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Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste.
inactive ingredients: hypromellose, anhydrous lactose, magnesium stearate and povidone.
Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e.,
MECHANISM OF ACTIONTheophylline 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
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 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.
Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.
PRECAUTIONSCareful 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
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
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).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)
There are no adequate and well-controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents
Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the
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.
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.
Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic
INFORMATION FOR PATIENTS
The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache,
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 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).
Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to
The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and
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 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 PANELDRUG: Theophylline Extended-Release
GENERIC: Theophylline Extended-Release
SCORE: Pliva 459
SIZE: 14 mm
Revised: 09/2010 REMEDYREPACK INC.
Reproduced with permission of U.S. National Library of Medicine
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