THEOPHYLLINE 80 mg/15mL Solution, 118 mL — NDC 0121-0820-04 (Billing 00121-0820-04)

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: 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).

(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 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 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).

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 re-evaluation 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 2 (n=14) Study 1 (n=92) Study 2 (n=102) Asymptomatic 0 NR ** 6 Gastrointestinal Vomiting 93 30 61 Abdominal Pain 21 NR ** 12 Diarrhea 0 NR ** 14 Hematemesis 0 NR ** 2 Metabolic / Other Hypokalemia 79 44 43 Hyperglycemia NR ** 18 NR ** Acid/base disturbance 21 9 5 Rhabdomyolysis 7 NR ** 0 Cardiovascular Sinus tachycardia 86 100 62 Other supraventricular tachycardias 21 12 14 Ventricular premature beats 21 10 19 Atrial fibrillation or flutter NR ** 12 NR ** Multifocal atrial tachycardia NR ** 2 NR ** Ventricular arrhythmias with hemodynamic instability 14 40 0 Hypotension/shock 21 NR ** 8 Neurologic Nervousness 64 NR ** 21 Tremors 29 16 14 Disorientation 7 NR ** 11 Seizures 14 14 5 Death 21 10 4 * 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… [Excerpted — this section continues on DailyMed.]

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 steady-state 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 Table 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.

Table II. Clinically significant drug interactions with theophylline*. Drug Type of Interaction Effect** Adenosine Theophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance doses at ≥600 mg/day.

25% increase at allopurinol Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2.

70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.

Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation.

50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.

Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state ser… [Excerpted — this section continues on DailyMed.]

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/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.

PRECAUTIONS General 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: When initiating therapy to guide final dosage adjustment after titration. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.

Whenever signs or symptoms of theophylline toxicity are present. Whenever there is a new illness, worsening of a chronic illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued). To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 1-2 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 two 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/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. 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… [Excerpted — this section continues on DailyMed.]