Theo-24

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.

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 . 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 . 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 . 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 . If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements , 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.

Table V. Dosing initiation and titration (as anhydrous theophylline).* * 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/day 1 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/day 1 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 1 If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly . 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 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 or if it is not feasible to monitor serum theophylline concentrations. Table VI. Dosage adjustment guided by serum theophylline concentration. 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 . <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 . >30 mcg/mL Treat overdose as indicated . If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

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: Age Neonates (term and premature) Children <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever; ≥102°F 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 theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin) . 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 healthcare professional may instruct the patient to resume the drug at a lower dosage . 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 beta 2 -selective agonists and systemically administered corticosteroids 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 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 . 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 .

Theo-24 is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Pregnancy: CATEGORY C: In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis) increased the incidence of skeletal variations. There are no adequate and well-controlled studies in pregnant women. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of 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 theophylline per day is likely to receive 10 - 20 mg of theophylline per day.

Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

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 . 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 . 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).

Table IV. Manifestations of theophylline toxicity.* 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