OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Theophylline – Generic, Slo-Phyllin®, Thio-Dur®, Uniphyl®

DRUG CLASS

Antiasthmatic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Theophylline	58-55-9	C7-H8-N4-O2

ANNOTATED BIBLIOGRAPHY

References updated: 18 July 2020

• Zimmerman HJ. Respiratory supportive drugs. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, p. 717.

  (Expert review of hepatotoxicity published in 1999; mentions that theophylline has been incriminated in hepatic injury rarely; no mention of montelukast, zafirlukast or zileuton).
• Barnes PJ. Pulmonary pharmacology. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 727-49.

  (Textbook of pharmacology and therapeutics).
• Strubelt O, Wegener F, Siegers CP. Arzneimittelforschung. 1970;20:473–6. [Hepatotoxicity of caffeine and theophylline] German. [PubMed: 5467807]

  (Administration of coffee or theophylline to rats sc and ip resulted in increases in serum free fatty acids levels and minimal increases in ALT and AST).
• Staib AH, Schuppan D, Lissner R, Zilly W, von Bomhard G, Richter E. Pharmacokinetics and metabolism of theophylline in patients with liver diseases. Int J Clin Pharmacol Ther Toxicol. 1980;18:500–2. [PubMed: 7203726]

  (Study of metabolism of single iv dose of theophylline in patients with various forms of liver disease showed only patients with decompensated cirrhosis had significantly lower clearance rates that might lead to higher plasma levels).
• Woodcock AA, Johnson MA, Geddes DM. Theophylline prescribing, serum concentrations, and toxicity. Lancet. 1983;2:610–3. [PubMed: 6136756]

  (Monitoring theophylline levels found high levels in 13 outpatient and 4 cases of serious adverse events and 3 deaths [seizures and cardiac arrest], but no frank clinical hepatotoxicity).
• Piperno D, Pacheco Y, Bastion Y, Favre-Monet PY, Gormand F, Copere B, Kofman J, et al. Therapie. 1988;43:481–3. [Theophylline-induced hepatitis. Apropos of 2 cases] French. [PubMed: 3067422]

  (65 year old woman and 69 year old man with asthma developed ALT elevations without jaundice 11 and 4 days after starting intravenous theophylline (peak ALT 520 and 1345 U/L), and positive rechallenge in one patient).
• Drent M, Kuks PF, van den Bosch JM, Brandt KH. Ned Tijdschr Geneeskd. 1993;137:1831–5. [Psychiatric symptoms due to theophylline overdose; the necessity of blood level monitoring] Dutch. [PubMed: 8377864]

  (Chronic overdosing with theophylline led to severe psychiatric symptoms and depression; one patient developed hypotension and ischemic hepatitis [ALT and LDH ~5000 U/L without mention of jaundice]).
• Makino S, Adachi M, Ohta K, Kihara N, Nakajima S, Nishima S, Fukuda T, et al. A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD. Allergol Int. 2006;55:395–402. [PubMed: 17130682]

  (Prospective study of 3921 patients at 66 centers receiving sustained release theophylline found no serious adverse events; only 1 patient with ALT elevation).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl. 2004;10:1018–23. [PubMed: 15390328]

  (Among ~50,000 liver transplants done in the US between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, one case was attributed to zafirlukast, but no other antiasthma medication mentioned).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J. Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to an antiasthma medication).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to theophylline or any other medications for asthma).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 4 cases [<1%] were attributed to medications for asthma, all due to montelukast and none to theophylline, zafirlukast or zileuton).
• Drugs for asthma. Med Lett Drugs Ther. 2017;59(1528):139–46. [PubMed: 28880849]

  (Concise review of medications used for asthma including theophylline; mentions that theophylline has been replaced by safer and better tolerated agents and that side effects include nausea, vomiting, headache and insomnia and with high doses, tachycardia, cardiac arrhythmias, irritability, tremors, seizures and even sudden death; no mention of liver injury).