet to fasted adults, the mean peak Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) when administered as two 5 mg chewable tablets versus one 10 mg film-coated tablet have not been evaluated.

Distribution

Zomont Theo (Montelukast) is more than 99% bound to plasma proteins. The steady state volume of distribution of Zomont Theo (Montelukast) averages 8 to 11 liters. Studies in rats with radiolabeled Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast). Clinical studies investigating the effect of known inhibitors of CYP3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on Zomont Theo (Montelukast) pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) is a potent inhibitor of CYP2C8; however, data from a clinical drug-drug interaction study involving Zomont Theo (Montelukast) and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled Zomont Theo (Montelukast), 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of Zomont Theo (Montelukast) oral bioavailability, this indicates that Zomont Theo (Montelukast) and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of Zomont Theo (Montelukast) ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Zomont Theo (Montelukast) are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10 mg Zomont Theo (Montelukast), 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 Zomont Theo (Montelukast) resulting in 41% (90% CI=7%, 85%) higher mean Zomont Theo (Montelukast) AUC following a single 10 mg dose. The elimination of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

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

Gender: The pharmacokinetics of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) and the variability of plasma Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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: Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.

Zomont Theo (Montelukast) 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]. Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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. Zomont Theo (Montelukast) 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. Zomont Theo (Montelukast) 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, Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) approximately 40% following a single 10 mg dose of Zomont Theo (Montelukast). No dosage adjustment for Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium.

Zomont Theo (Montelukast) is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) does not inhibit CYP2C8 in vivo. Therefore, Zomont Theo (Montelukast) 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.

Zomont Theo 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, Zomont Theo (Montelukast) produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). 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). Zomont Theo (Montelukast) 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. Zomont Theo (Montelukast) 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 Zomont Theo doses above 10 mg once daily.

The efficacy of Zomont Theo (Montelukast) sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with Zomont Theo (Montelukast), 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV₁ for Zomont Theo (Montelukast) 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: Zomont Theo (Montelukast) Sodium N=406; Placebo N=270) (ANOVA Model)

The effect of Zomont Theo (Montelukast) 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.

*p<0.001, compared with placebo

Both studies evaluated the effect of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium experienced asthma attacks compared with patients on placebo (27.3%, p< 0.001). In the US study, 7.8% of patients on Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium chewable tablet daily resulted in a significant improvement in mean morning FEV₁ percent change from baseline (8.7% in the group treated with Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of Zomont Theo (Montelukast) sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast), 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 Zomont Theo (Montelukast) 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.

^*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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium for prevention of EIB in patients below 6 years of age has not been established.

Daily administration of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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. Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium tablets, loratadine, and placebo are shown in TABLE 4. The remaining three trials that demonstrated efficacy showed similar results.

^*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 Zomont Theo (Montelukast) sodium and the active control (loratadine).

Perennial Allergic Rhinitis

The efficacy of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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. Zomont Theo (Montelukast) 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).

^*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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between Zomont Theo (Montelukast) sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) 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)

Zomont Theo (Montelukast) 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)

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
• Patients should be advised that, while using Zomont Theo (Montelukast), 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium.
• Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Zomont Theo (Montelukast) sodium.
• Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame).

Patient Information

Zomont Theo (Montelukast) Sodium Tablets

Read the Patient Information Leaflet that comes with Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium?

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

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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). Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium?

Do not take Zomont Theo (Montelukast) sodium if you are allergic to any of its ingredients.

See the end of this leaflet for a complete list of the ingredients in Zomont Theo (Montelukast) sodium.

What should I tell my healthcare provider before taking Zomont Theo (Montelukast) sodium?

Before taking Zomont Theo (Montelukast) sodium, tell your healthcare provider if you:

• are allergic to aspirin
• have phenylketonuria. Zomont Theo (Montelukast) 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, Zomont Theo (Montelukast) sodium may not be right for you.
• are breast-feeding or plan to breast-feed. It is not known if Zomont Theo (Montelukast) sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium works, or Zomont Theo (Montelukast) sodium may affect how your other medicines work.

How should I take Zomont Theo (Montelukast) sodium?

For anyone who takes Zomont Theo (Montelukast) sodium:

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

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

• Take Zomont Theo (Montelukast) sodium one time each day, in the evening. Continue to take Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium at least 2 hours before exercise.
• Always have your rescue inhaler medicine with you for asthma attacks.
• If you take Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium one time each day, at about the same time each day.

What is the dose of Zomont Theo (Montelukast) sodium?

The dose of Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium.

What are the possible side effects of Zomont Theo (Montelukast) sodium?

Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) sodium?

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

General information about the safe and effective use of Zomont Theo (Montelukast) sodium

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

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

What are the ingredients in Zomont Theo (Montelukast) sodium?

Active ingredient: Zomont Theo (Montelukast) 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 Zomont Theo (Montelukast) 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

Zomont Theo (Montelukast) Sodium 10mg Tablet

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

Theophylline:

• Description
• Clinical pharmacology
• Clinical studies
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Zomont Theo (Theophylline) reviews

DESCRIPTION

Zomont Theo (Theophylline)^® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.

Zomont Theo (Theophylline) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Zomont Theo (Theophylline) has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous Zomont Theo (Theophylline) is C₇H₈N₄O₂ with a molecular weight of 180.17.

Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Zomont Theo (Theophylline).

Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.

Zomont Theo (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Zomont Theo has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Zomont Theo (Theophylline) are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Zomont Theo (Theophylline) appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Zomont Theo (Theophylline) increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship

Bronchodilation occurs over the serum Zomont Theo (Theophylline) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Zomont Theo (Theophylline) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Zomont Theo (Theophylline) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Zomont Theo (Theophylline) concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics

Overview: Zomont Theo is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Zomont Theo (Theophylline) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Zomont Theo (Theophylline) vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I ) and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Zomont Theo (Theophylline). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Zomont Theo (Theophylline) concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Zomont Theo (Theophylline) clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, Zomont Theo (Theophylline) clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Zomont Theo (Theophylline).

Absorption

Zomont Theo (Theophylline)^® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Zomont Theo (Theophylline) Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9±83.0 mcg hr/mL, C_max=9.3±2.0 mcg/mL, T_max=12.8±4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7±83.0 mcg hr/mL, C_max=9.2±2.0 mcg/mL, T_max=12.5±4.2 hours.

A study in which Zomont Theo (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Zomont Theo (Theophylline) level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.

A single-dose study in 15 normal fasting male volunteers whose Zomont Theo (Theophylline) inherent mean elimination half-life was verified by a liquid Zomont Theo (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Zomont Theo (Theophylline)^® Tablets. The relative bioavailability of Zomont Theo (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Zomont Theo (Theophylline) levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Zomont Theo (Theophylline) Tablets was 17.2±5.8 (SD) hours.

Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Zomont Theo (Theophylline) Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Zomont Theo (Theophylline) Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C_max and C_min values obtained in this study were as follows:

Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, C_max=8.4±2.6 mcg/mL, T_max=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, C_max=5.5±1.5 mcg/mL, T_max=6.5±2.1 hours.

Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Zomont Theo (Theophylline)^® 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Zomont Theo (Theophylline) Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, C_max=10.9±1.7 mcg/mL, T_max=11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, C_max=6.7±1.7 mcg/mL, T_max=7.3±2.2 hours.

Thus, administration of single Zomont Theo (Theophylline) doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of Zomont Theo (Theophylline) with Zomont Theo (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Zomont Theo (Theophylline) Tablet. A single-dose study in 24 subjects with an established Zomont Theo (Theophylline) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Zomont Theo (Theophylline) Tablet and one and one-half 400 mg Zomont Theo (Theophylline) Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Zomont Theo (Theophylline) Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, C_max=10.58±2.21 mcg/mL and T_max=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, C_max=10.39±1.91 mcg/mL and T_max=9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, C_max= 7.37±1.83 mcg/mL and T_max=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, C_max=7.66±2.09 mcg/mL and T_max=9.67±4.89 hours.

In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.

In another study, the bioavailability of the 600 mg Zomont Theo (Theophylline) Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Zomont Theo (Theophylline) Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, C_max=10.6±1.3 mcg/mL and T_max=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, C_max=9.7±1.4 mcg/mL and T_max=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of Zomont Theo (Theophylline)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Zomont Theo (Theophylline) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Zomont Theo (Theophylline) product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).

The pharmacokinetic parameters for Zomont Theo (Theophylline) 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, C_max=12.1±3.8 mcg/mL, C_min=4.50±3.6, T_max=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, C_max =11.0±4.1 mcg/mL, C_min=7.28±3.5, T_max=6.9±3.4 hours. The mean percent fluctuation [(C_max-C_min/C_min)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg Zomont Theo (Theophylline) Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Zomont Theo (Theophylline) Tablets. All subjects had previously established Zomont Theo (Theophylline) clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Zomont Theo (Theophylline) Tablet regimens. Steady-state results were:

The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.

Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Zomont Theo (Theophylline) Tablets whether dosed in the morning or evening.

Distribution

Once Zomont Theo enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Zomont Theo (Theophylline) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Zomont Theo (Theophylline) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Zomont Theo (Theophylline) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Zomont Theo (Theophylline) concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of Zomont Theo (Theophylline), primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound+unbound) serum concentrations of Zomont Theo (Theophylline) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Zomont Theo (Theophylline) binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Zomont Theo (Theophylline) concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Zomont Theo (Theophylline) concentration provides a more reliable means of dosage adjustment than measurement of total serum Zomont Theo (Theophylline) concentration. Generally, concentrations of unbound Zomont Theo (Theophylline) should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Zomont Theo (Theophylline) does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Zomont Theo (Theophylline) dose is N-methylated to caffeine. Zomont Theo (Theophylline) demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Zomont Theo (Theophylline) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Zomont Theo (Theophylline) and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized Zomont Theo (Theophylline) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Zomont Theo (Theophylline) concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Zomont Theo (Theophylline) biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Zomont Theo (Theophylline) metabolism, non-linearity of elimination may begin in some patients at serum Zomont Theo (Theophylline) concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Zomont Theo (Theophylline) concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum Zomont Theo (Theophylline) concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Zomont Theo (Theophylline) metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Zomont Theo (Theophylline) concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Zomont Theo (Theophylline) concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the Zomont Theo dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Zomont Theo (Theophylline) dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Zomont Theo (Theophylline) is excreted unchanged in the urine and since active metabolites of Zomont Theo (Theophylline) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the Zomont Theo (Theophylline) dose excreted in the urine as unchanged Zomont Theo (Theophylline) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Zomont Theo (Theophylline), steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Zomont Theo (Theophylline) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Zomont Theo (Theophylline) clearance. In these patients administration of Zomont Theo (Theophylline)^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

The clearance of Zomont Theo (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Zomont Theo is very low in neonates (see WARNINGS ). Zomont Theo (Theophylline) clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Zomont Theo (Theophylline) in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Zomont Theo (Theophylline) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Zomont Theo (Theophylline) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Zomont Theo (Theophylline) clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race

Pharmacokinetic differences in Zomont Theo clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Zomont Theo (Theophylline) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Zomont Theo (Theophylline) is excreted unchanged in the urine and since active metabolites of Zomont Theo (Theophylline) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered Zomont Theo (Theophylline) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in neonates with decreased renal function (see WARNINGS ).

Hepatic Insufficiency

Zomont Theo clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure (CHF)

Zomont Theo (Theophylline) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Zomont Theo (Theophylline) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Zomont Theo (Theophylline) clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in patients with CHF (see WARNINGS ).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Zomont Theo by induction of metabolic pathways. Zomont Theo (Theophylline) clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Zomont Theo (Theophylline) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Zomont Theo (Theophylline) clearance. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Zomont Theo (Theophylline) clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Zomont Theo (Theophylline). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Zomont Theo (Theophylline) clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum Zomont Theo (Theophylline) concentrations. Children with rapid rates of Zomont Theo (Theophylline) clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Zomont Theo (Theophylline) concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased Zomont Theo (Theophylline) clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Zomont Theo (Theophylline) clearance include hyperthyroidism and cystic fibrosis.

CLINICAL STUDIES

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Zomont Theo (Theophylline) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. Zomont Theo (Theophylline) has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that Zomont Theo (Theophylline) decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

INDICATIONS AND USAGE

Zomont Theo (Theophylline) is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

CONTRAINDICATIONS

Zomont Theo (Theophylline)^® is contraindicated in patients with a history of hypersensitivity to Zomont Theo (Theophylline) or other components in the product.

WARNINGS

Concurrent Illness

Zomont Theo should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Zomont Theo (Theophylline) Clearance

There are several readily identifiable causes of reduced Zomont Theo (Theophylline) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Zomont Theo (Theophylline) toxicity can occur . Careful consideration must be given to the benefits and risks of Zomont Theo (Theophylline) use and the need for more intensive monitoring of serum Zomont Theo (Theophylline) concentrations in patients with the following risk factors:

Age

• Neonates (term and premature)
• Children <1 year
• Elderly (>60 years)

Concurrent Diseases

• Acute pulmonary edema
• Congestive heart failure
• Cor-pulmonale
• Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
• Hypothyroidism
• Liver disease; cirrhosis, acute hepatitis
• Reduced renal function in infants <3 months of age
• Sepsis with multi-organ failure
• Shock

Cessation of Smoking

Drug Interactions

Adding a drug that inhibits Zomont Theo metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Zomont Theo (Theophylline) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of Zomont Theo (Theophylline) Toxicity Are Present

Whenever a patient receiving Zomont Theo (Theophylline) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Zomont Theo (Theophylline) toxicity (even if another cause may be suspected), additional doses of Zomont Theo (Theophylline) should be withheld and a serum Zomont Theo (Theophylline) concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI ).

Dosage Increases

Increases in the dose of Zomont Theo (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Zomont Theo (Theophylline) provides little added benefit to inhaled beta₂-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Zomont Theo (Theophylline) concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the Zomont Theo (Theophylline) dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests ).

As the rate of Zomont Theo (Theophylline) clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Zomont Theo (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Zomont Theo clearance and require dosage adjustment should occur prior to initiation of Zomont Theo (Theophylline) therapy, prior to increases in Zomont Theo (Theophylline) dose, and during follow up (see WARNINGS ). The dose of Zomont Theo (Theophylline) selected for initiation of therapy should be low and, if tolerated , increased slowly over a period of a week or longer with the final dose guided by monitoring serum Zomont Theo (Theophylline) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Zomont Theo (Theophylline) Concentrations

Serum Zomont Theo (Theophylline) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Zomont Theo (Theophylline) concentration should be measured as follows:

• When initiating therapy to guide final dosage adjustment after titration.
• Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
• Whenever signs or symptoms of Zomont Theo (Theophylline) toxicity are present.
• Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Zomont Theo (Theophylline) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Zomont Theo (Theophylline) concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Zomont Theo (Theophylline) concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Zomont Theo (Theophylline) toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Zomont Theo (Theophylline) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Zomont Theo (Theophylline) cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Zomont Theo at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Zomont Theo (Theophylline) at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Zomont Theo (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Zomont Theo (Theophylline) in individual patients.

Information for Patients

The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Zomont Theo (Theophylline), even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Zomont Theo (Theophylline) interacts with a wide variety of drugs. The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as Zomont Theo (Theophylline), since it may result in decreased Zomont Theo (Theophylline) levels. If patients are already taking St. John’s Wort and Zomont Theo (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Zomont Theo (Theophylline) concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Zomont Theo (Theophylline), especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Zomont Theo (Theophylline)^® Tablets can be taken once a day in the morning or evening. It is recommended that Zomont Theo (Theophylline) be taken with meals. Patients should be advised that if they choose to take Zomont Theo (Theophylline) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Zomont Theo (Theophylline) Tablets are not to be chewed or crushed because it may lead to a rapid release of Zomont Theo (Theophylline) with the potential for toxicity. The scored tablet may be split. Patients receiving Zomont Theo (Theophylline) Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Zomont Theo (Theophylline).

Drug Interactions

Zomont Theo interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Zomont Theo (Theophylline) or another drug or occurrence of adverse effects without a change in serum Zomont Theo (Theophylline) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Zomont Theo (Theophylline) clearance is altered by another drug resulting in increased or decreased serum Zomont Theo (Theophylline) concentrations. Zomont Theo (Theophylline) only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with Zomont Theo (Theophylline). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Zomont Theo (Theophylline) regimen. If Zomont Theo (Theophylline) is being initiated in a patient who is already taking a drug that inhibits Zomont Theo (Theophylline) clearance (e.g., cimetidine, erythromycin), the dose of Zomont Theo (Theophylline) required to achieve a therapeutic serum Zomont Theo (Theophylline) concentration will be smaller. Conversely, if Zomont Theo (Theophylline) is being initiated in a patient who is already taking a drug that enhances Zomont Theo (Theophylline) clearance (e.g., rifampin), the dose of Zomont Theo (Theophylline) required to achieve a therapeutic serum Zomont Theo (Theophylline) concentration will be larger. Discontinuation of a concomitant drug that increases Zomont Theo (Theophylline) clearance will result in accumulation of Zomont Theo (Theophylline) to potentially toxic levels, unless the Zomont Theo (Theophylline) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Zomont Theo (Theophylline) clearance will result in decreased serum Zomont Theo (Theophylline) concentrations, unless the Zomont Theo (Theophylline) dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with Zomont Theo (Theophylline) or do not produce a clinically significant interaction (i.e., <15% change in Zomont Theo (Theophylline) clearance).

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Zomont Theo (Theophylline), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Zomont Theo (Theophylline) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Zomont Theo (Theophylline), the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Zomont Theo (Theophylline) has been reported.

Drug-Food Interactions

The bioavailability of Zomont Theo (Theophylline)^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Zomont Theo (Theophylline) 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics , Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.

The Effect of Other Drugs on Zomont Theo Serum Concentration Measurements

Most serum Zomont Theo (Theophylline) assays in clinical use are immunoassays which are specific for Zomont Theo (Theophylline). Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum Zomont Theo (Theophylline) concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long term carcinogenicity studies have been carried out in mice and rats (oral doses 5-75 mg/kg). Results are pending.

Zomont Theo (Theophylline) has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, Zomont Theo (Theophylline), administered to mating pairs of B6C3F₁ mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m² basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Zomont Theo (Theophylline) was administered to F344 rats and B6C3F₁ mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m² basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy: Teratogenic Effects: Category C

In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Zomont Theo (Theophylline) produced teratogenic effects.

In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m² basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis.

In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m² basis).

In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m² basis) increased the incidence of skeletal variations.

There are no adequate and well-controlled studies in pregnant women. Zomont Theo (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Zomont Theo is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Zomont Theo (Theophylline) in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Zomont Theo (Theophylline) per day is likely to receive 10-20 mg of Zomont Theo (Theophylline) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Zomont Theo (Theophylline) concentrations.

Pediatric Use

Zomont Theo (Theophylline) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Zomont Theo (Theophylline) must be selected with caution in pediatric patients since the rate of Zomont Theo (Theophylline) clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V ).

Geriatric Use

Elderly patients are at a significantly greater risk of experiencing serious toxicity from Zomont Theo (Theophylline) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Zomont Theo (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Zomont Theo (Theophylline) clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Zomont Theo (Theophylline) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Zomont Theo (Theophylline) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Zomont Theo (Theophylline) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Zomont Theo (Theophylline) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Zomont Theo (Theophylline) in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Zomont Theo (Theophylline) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Zomont Theo (Theophylline) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Zomont Theo (Theophylline) should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.

ADVERSE REACTIONS

Adverse reactions associated with Zomont Theo (Theophylline) are generally mild when peak serum Zomont Theo (Theophylline) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Zomont Theo (Theophylline) concentrations exceed 20 mcg/mL, however, Zomont Theo (Theophylline) produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). The transient caffeine-like adverse reactions occur in about 50% of patients when Zomont Theo (Theophylline) therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Zomont Theo (Theophylline) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Zomont Theo (Theophylline) therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Zomont Theo (Theophylline) concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Zomont Theo (Theophylline) therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Zomont Theo (Theophylline) concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Zomont Theo (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Zomont Theo (Theophylline) concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Zomont Theo (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Zomont Theo (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Zomont Theo (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Zomont Theo (Theophylline) concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

OVERDOSAGE

General

The chronicity and pattern of Zomont Theo overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Zomont Theo (Theophylline) clearance. The most common causes of chronic Zomont Theo (Theophylline) overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Zomont Theo (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Zomont Theo (Theophylline) concentration to determine whether a dose increase is safe.

Severe toxicity from Zomont Theo (Theophylline) overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Zomont Theo (Theophylline) was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Zomont Theo (Theophylline) concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Zomont Theo (Theophylline) concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Zomont Theo (Theophylline) concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Zomont Theo (Theophylline) is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of Zomont Theo (Theophylline) overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum Zomont Theo (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Zomont Theo (Theophylline) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Zomont Theo (Theophylline) concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Zomont Theo (Theophylline) concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of Zomont Theo (Theophylline) overdose according to the mode of overdose are listed in Table IV.

Other manifestations of Zomont Theo (Theophylline) toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.

Seizures associated with serum Zomont Theo (Theophylline) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Zomont Theo (Theophylline) toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management

General Recommendations for Patients with Symptoms of Zomont Theo (Theophylline) Overdose or Serum Zomont Theo (Theophylline) Concentrations >30 mcg/mL (Note: Serum Zomont Theo (Theophylline) concentrations may continue to increase after presentation of the patient for medical care.)

• While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
• Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
• Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of Zomont Theo (Theophylline) overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with Zomont Theo (Theophylline) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Zomont Theo (Theophylline). Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
• Anticipate Need for Anticonvulsants In patients with Zomont Theo (Theophylline) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Zomont Theo (Theophylline) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Zomont Theo (Theophylline) concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Zomont Theo (Theophylline) (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Zomont Theo (Theophylline) clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Zomont Theo (Theophylline) required to induce seizures (i.e., markedly increases the LD₅₀). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Zomont Theo (Theophylline) clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
• Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Zomont Theo (Theophylline) concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
• Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Zomont Theo (Theophylline) throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Zomont Theo (Theophylline) bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in Zomont Theo (Theophylline) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Zomont Theo (Theophylline) unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
• Serum Zomont Theo (Theophylline) Concentration Monitoring The serum Zomont Theo (Theophylline) concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Zomont Theo (Theophylline) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Zomont Theo (Theophylline) from the gastrointestinal tract. Serial monitoring of serum Zomont Theo (Theophylline) serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
• General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Zomont Theo (Theophylline) level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
• Enhance clearance of Zomont Theo (Theophylline) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Zomont Theo (Theophylline) at least twofold by adsorption of Zomont Theo (Theophylline) secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Zomont Theo (Theophylline) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Zomont Theo (Theophylline) and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Zomont Theo (Theophylline) removal should be instituted (see OVERDOSAGE, Extracorporeal Removal ).

Specific Recommendations

Acute Overdose

• Serum Concentration >20<30 mcg/mL
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Zomont Theo concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30<100 mcg/mL
  • Administer multiple dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Zomont Theo (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration>100 mcg/mL
  • Consider prophylactic anticonvulsant therapy.
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
  • Monitor the patient and obtain serial Zomont Theo (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage

• Serum Concentration >20<30 mcg/mL (with manifestations of Zomont Theo (Theophylline) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Zomont Theo (Theophylline) concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30 mcg/mL in patients <60 years of age
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Zomont Theo (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration >30 mcg/mL in patients ≥ 60 years of age
  • Consider prophylactic anticonvulsant therapy.
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Consider extracorporeal removal even if the patient has not experienced a seizure.
  • Monitor the patient and obtain serial Zomont Theo (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of Zomont Theo (Theophylline) clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing Zomont Theo (Theophylline) clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum Zomont Theo (Theophylline) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Zomont Theo (Theophylline) from the tissue compartment. Peritoneal dialysis is ineffective for Zomont Theo (Theophylline) removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Zomont Theo ^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Zomont Theo (Theophylline) be taken with meals. Patients should be advised that if they choose to take Zomont Theo (Theophylline) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Zomont Theo (Theophylline)^® Tablets are not to be chewed or crushed because it may lead to a rapid release of Zomont Theo (Theophylline) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Zomont Theo (Theophylline) 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Zomont Theo (Theophylline).

Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Zomont Theo (Theophylline) product may be transferred to once-daily administration of 400 mg or 600 mg Zomont Theo (Theophylline) Tablets on a mg-for-mg basis.

It must be recognized that the peak and trough serum Zomont Theo (Theophylline) levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.

General Considerations

The steady-state peak serum Zomont Theo (Theophylline) concentration is a function of the dose, the dosing interval, and the rate of Zomont Theo (Theophylline) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Zomont Theo (Theophylline) clearance, the dose required to achieve a peak serum Zomont Theo (Theophylline) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Zomont Theo (Theophylline) clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Zomont Theo (Theophylline) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Zomont Theo (Theophylline) dose required to achieve a therapeutic serum Zomont Theo (Theophylline) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Zomont Theo (Theophylline) concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Zomont Theo (Theophylline) concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Zomont Theo (Theophylline) must be individualized on the basis of peak serum Zomont Theo (Theophylline) concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Zomont Theo (Theophylline) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Zomont Theo (Theophylline) concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum Zomont Theo (Theophylline) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Zomont Theo (Theophylline) concentrations should be monitored at frequent intervals, e.g., every 24 hours.

Zomont Theo (Theophylline) distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

Table V contains Zomont Theo (Theophylline) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Zomont Theo (Theophylline) dosage adjustment based upon serum Zomont Theo (Theophylline) concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum Zomont Theo (Theophylline) concentration.

Table V. Dosing initiation and titration (as anhydrous Zomont Theo (Theophylline)). *

• A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.

• B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Zomont Theo (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Zomont Theo (Theophylline) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Zomont Theo (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Zomont Theo (Theophylline) concentrations.
    

  • In adolescents ≥16 years and adults, including the elderly, the Zomont Theo (Theophylline) dose should not exceed 400 mg/day in the presence of risk factors for reduced Zomont Theo (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Zomont Theo (Theophylline) concentrations.

*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

HOW SUPPLIED

Zomont Theo (Theophylline)^® (theophylline, anhydrous) Controlled-Release Tablets 400 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-251-01) or 500 tablets (NDC 67781-251-05). Each round, white 400 mg tablet bears the symbol PF on the scored side and U400 on the other side.

Zomont Theo (Theophylline)^® (theophylline, anhydrous) Controlled-Release Tablets 600 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-252-01). Each rectangular, concave, white 600 mg tablet bears the symbol PF on the scored side and U 600 on the other side.

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container.

©2011, Purdue Pharmaceutical Products L.P.

Dist. by: Purdue Pharmaceutical Products L.P.

Stamford, CT 06901-3431

Revised 10/2011

300945-0B

Zomont Theo (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

Zomont Theo (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01

Zomont Theo (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

Zomont Theo (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01