FDA Label for Theo-24
View Indications, Usage & Precautions
Theo-24 Product Label
The following document was submitted to the FDA by the labeler of this product Endo Pharmaceuticals, Inc.. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.
Theophylline
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:
The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17.
Theo-24 is available as capsules intended for oral administration, containing 100 mg, 200 mg, 300 mg, or 400 mg of anhydrous theophylline per capsule, in an extended-release formulation which allows a 24-hour dosing interval for appropriate patients.
Inactive ingredients are edible ink (which contains synthetic black iron oxide, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Yellow No. 6, D&C Yellow No. 10, FD&C Red No. 40), ethylcellulose, gelatin, pharmaceutical glaze, colloidal silicon dioxide, starch, sucrose, talc, titanium dioxide, and coloring agents: 100 mg - includes FD&C Yellow No. 6; 200 mg - FD&C Red No. 3 and D&C Yellow No. 10; 300 mg - FD&C Blue No. 1 and FD&C Red No. 40; 400 mg - FD&C Red No. 40 and D&C Red No. 28.
Theo-24 Extended-release capsules meet Drug Release Test 6 as published in the current USP monograph for Theophylline Extended-release Capsules.
Indications And Usage
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
Theo-24 is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.
Adverse Reactions
Adverse reactions associated with theophylline are generally mild when peak serum 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 theophylline concentrations exceed 20 mcg/mL, however, 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 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 theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of 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 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 theophylline therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum 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 theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum 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).
Percentage of patients reported
with sign or symptom | ||||
Acute Overdose
(Large Single Ingestion) | Chronic Overdosage
(Multiple Excessive Doses) | |||
Sign/Symptom | Study 1
(n=157) | Study 2
(n=14) | Study 1
(n=92) | Study 2
(n=102) |
* These data are derived from two studies in patients with serum theophylline concentrations >30 mcg/mL. In
the first study (Study #1—Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2—Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10 in Study #2) and different methods of reporting results. | ||||
† NR =Not reported in a comparable manner. | ||||
Asymptomatic | NR† | 0 | NR† | 6 |
Gastrointestinal | ||||
Vomiting | 73 | 93 | 30 | 61 |
Abdominal pain | NR† | 21 | NR† | 12 |
Diarrhea | NR† | 0 | NR† | 14 |
Hematemesis | NR† | 0 | NR† | 2 |
Metabolic/Other | ||||
Hypokalemia | 85 | 79 | 44 | 43 |
Hyperglycemia | 98 | NR† | 18 | NR† |
Acid/base disturbance | 34 | 21 | 9 | 5 |
Rhabdomyolysis | NR† | 7 | NR† | 0 |
Cardiovascular | ||||
Sinus tachycardia | 100 | 86 | 100 | 62 |
Other supraventricular | ||||
tachycardias | 2 | 21 | 12 | 14 |
Ventricular premature beats | 3 | 21 | 10 | 19 |
Atrial fibrillation or flutter | 1 | NR† | 12 | NR† |
Multifocal atrial tachycardia | 0 | NR† | 2 | NR† |
Ventricular arrhythmias with | ||||
hemodynamic instability | 7 | 14 | 40 | 0 |
Hypotension/shock | NR† | 21 | NR† | 8 |
Neurologic | ||||
Nervousness | NR† | 64 | NR† | 21 |
Tremors | 38 | 29 | 16 | 14 |
Disorientation | NR† | 7 | NR† | 11 |
Seizures | 5 | 14 | 14 | 5 |
Death | 3 | 21 | 10 | 4 |
Acute Overdose
- Serum Concentration > 20 < 30 mcg/mL
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum theophylline 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 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 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 theophylline toxicity)
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum 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 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 (see OVERDOSAGE, Extracorporeal Removal).
- Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Extracorporeal Removal:
Increasing the rate of 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 theophylline clearance up to six fold, 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 theophylline concentrations may rebound 5 - 10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.
General Considerations:
Theo-24, like other extended-release theophylline products, is intended for patients with relatively continuous or recurring symptoms who have a need to maintain therapeutic serum levels of theophylline. It is not intended for patients experiencing an acute episode of bronchospasm (associated with asthma, chronic bronchitis, or emphysema). Such patients require rapid relief of symptoms and should be treated with an immediate-release or intravenous theophylline preparation (or other bronchodilators) and not with extended-release products.
Patients who metabolize theophylline at a normal or slow rate are reasonable candidates for once-daily dosing with Theo-24. Patients who metabolize theophylline rapidly (e.g., the young, smokers, and some nonsmoking adults) and who have symptoms repeatedly at the end of a dosing interval, will require either increased doses given once a day or preferably, are likely to be better controlled by a schedule of twice-daily dosing. Those patients who require increased daily doses are more likely to experience relatively wide peak-trough differences and may be candidates for twice-a-day dosing with Theo-24.
Patients should be instructed to take this medication each morning at approximately the same time and not to exceed the prescribed dose.
Recent studies suggest that dosing of extended-release theophylline products at night (after the evening meal) results in serum concentrations of theophylline which are not identical to those recorded during waking hours and may be characterized by early trough and delayed peak levels. This appears to occur whether the drug is given as an immediate-release, extended-release, or intravenous product. To avoid this phenomenon when two doses per day are prescribed, it is recommended that the second dose be given 10 to 12 hours after the morning dose and before the evening meal.
Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates of theophylline from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended that Theo-24 (when used as a once-a-day product) be administered at night.
Patients who require a relatively high dose of theophylline (i.e., a dose equal to or greater than 900 mg or 13 mg/kg, whichever is less) should not take Theo-24 less than 1 hour before a high-fat-content meal since this may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state (see PRECAUTIONS, Drug/Food Interactions).
The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10 - 20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter 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 theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/day in adults <60 years or 22 mg/kg/day in children 1-9 years, the steady-state peak serum 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 theophylline must be individualized on the basis of peak serum 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 theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI). Health care providers should instruct patients and care givers 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 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 theophylline concentrations should be monitored 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.
* Patients with more rapid metabolism, clinically identified by higher than average dose
requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals. | |||
A. | Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance. | ||
Titration Step | Children <45 kg | Children >45 kg and adults | |
1. | Starting Dosage | 12 - 14 mg/kg/day up to a
maximum of 300 mg/day divided Q 24 hrs* | 300 - 400 mg/day1 divided Q
24 hrs* |
2. | After 3 days, if
tolerated, increase dose to: | 16 mg/kg/day up to a
maximum of 400 mg/day divided Q 24 hrs* | 400 - 600 mg/day1 divided Q
24 hrs* |
3. | After 3 more days, if
tolerated and if needed, increase dose to: | 20 mg/kg/day up to a
maximum of 600 mg/day divided Q 24 hrs* | As with all theophylline
products, doses greater than 600 mg should be titrated according to blood level (see Table VI) |
1 | If caffeine-like adverse effects occur, then consideration should be given to a lower
dose and titrating the dose more slowly (see ADVERSE REACTIONS). | ||
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 12-15 years of age, the final 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 theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations. |
Peak Serum
Concentration | Dosage Adjustment |
---|---|
* Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present,
physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS). | |
<9.9 mcg/mL | If symptoms are not controlled and current dosage is tolerated, increase dose about 25%.
Recheck serum concentration after three days for further dosage adjustment. |
10 - 14.9 mcg/mL | If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum
concentration at 6-12 month intervals.* If symptoms are not controlled and current dosage is tolerated consider adding additional medication(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 days to 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, consider whether overdosage treatment is indicated (see recommendations for chronic overdosage). |
>30 mcg/mL | Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is
subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment. |
How Supplied
Theo-24 (theophylline anhydrous) is supplied in extended-release capsules containing 100, 200, 300 or 400 mg of anhydrous theophylline.
Theo-24 100 mg capsules are orange opaque and natural, with markings Theo-24, 100 mg, AP, and 2832, supplied as:
NDC Number Size
52244-100-10 bottle of 100
Theo-24 200 mg capsules are orange opaque and clear, with markings Theo-24, 200 mg, AP, and 2842, supplied as:
NDC Number Size
52244-200-10 bottle of 100
Theo-24 300 mg capsules are Swedish orange and natural, with markings Theo-24, 300 mg, AP, and 2852, supplied as:
NDC Number Size
52244-300-10 bottle of 100
Theo-24 400 mg capsules are pink opaque and natural, with markings Theo-24, 400 mg, AP, and 2902, supplied as:
NDC Number Size
52244-400-10 bottle of 100
Storage
Store below 77° F (25° C).
For Medical Information
Contact: Endo Pharmaceuticals Inc.
Phone: 1-800-462-3636
Distributed by:
Endo Pharmaceuticals Inc.
Malvern, PA 19355
Manufactured by:
Neolpharma, Inc.
Caguas, PR 00725
Revised 11/2016
P08997
* Please review the disclaimer below.