Aminophylline (Page 4 of 8)

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:

  1. When initiating therapy to guide final dosage adjustment after titration.
  2. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
  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 ≥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 μεq/1 to 800 μεq/1), 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 instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

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 Tables 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*.

* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.

** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

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 at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increase 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 of nausea, nervousness, and insomnia. Increased frequency of nausea, nervousness, and insomnia
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine Similar to cimetidine
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine. Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline andphenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction 100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increase renal clearance of theophylline. 90% increase
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending ontroleandomycin dose.
Verapamil Similar to disulfiram. 20% increase
Table IIl Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

albuterol, systemic and inhaled hydrocortisone nizatidine
amoxicillin isoflurane norfloxacin
ampicillin, with or without sulbactam isoniazid ofloxacin
atenolol isradipine omeprazole
azithromycin influenza vaccine prednisone, prednisolone
caffeine, dietary ingestion ketoconazole ranitidine
cefaclor lomefloxacin rifabutin
co-trimoxazole mebendazole roxithromycin
(trimethoprim and sulfamethoxazole) diltiazem medroxyprogesterone sorbitol
dirithromycin methylprednisolone (purgative doses do not inhibit theophylline absorption)
enflurane metronidazole sucralfate
famotidine metoprolol terbutaline, systemic
felodipine nadolol terfenadine
finasteride nifedipine tetracyclinetocainide

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