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Name:Theophylline Extended-release
Manufacturer:Remedyrepack Inc.
Category:Prescription Marketed Drugs


THEOPHYLLINE EXTENDED-RELEASE  - theophylline tablet 
REMEDYREPACK INC.

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DESCRIPTION

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste.
Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following
structural formula:
This product allows a 12-hour dosing interval for a majority of patients and a 24-hour dosing interval for selected patients (see
DOSAGE AND ADMINISTRATION section for description of appropriate patient populations).
Each extended-release tablet for oral administration contains either 100 mg, 200 mg, 300 mg or 450 mg of anhydrous theophylline.
Tablets also contain as inactive ingredients: hypromellose, anhydrous lactose, magnesium stearate and povidone.

INACTIVE INGREDIENT

inactive ingredients: hypromellose, anhydrous lactose, magnesium stearate and povidone.

CLINICAL PHARMACOLOGY

Theophylline 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 theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by
the inhibition of two isozymes of phosphodiesterase (PDE lll 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 lll or
antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of
PDE lll (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood
flow).
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.

MECHANISM OF ACTION

Theophylline 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 theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by
the inhibition of two isozymes of phosphodiesterase (PDE lll 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 lll or
antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of
PDE lll (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood
flow).
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.

ADVERSE REACTIONS

adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mLwill achieve most of the drug222s potential therapeutic benefit while minimizing the risk of serious adverse events.

PHARMACOKINETICS

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.
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 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 coadministration
of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject
variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended
that serum 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 theophylline clearance (see PRECAUTIONS, Laboratory Tests).

PRECAUTIONS

Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require
dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow
up (see WARNINGS). The dose of 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 theophylline concentrations and the patient’s clinical
response (see DOSAGE AND ADMINISTRATION, Table V).
Monitoring Serum Theophylline Concentrations: Serum theophylline concentration measurements are readily available and should
be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as
follows:
1. When initiating therapy to guide final dosage adjustment after titration.
2. Before making a dose increase to determine whether the serum concentration is subtherapeutic in a patient who continues to be
symptomatic.
3. Whenever signs or symptoms of theophylline toxicity are present.
4. Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter
theophylline clearance (e.g., fever >102°F sustained for ³24 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 theophylline concentration:
6-7 hours after a 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 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 seven hours after the 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 theophylline toxicity are
present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician
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 theophylline should be measured and the dosage adjusted to achieve an unbound
concentration of 6-12 mcg/mL.
Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.
Effects on Laboratory Tests: As a result of its pharmacological effects, theophylline 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/
page 8 of 17
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). 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 theophylline). The clinical importance of these
changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

LABORATORY TESTS

Laboratory Tests).Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.* Population CharacteristicsAge Total body clearance206mean (range)207(mL/kg/min) Half-lifemean (range)207(hr) page 2 of 17 Premature neonates postnatal age 3-15 days postnatal age 25-57 days 0.29(0.09-0.49)0.64(0.04-1.2) 30(17-43)20(9.4-30.6) Term infants postnatal age 1-2 postnatal age 3-30 weeks NR247NR247 25.7(25-26.5)11(6-29) Children 1-4 years 4-12 years 13-15 years 6-17 years 1.7(0.5-2.9)1.6(0.8-2.4)0.9(0.48-1.3)1.4(0.2-2.6) 3.4(1.2-5.6)NR247NR2473.7(1.5-5.9) Adults (16-60 years) otherwise healthy non-smoking asthmatics 0.65(0.27-1.03) 8.7(6.1-12.8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0.41(0.21-0.61) 9.8(1.6-18) Concurrent illness oraltered physiological state Acute pulmonary edema 0.33266(0.07-2.45) 19266(3.1-82) COPD->60 years, stable non-smoker > 1 year 0.54(0.44-0.64) 11(9.4-12.6) COPD with cor pulmonale 0.48(0.08-0.88) NR247 Cystic fibrosis (14-28 years)Fever associated with acute viralrespiratory illness(children 9-15 years) 1.25(0.31-2.2) NR247 6.0(1.8-10.2) 7.0(1.0-13) page 3 of 17 Liver disease cirrhosis acute hepatitis cholestasis 0.31266(0.1-0.7)0.35(0.25-0.45)0.65(0.25-1.45) 32266(10-56)19.2(16.6-21.8)14.4(5.7-31.8)

PREGNANCY

There are no adequate and well-controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents
(e.g., rabbits). Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the
human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose
on a mg/m2 basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

WARNINGS

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

Cessation of Smoking.
Drug Interactions: Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a
concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See PRECAUTIONS, Drug
Interactions, Table II.)
When Signs or Symptoms of Theophylline Toxicity Are Present:
Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms
consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld
and a serum 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 clinician 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 theophylline should not be made in response to an acute exacerbation of symptoms of
chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered
cortico-steroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum 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 theophylline dose on the basis of a low serum concentration, the clinician 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 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 theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

CLINICAL STUDIES

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 theophylline decreases the frequency and severity of symptoms,including nocturnal exacerbations, and decreases the 223as needed224 use of inhaled beta-2 agonists. Theophylline has also been shownto reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive tobronchodilators in asthmatics.In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea,air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonaryfunction measurements.INDICATIONS AND USAGETheophylline extended-release tablets are indicated for the treatment of the symptoms and reversible airflow obstruction associatedwith chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

CONTRAINDICATIONS

CONTRAINDICATIONSTheophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or othercomponents in the product.WARNINGSConcurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to theincreased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias).Conditions that Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur . Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring ofserum theophylline concentrations in patients with the following risk factors:Age: Neonates (term and premature), children <1 year, elderly (>60 years). page 7 of 17 Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (263 102260 for 24 hours or more; or lessertemperature elevations for longer periods), reduced renal function in infants <3 months of age, sepsis with multi-organ failure, andshock.Cessation of Smoking.

DRUG INTERACTIONS

Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic
response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More
frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in
increased or decreased serum theophylline concentrations. 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 theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steadystate
theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline
clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration
will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline
clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger.
Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially
toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline
clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.
The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant
interaction (i.e., 15% change in 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
theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if
it is not listed in Table II. Before addition of a newly available drug in a patient receiving 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 theophylline has been
reported.

INFORMATION FOR PATIENTS

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache,
insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient should be
instructed to contact their clinician 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 clinician adds a new medication or
discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they
are taking 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 clinician. 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.
Theophylline extended-release tablets should not be chewed or crushed. When dosing on a once daily (q24h) basis, tablets should be
taken whole and not split.

NURSING MOTHERS

Nursing MothersTheophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. Theconcentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter ofbreast milk containing 10-20 mcg/mL of theophylline a day is likely to receive 10-20 mg of theophylline per day. Serious adverseeffects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

PEDIATRIC USE

Pediatric UseTheophylline is safe and effective for the approved indications in pediatric patients. The maintenance dose of theophylline must beselected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates toadolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V).

GERIATRIC USE

Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to
pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than
60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline dose. Protein binding
may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically
active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage
than younger patients. For these reasons, the maximum daily dose of 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 theophylline
concentration is 10 mcg/mL (see DOSAGE AND ADMINISTRATION). Theophylline doses greater than 400 mg/d should be
prescribed with caution in elderly patients.

OVERDOSAGE

The chronicity and pattern of theophylline 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 theophylline clearance. The most common causes of chronic theophylline overdosage
include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors
known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first
measuring the serum theophylline concentration to determine whether a dose increase is safe.
Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital
admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure. In another study, among 6000
page 13 of 17
blood samples obtained for measurement of serum 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
theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while 90% of patients with serum
theophylline concentrations 30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is
seen principally at serum concentrations 30 mcg/mL.
Several studies have described the clinical manifestations of 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 theophylline concentration is 100 mcg/mL. After a chronic
overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum 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
theophylline concentration; patients 60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage.
Preexisting 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 theophylline concentration compared to patients without the underlying disease.
The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV.
Other manifestations of 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 theophylline concentrations 30 mcg/mL are often resistant to anticonvulsant therapy and may result
in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory
arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing
hemodynamic compromise.

WARNINGS AND PRECAUTIONS

WARNINGS and PRECAUTIONS), serum theophylline concentrations should be monitored at 6 month intervalsfor rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should bemonitored at frequent intervals, e.g. every 24 hours.Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances.Table VI contains recommendations for theophylline dosage adjustment based upon serum 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 theophylline concentration. A. Children (6-15 years) and adults (16-60 years) without risk factors for impaired clearance .Table V. Dosing initiation and titration (as anhydrous theophylline).* Titration Step1. Starting Dosage Children <45 kg12-14 mg/kg/day upto a maximum of300 mg/day dividedQ12 hrs* Children >45 kg and adults 300 mg/daydivided Q12 hrs* 2. After 3 days,if tolerated .increase dose to: 16 mf/kg/day upto a maximum of400 mg/day dividedQ12 hrs* 400 mg/day dividedQ12 hrs* 3. After 3 more days,if tolerated .increase dose to: 20 mg/kg/day up toa maximum of600 mg/daydivided Q12 hrs* 600 mg/day dividedQ12 hrs* *Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dosemore frequently (every 8 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 6-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in thepresence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophyllineconcentrations.In adolescents 26316 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence ofrisk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.Table VI. Dosage adjustment guided by serum theophylline concentration. Peak SerumConcentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheckserum concentration after three days for further dosage adjustment. 10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serumconcentration at 6-12 month intervals.*If symptoms are not controlled and current dosage is tolerated consider adding additionalmedication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.* 20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 daysto guide further dosage adjustment. 25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present.Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, considerwhether overdose treatment is indicated (see recommendations for chronic overdosage). >30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline issubsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days toguide further dosage adjustment. page 17 of 17 *Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologicabnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added ordiscontinued (see WARNINGS). Once-Daily Dosing: The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers withappropriate total body clearance and other patients with low dosage requirements. Once-daily dosing should be considered only afterthe patient has been gradually and satisfactorily titrated to therapeutic levels with q12h dosing. Once-daily dosing should be basedon twice the q12h dose and should be initiated at the end of the last q12h dosing interval. The trough concentration (Cmin) obtainedfollowing conversion to once-daily dosing may be lower (especially in high clearance patients) and the peak concentration (Cmax) maybe higher (especially in low clearance patients) than that obtained with q12h dosing. If symptoms recur, or signs of toxicity appearduring the once-daily dosing interval, dosing on the q12h basis should be reinstituted.It is essential that serum theophylline concentrations be monitored before and after transfer to once-daily dosing.Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates oftheophylline from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttimeserum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended thattheophylline extended-release once-daily dosing be administered at night.

HOW SUPPLIED

HOW SUPPLIEDTheophylline Extended-release Tablets:100 mg - White, round, bisected tablets in bottles of 100 and 500. Debossed: PLIVA 483200 mg - White, oval-shaped, bisected tablets in bottles of 100, 500 and 1000. Debossed: PLIVA 482300 mg - White, capsule-shaped, bisected tablets in bottles of 100, 500 and 1000. Debossed: PLIVA 459450 mg - White, capsule-shaped, bisected tablets in bottles of 100, 250 and 500. Debossed: PLIVA 518Dispense in a well-closed container as defined in the USP.Store at 20260-25260C (68260-77260F) [see USP Controlled Room Temperature].Manufactured by: PLIVA256 Inc., Pomona, NY 10970Distributed by: Barr Laboratories, Inc., Pomona, NY 10970Revised FEBRUARY 2007BR-483, 482, 459, 518B21-0483

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

DRUG: Theophylline Extended-Release
GENERIC: Theophylline Extended-Release
DOSAGE: TABLET
ADMINSTRATION: ORAL
NDC: 49349-010-02
STRENGTH:300 mg
COLOR: white
SHAPE: CAPSULE
SCORE: Pliva 459
SIZE: 14 mm
IMPRINT: 30
QTY: 30

IMAGE OF PRODUCT LABEL
IMAGE OF CARD

THEOPHYLLINE EXTENDED-RELEASE 
theophylline extended-release tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49349-010(NDC:50111-459-01)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
THEOPHYLLINE (THEOPHYLLINE) THEOPHYLLINE 300 mg
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS LACTOSE  
hypromellose  
MAGNESIUM STEARATE  
povidone  
Product Characteristics
Color white Score no score
Shape CAPSULE (TABLET) Size 14mm
Flavor Imprint Code Pliva;459
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:49349-010-02 30 TABLET ( TABLET) in 1 BLISTER PACK None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA075659 09/13/2010

Labeler - REMEDYREPACK INC. (829572556)

Revised: 09/2010 REMEDYREPACK INC.



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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