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Medication Safety Issues
Sound-alike/look-alike issues:
Aminophylline may be confused with amitriptyline, ampicillin
Pronunciation
(am in OFF i lin)
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Bronchodilator in reversible airway obstruction due to asthma or COPD; increase diaphragmatic contractility
Use: Unlabeled/Investigational
Reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing
Pregnancy Risk Factor
C
Pregnancy Considerations
Theophylline crosses the placenta; adverse effects may be seen in the newborn. Theophylline metabolism may change during pregnancy; monitor serum levels.
Lactation
Enters breast milk/compatible (AAP rates “compatible”)
Breast-Feeding Considerations
Irritability may be observed in the nursing infant.
Contraindications
Hypersensitivity to theophylline, ethylenediamine, or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Theophylline toxicity: If a patient develops signs and symptoms of theophylline toxicity (eg, persistent, repetitive vomiting), a serum level should be measured and subsequent doses held.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with hypertension or cardiac arrhythmias (excluding bradyarrhythmias).
• Hyperthyroidism: Use with caution in patients with hyperthyroidism.
• Peptic ulcer disease: Use with caution in patient with peptic ulcer disease.
• Seizure disorder: Use with caution in patients with a history of seizure disorder.
Other warnings/precautions:
• Dosage adjustments: Due to potential saturation of theophylline clearance at serum levels within (or in some patients less than) the therapeutic range, dosage adjustment should be made in small increments (maximum: 25% reduction).
• Monitoring: Due to wide interpatient variability, theophylline serum level measurements must be used to optimize therapy and prevent serious toxicity.
Adverse Reactions
Uncommon at serum theophylline concentrations ?15 mcg/mL
1% to 10%:
Cardiovascular: Tachycardia
Central nervous system: Nervousness, restlessness
Gastrointestinal: Nausea, vomiting
<1%: Insomnia, irritability, seizure, skin rash, gastric irritation, tremor, allergic reactions
Metabolism/Transport Effects
Substrate of CYP1A2 (major), 2E1 (minor), 3A4 (minor)
Drug Interactions
Adenosine: Theophylline Derivatives may diminish the therapeutic effect of Adenosine. Risk D: Consider therapy modification
Allopurinol: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Aminoglutethimide: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Barbiturates: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Benzodiazepines: Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification
Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Theophylline Derivatives. This is true at higher beta-blockers doses where cardioselectivity is lost. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Theophylline Derivatives. Risk D: Consider therapy modification
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Cimetidine: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
Disulfiram: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Febuxostat: May increase the serum concentration of Theophylline Derivatives. Risk X: Avoid combination
Fluvoxamine: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification
Interferons: May decrease the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Isoniazid: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification
Lithium: Theophylline Derivatives may increase the excretion of Lithium. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Theophylline Derivatives. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin; Telithromycin. Risk D: Consider therapy modification
Mexiletine: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification
Moricizine: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Pentoxifylline: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Phenytoin: May increase the metabolism of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Phenytoin. Risk C: Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Theophylline Derivatives. Exceptions: Amprenavir; Fosamprenavir. Risk C: Monitor therapy
QuiNINE: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Quinolone Antibiotics: May decrease the metabolism of Theophylline Derivatives. Ciprofloxacin and enoxacin are of greatest concern. Theophylline/quinolone therapy might augment the seizure-producing potential of each of the individual agents. Exceptions: Gatifloxacin; Gemifloxacin; Levofloxacin; Lomefloxacin; Moxifloxacin; Nalidixic Acid; Sparfloxacin; Trovafloxacin. Risk D: Consider therapy modification
Regadenoson: Aminophylline may diminish the vasodilatory effect of Regadenoson. Risk D: Consider therapy modification
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tacrine: May decrease the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Thiabendazole: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification
Thyroid Products: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Ticlopidine: May decrease the metabolism of Theophylline Derivatives. Risk C: Monitor therapy
Zafirlukast: Theophylline Derivatives may decrease the serum concentration of Zafirlukast. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Food does not appreciably affect absorption. Avoid extremes of dietary protein and carbohydrate intake. Changes in diet may affect the elimination of theophylline; charcoal-broiled foods may increase elimination, reducing half-life by 50%.
Storage
Do not use solutions if discolored or if crystals are present.
Compatibility
Stable in dextran 6% in D5W, dextran 6% in NS, D5LR, D5NS, D51/2NS, D51/4NS, D5W, D10W, D20W, LR, 1/2NS, NS; variable stability (consult detailed reference) in fat emulsion 10%.
Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, ceftazidime, cimetidine, cladribine, docetaxel, doxorubicin liposome, enalaprilat, esmolol, etoposide, famotidine, filgrastim, fluconazole, fludarabine, foscarnet, gatifloxacin, gemcitabine, granisetron, heparin with hydrocortisone sodium succinate, inamrinone, labetalol, levofloxacin, linezolid, melphalan, meropenem, morphine, paclitaxel, pancuronium, piperacillin/tazobactam, potassium chloride, propofol, ranitidine, remifentanil, sargramostim, tacrolimus, teniposide, thiotepa, tolazoline, vecuronium, vitamin B complex with C. Incompatible: Amiodarone, ciprofloxacin, clarithromycin, dobutamine, hydralazine, ondansetron, vinorelbine, warfarin. Variable (consult detailed reference): Cisatracurium, diltiazem.
Compatibility in syringe: Compatible: Heparin, metoclopramide, pentobarbital, thiopental. Incompatible: Doxapram.
Compatibility when admixed: Compatible: Amobarbital, bretylium, calcium gluconate, chloramphenicol, cimetidine, dexamethasone, diphenhydramine, dopamine, erythromycin lactobionate, esmolol, floxacillin, flumazenil, furosemide, heparin, hydrocortisone sodium succinate, lidocaine, mephentermine, meropenem, methyldopate, metronidazole with sodium bicarbonate, nitroglycerin, pentobarbital, phenobarbital, potassium chloride, ranitidine, sodium bicarbonate, terbutaline. Incompatible: Atracurium, bleomycin, cefepime, ceftazidime, ceftriaxone, chlorpromazine, ciprofloxacin, clindamycin, dobutamine, doxorubicin, epinephrine, hydralazine, hydrocortisone sodium succinate with cephalothin sodium, hydroxyzine, insulin (regular), isoproterenol, levorphanol, meperidine, morphine, norepinephrine, papaverine with trimecaine, penicillin G potassium, pentazocine, prochlorperazine edisylate, prochlorperazine mesylate, promazine, promethazine, vitamin B complex with C. Variable (consult detailed reference): Amikacin, ascorbic acid, corticotropin, dimenhydrinate, methylprednisolone sodium succinate, nafcillin, procaine, vancomycin, verapamil, zinc.
Mechanism of Action
Causes bronchodilatation, diuresis, CNS and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenine monophosphate (cAMP) which in turn promote catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induce release of epinephrine from adrenal medulla cells
Pharmacodynamics/Kinetics
Theophylline:
Absorption: Oral: Dosage form dependent
Distribution: 0.45 L/kg based on ideal body weight
Protein binding: 40%, primarily to albumin
Metabolism: Children >1 year and Adults: Hepatic; involves CYP1A2, 2E1, and 3A4; forms active metabolites (caffeine and 3-methylxanthine)
Half-life elimination: Highly variable and dependent upon age, liver function, cardiac function, lung disease, and smoking history
Time to peak, serum:
Oral: Immediate release: 1-2 hours
I.V.: Within 30 minutes
Excretion: Children >3 months and Adults: Urine (10% as unchanged drug)
Dosage
Treatment of acute bronchospasm: I.V.:
Loading dose (in patients not currently receiving aminophylline or theophylline): 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages are based upon continuous infusions; bolus dosing (often used in children <6 months of age) may be determined by multiplying the hourly infusion rate by 24 hours and dividing by the desired number of doses/day
6 weeks to 6 months: 0.5 mg/kg/hour
6 months to 1 year: 0.6-0.7 mg/kg/hour
1-9 years: 1 mg/kg/hour
9-16 years and smokers: 0.8 mg/kg/hour
Adults, nonsmoking: 0.5 mg/kg/hour
Older patients and patients with cor pulmonale: 0.3 mg/kg/hour
Patients with congestive heart failure: 0.1-0.2 mg/kg/hour
Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period.
Reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing (unlabeled use): I.V.: 50-250 mg administered over 30-60 seconds, repeat as necessary
Note: Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required.
Bronchodilator: Oral: Children ?45 kg and Adults: Initial: 380 mg/day (equivalent to theophylline 300 mg/day) in divided doses every 6-8 hours; may increase dose after 3 days; maximum dose: 928 mg/day (equivalent to theophylline 800 mg/day)
Administration: Oral
Should be administered around-the-clock rather than 4 times/day, 3 times/day, etc (ie, 12-6-12-6, not 9-1-5-9) to promote less variation in peak and trough serum levels.
Administration: I.M.
Not recommended
Administration: I.V.
Dilute with I.V. fluid to a concentration of 1 mg/mL and infuse over 20-30 minutes; maximum concentration: 25 mg/mL; maximum rate of infusion: 0.36 mg/kg/minute, and no greater than 25 mg/minute. I.M. administration is not recommended. Should be administered around-the-clock rather than 4 times/day, 3 times/day, etc (ie, 12-6-12-6, not 9-1-5-9) to promote less variation in peak and trough serum levels.
For reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse events during nuclear cardiac stress testing, administer I.V. undiluted over 30-60 seconds, repeat as necessary. Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required.
Geriatric Considerations
Although there is a great intersubject variability for half-lives of methylxanthines (2-10 hours), elderly, as a group, have slower hepatic clearance. Therefore, use lower initial doses and monitor closely for response and adverse reactions. Additionally, elderly patients are at greater risk for toxicity due to concomitant disease (eg, congestive heart failure, arrhythmias), and drug use (eg, cimetidine, ciprofloxacin, etc).
Additional Information
Aminophylline is a 2:1 complex of theophylline and ethylenediamine.
Cardiovascular Considerations
Theophylline results in significant tachycardia and, at higher doses, may impair ventricular rate control in patients with atrial fibrillation. This is particularly a concern since patients with underlying chronic obstructive lung disease often have coexisting atrial fibrillation. Aminophylline can be used to treat patients who have adverse hemodynamic responses to adenosine, dipyridamole or regadenoson, when used during cardiovascular stress testing. Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required.
Dental Health: Effects on Dental Treatment
Prescribe erythromycin products with caution to patients taking theophylline products. Erythromycin will delay the normal metabolic inactivation of theophyllines leading to increased blood levels; this has resulted in nausea, vomiting, and CNS restlessness.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause nervousness or restlessness
Mental Health: Effects on Psychiatric Treatment
Carbamazepine and barbiturates may decrease aminophylline levels; disulfiram and propranolol may increase aminophylline levels
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as dihydrate: 25 mg/mL (10 mL, 20 mL)
Injection, solution, as dihydrate [preservative free]: 25 mg/mL (10 mL, 20 mL)
Tablet, as dihydrate: 100 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Aminophylline)
100 mg (30): $12.99
200 mg (90): $19.00
References
“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.
American Society of Nuclear Cardiology, “Imaging Guidelines for Nuclear Cardiology Procedures: A Report of The American Society of Nuclear Cardiology Quality Assurance Committee,” J Nucl Cardiol, 2006, 13(6):e21-171.
Cummins LH, et al, “Erythromycin's Effect on Theophylline Blood Levels. Correspondence,” Pediatrics, 1977, 59:144-5.
Delaforge M and Sartori E, “In Vivo Effects of Erythromycin, Oleandomycin, and Erythralosamine Derivatives on Hepatic Cytochrome P450,” Biochem Pharmacol, 1990, 40(2):223-8.
Homma S, Gilliland Y, Guiney TE, et al,“Safety of Intravenous Dipyridamole for Stress Testing With Thallium Imaging,” Am J Cardiol, 1987, 59(1):152-4.
Klocke FJ, Baird MG, Lorell BH, et al, “ACC/AHA/ASNC Guidelines for the Clinical Use of Cardiac Radionuclide Imaging: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging),” J Am Coll Cardiol, 2003, 42(7):1318-33.
Ludden TM, “Pharmacokinetic Interactions of the Macrolide Antibiotics,” Clin Pharmacokinet, 1985, 10(1):63-79.
Ranhosky A and Kempthorne-Rawson J, “The Safety of Intravenous Dipyridamole Thallium Myocardial Perfusion Imaging. Intravenous Dipyridamole Thallium Imaging Study Group,” Circulation, 1990, 81(4):1205-9.
International Brand Names
Lexi-Comp.com
Last full review/revision June 2009
Content last modified June 2009
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