FDA label 3eaf27ca-37ad-1f0d-e054-00144ff88e88

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° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants <3 months of age, sepsis with multi-organ failure, and 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 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 ).

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 to 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. 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. Percentage of patients reported with sign or symptom Acute Overdose (Large Single Ingestion) Chronic Overdosage (Multiple Excessive Doses) Sign/Symptom Asymotomatic Gastointestinal Study 1 Study 2 (n = 157) (n = 14) NR NR = Not reported in a comparable manner. 0 Study 1 Study 2 (n = 92) (n = 102) NR 6 Vomiting Abdominal Pain Diarrhea Hematemesis 73 93 NR 21 NR 0 NR 0 30 61 NR 12 NR 14 NR 2 Metabolic/Other Hypokalemia Hyperglycemia Acid/base disturbance Rhabdomyolysis 85 79 98 NR 34 21 NR 7 44 43 18 NR 9 5 NR 0 Cardiovascular Sinus tachycardia Other supraventricular tachycardias Ventricular premature beats Atrial fibrillation or flutter Multifocal atrial tachycardia Ventricular arrhythmias hemodynamic instability Hypotension/shock 100 86 2 21 3 21 1 NR 0 NR 7 14 NR 21 100 62 12 14 10 19 12 NR 2 NR 40 0 NR 8 Neurologic Nervousness Tremors Disorientation Seizures Death NR 64 38 29 NR 7 5 14 3 21 NR 21 16 14 NR 11 14 5 10 4

<table border="none" width="482.000" ID="id_8217bb3c-9c92-49a3-99bf-097b1b08d701"> <caption ID="id_157cd59a-8ac1-4347-be50-b83bf5e5f2b7">Table IV. Manifestations of theophylline toxicity. <footnote ID="id-5dd182f7-4639-464d-8dd4-0bccc89c2eab">These data are derived from two studies in patients with serum theophylline concentrations &gt;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 &gt;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.</footnote> Percentage of patients reported with sign or symptom </caption> <col width="36.5%"/> <col width="30.7%"/> <col width="32.8%"/> <tbody> <tr ID="id_cefbf78e-c989-4cf1-b1b1-225c92c2f5d8"> <td align="left" styleCode="Toprule" valign="top"/> <td align="left" styleCode="Toprule" valign="top"> <paragraph> <content styleCode="bold">Acute Overdose</content> </paragraph> <content styleCode="bold">(Large Single Ingestion)</content> </td> <td align="left" valign="top"> <paragraph> <content styleCode="bold">Chronic Overdosage</content> </paragraph> <content styleCode="bold">(Multiple Excessive Doses)</content> </td> </tr> <tr ID="id_fcc7cfa9-7787-4343-9af2-ab74b1c8049f"> <td align="left" valign="top"> <paragraph> <content styleCode="bold"> <content styleCode="underline">Sign/Symptom </content> </content> </paragraph> <paragraph> <content styleCode="bold"> <content styleCode="underline">Asymotomatic </content> </content> </paragraph> <content styleCode="bold"> <content styleCode="underline">Gastointestinal</content> </content> </td> <td align="left" valign="top"> <paragraph>Study 1 Study 2</paragraph> <paragraph> <content styleCode="underline">(n = 157)</content> <content styleCode="underline">(n = 14)</content> </paragraph>NR <footnote ID="id-779545d1-412a-4c9f-8706-fcd776fed140">NR = Not reported in a comparable manner.</footnote> 0 </td> <td align="left" valign="top"> <paragraph>Study 1 Study 2</paragraph> <paragraph> <content styleCode="underline">(n = 92)</content> <content styleCode="underline">(n = 102)</content> </paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 6 </paragraph> </td> </tr> <tr ID="id_dd9e3a6d-2088-4553-9175-ffd86d021d93"> <td align="left" valign="top"> <paragraph>Vomiting</paragraph> <paragraph>Abdominal Pain</paragraph> <paragraph>Diarrhea</paragraph>Hematemesis </td> <td align="left" valign="top"> <paragraph>73 93</paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 21 </paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 0 </paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 0 </td> <td align="left" valign="top"> <paragraph>30 61</paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 12 </paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 14 </paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 2 </td> </tr> <tr ID="id_042886da-cac3-4318-8755-fb0592795e9e"> <td align="left" valign="top"> <paragraph> <content styleCode="bold"> <content styleCode="italics"> <content styleCode="underline">Metabolic/Other</content> </content> </content> </paragraph> <paragraph>Hypokalemia</paragraph> <paragraph>Hyperglycemia</paragraph> <paragraph>Acid/base disturbance</paragraph>Rhabdomyolysis </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph>85 79</paragraph> <paragraph>98 NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> </paragraph> <paragraph>34 21</paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 7 </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph>44 43</paragraph> <paragraph>18 NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> </paragraph> <paragraph>9 5</paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 0 </td> </tr> <tr ID="id_dd0668a0-8ac9-4f1d-a72d-4f7b084300cb"> <td align="left" valign="top"> <paragraph> <content styleCode="bold"> <content styleCode="italics"> <content styleCode="underline">Cardiovascular</content> </content> </content> </paragraph> <paragraph>Sinus tachycardia</paragraph> <paragraph>Other supraventricular</paragraph> <paragraph> tachycardias</paragraph> <paragraph>Ventricular premature beats</paragraph> <paragraph>Atrial fibrillation or flutter</paragraph> <paragraph>Multifocal atrial tachycardia</paragraph> <paragraph>Ventricular arrhythmias</paragraph> <paragraph> hemodynamic instability</paragraph>Hypotension/shock </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph>100 86 </paragraph> <paragraph>2 21</paragraph> <paragraph> </paragraph> <paragraph>3 21</paragraph> <paragraph>1 NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> </paragraph> <paragraph>0 NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> </paragraph> <paragraph>7 14</paragraph> <paragraph> </paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 21 </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph>100 62</paragraph> <paragraph>12 14</paragraph> <paragraph> </paragraph> <paragraph>10 19</paragraph> <paragraph>12 NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> </paragraph> <paragraph>2 NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> </paragraph> <paragraph>40 0</paragraph> <paragraph> </paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 8 </td> </tr> <tr ID="id_dffd5203-af26-4732-95cc-d96a13467e6a"> <td align="left" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold"> <content styleCode="italics"> <content styleCode="underline">Neurologic </content> </content> </content> </paragraph> <paragraph>Nervousness</paragraph> <paragraph>Tremors</paragraph> <paragraph>Disorientation</paragraph> <paragraph>Seizures</paragraph> <content styleCode="bold"> <content styleCode="italics"> <content styleCode="underline">Death</content> </content> </content> </td> <td align="left" styleCode="Botrule" valign="top"> <paragraph> </paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 64 </paragraph> <paragraph>38 29</paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 7 </paragraph> <paragraph>5 14</paragraph>3 21 </td> <td align="left" styleCode="Botrule" valign="top"> <paragraph> </paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 21 </paragraph> <paragraph>16 14</paragraph> <paragraph>NR <footnoteRef IDREF="id-779545d1-412a-4c9f-8706-fcd776fed140"/> 11 </paragraph> <paragraph>14 5 </paragraph>10 4 </td> </tr> </tbody> </table>