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Controlled Release Drugs in Overdose

Clinical Considerations

  • Review Articles
  • Poisoning Management
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Summary

The main characteristic of overdose with controlled release formulations is the delay in presentation and onset of clinical effects. There is a prolonged absorption phase which leads to a delayed time to maximum plasma concentration and usually a prolonged time with levels close to the peak concentration. Absorption may continue for more than 24 hours. Overdose with controlled release formulations of toxic drugs therefore requires a longer period of observation as the onset of symptoms may be as late as 16 to 20 hours after ingestion.

Treatment nomograms calculated for standard formulations are not appropriate for controlled release formulations. The optimal gastrointestinal decontamination method is controversial, but in serious overdoses it should include gastric lavage and activated charcoal followed by whole bowel irrigation as a means of clearing whole tablets from the gastrointestinal tract. Pharmacobezoar formation should be suspected if, despite apparently effective gastrointestinal decontamination, there is evidence of continuing absorption. These are best diagnosed with endoscopy and the treatment options include endoscopic removal, whole bowel irrigation and surgery.

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References

  1. Senel S, Capan Y, Hincal AA. Factors affecting the formulation of sustained release potassium chloride tablets. Pharmazie 1991; 46: 792–5

    PubMed  CAS  Google Scholar 

  2. Todd PA, Faulds D. Felodipine. A review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular disorders. Drugs 1992; 44(2): 251–77

    Article  PubMed  CAS  Google Scholar 

  3. Powers-Cramer M, Saks SR. Translating safety, efficacy and compliance into economic value for controlled release dosage forms. Pharmacoeconomics 1994; 5(6): 482–504

    Article  Google Scholar 

  4. CPMP Working Party on Efficacy of Medicinal Products. EEC Note for Guidance. Clinical testing of prolonged action forms with special reference to extended release forms. Pharmacol Toxicol 1991; 68: 449–53

    Google Scholar 

  5. Urquhart J. Rate-controlled drug dosage. Drugs 1982; 23: 207–26

    Article  PubMed  CAS  Google Scholar 

  6. Prisant LM, Bottini B, DiPiro JT (1992). Novel drug-delivery systems for hypertension. Am J Med 1992 Aug 31; 93 Suppl. 2A: 45S–55S

    Article  PubMed  CAS  Google Scholar 

  7. Robinson JR, Gauger LJ. Formulation of controlled-release products. J Allergy Clin Immunol 1986 Oct; 78(4): 676–81

    Article  PubMed  CAS  Google Scholar 

  8. Ranade VV. Drug delivery system 5A oral drug delivery. J Clin Pharmacol 1991; 31(2): 2–16

    PubMed  CAS  Google Scholar 

  9. Sommers DEK, van Wyk M, Meyer EC, et al. The absorption characteristics of six sustained-release theophylline preparations. S Afr Med J 1992 Mar 26; 81: 20–2

    PubMed  CAS  Google Scholar 

  10. Benet LZ, Massoud N, editors. Pharmacokinetic basis for drug treatment. New York: Raven Press, 1984

    Google Scholar 

  11. Staib AH, Loew D, Harder S, et al. Measurement of theophylline absorption from different regions of the gastro-intestinal tract using a remote controlled delivery device. Eur J Clin Pharmacol 1986; 30: 691–7

    Article  PubMed  CAS  Google Scholar 

  12. Minocha A, Spyker DA. Acute overdose with sustained release drug formulations. Perspectives in treatment. Med Toxicol 1986; 1: 300–7

    PubMed  CAS  Google Scholar 

  13. Welling PG. Pharacokinetics: processes and mathematics. Washington DC: American Chemical Society, 1986

    Google Scholar 

  14. Hendeles L, Weinberger M, Milavetz G, et al. Food-induced ‘dose-dumping’ from a once-a-day theophylline product as a cause of theophylline toxicity. Chest 1985 Jun; 87(6): 758–65

    Article  PubMed  CAS  Google Scholar 

  15. Meyer-Harris J. Clonidine patch toxicity. Pediatrics 1990 Dec; 24: 1191–3

    Google Scholar 

  16. Harchelroad F, Potts K, Burdick J, et al. Oral absorption of nicotine from transdermal therapeutic systems. Vet Hum Toxicol 1992 Aug; 34(4): 332

    Google Scholar 

  17. Raber JH, Shinar C, Finkelstein S. Clonidine patch ingestion in an adult. Ann Pharmacother 1993 Jun; 27: 719–21

    PubMed  CAS  Google Scholar 

  18. Day TK. Intestinal perforation associated with osmotic slow release indomethacin capsules. BMJ 1983; 287: 1671–2

    Article  PubMed  CAS  Google Scholar 

  19. Prisant LM, Carr AA, Bottini PB, et al. Nifedipine GITS (gastrointestinal therapeutic system) bezoar. Arch Intern Med 1991 Sept; 151: 1868–9

    Article  PubMed  CAS  Google Scholar 

  20. Bogacz K, Caldron P. Enteric-coated aspirin bezoar. Elevation of serum salicylate level by barium study. Case report and review of medical management. Am J Med 1987 Oct: 83: 783–6

    Article  PubMed  CAS  Google Scholar 

  21. D’Arcy PF. Theophylline toxicity from ‘dose-dumping’. Pharm Int 1985; 6(12): 289–90

    Google Scholar 

  22. Bosse GM, Arnold TC. Overdose with sustained-release lithium preparations. J Emerg Med 1992; 10: 719–21

    Article  PubMed  CAS  Google Scholar 

  23. Kwong TC, Laczin J, Baum J. Self-poisoning with enteric-coated aspirin. Am J Clin Pathol 1983 Dec; 80: 888–90

    PubMed  CAS  Google Scholar 

  24. Todd PJ, Sills JA, Harris F, et al. Problems with overdoses of sustained-release aspirin [letter]. Lancet 1981 Apr 4; 1(8223): 777

    Article  PubMed  CAS  Google Scholar 

  25. Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated aspirin overdose. Ann Emerg Med 1987 Apr; 16(4): 434–6

    Article  PubMed  CAS  Google Scholar 

  26. Olson KR, Benowitz NL, Woo OF, et al. Theophylline overdose: acute single ingestion versus chronic repeated over-medication. Am J Emerg Med 1985; 3: 386–94

    Article  PubMed  CAS  Google Scholar 

  27. Buckley BM, Braithwaite RA, Vale JA. Theophylline poisoning. Lancet 1983; 2: 618

    Article  PubMed  CAS  Google Scholar 

  28. Connell JMC, McGeachie JF, Knepil J, et al. Self-poisoning with sustained release aminophylline: secondary rise in serum theophylline concentration after charcoal haemoperfusion. BMJ 1982 March 27; 284: 943

    Article  PubMed  CAS  Google Scholar 

  29. Hendren WG, Schieber RS, Garrettson LK. Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med 1989 Sept 9; 18: 984–7

    Article  PubMed  CAS  Google Scholar 

  30. Amitai Y, Lovejoy FH. Characteristics of vomiting associated with acute sustained release theophylline poisoning, implications for management with oral activated charcoal. Clin Toxicol 1987; 25(7): 539–54

    Article  CAS  Google Scholar 

  31. Gaudreault P, Wason S, Lovejoy FH (1983). Acute pediatric theophylline overdose. A summary of 28 cases. J Pediatr 1983 March; 102(3): 474–6

    Article  PubMed  CAS  Google Scholar 

  32. Castaneda-Hernandez G, Caille G, du Souich P. Influence of drug-formulation on drug concentration-effect relationships. Clin Pharmacokinet 1994; 26: 135–43

    Article  PubMed  CAS  Google Scholar 

  33. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993 Dec 15; 119: 1161–7

    PubMed  CAS  Google Scholar 

  34. Buckley NA, Whyte IM, Dawson AH, et al. Six years of poisoning in Newcastle 1987–1992. Med J Aust. In press

  35. Buckley N, Dawson AH, Howarth D, et al. Slow-release verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993 Feb 1; 158(3): 202–4

    PubMed  CAS  Google Scholar 

  36. Spiller HA, Meyers A, Ziemba T, et al. Delayed onset of cardiac arrhythmias from sustained-release verapamil. Ann Emerg Med 1991 Feb; 20(2): 201–3

    Article  PubMed  CAS  Google Scholar 

  37. Colledge NR, Northridge B, Fraser DM (1988). Survival after massive overdose of slow-release potassium. Scott Med J 1988; 33: 279

    PubMed  CAS  Google Scholar 

  38. McDonald D, Alguire PC. Case report. Fatal overdose with sustained-release verapamil. Am J Med Sci 1992 Feb; 303(2): 115–7

    Article  Google Scholar 

  39. Rankin RJ, Edwards IR. Overdose of sustained release verapamil [letter]. NZ Med J 1990 Apr 11; 103(887): 165

    CAS  Google Scholar 

  40. Coupe M. Self-poisoning with sustained-release aminophylline. A mechanism for observed secondary rise in serum theophylline. Hum Toxicol 1986; 5: 341–2

    Article  PubMed  CAS  Google Scholar 

  41. Cereda JM, Scott J, Quigley EMM. Endoscopic removal of pharmacobezoar of slow release theophylline. BMJ 1986 Nov 1; 293: 1143

    Article  PubMed  CAS  Google Scholar 

  42. Sporer KA, Manning JJ. Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann Emerg Med 1993 Mar; 22(3): 603–5

    Article  PubMed  CAS  Google Scholar 

  43. Whyte KF, Addis GJ. Toxicity of salbutamol and theophylline together. Lancet 1983; 2: 618–9

    Article  PubMed  CAS  Google Scholar 

  44. Bernstein G, Jehle D, Bernaski E, et al. Failure of gastric emptying and charcoal administration in fatal sustained-release theophylline overdose, pharmacobezoar formation. Ann Emerg Med 1992 Nov; 21(11): 1388–90

    Article  PubMed  CAS  Google Scholar 

  45. Coutselinis A, Poulus L. An unusual case of carbamazepine poisoning. Clin Toxicol 1980; 16: 385–7

    Article  PubMed  CAS  Google Scholar 

  46. Vree TB, Janssen TJ, Hekster YA, et al. Clinical pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose. Ther Drug Monit 1986; 8(3): 297–304

    Article  PubMed  CAS  Google Scholar 

  47. Ellenhorn MJ, Barceloux DG, editors. Medical toxicology. New York: Elsevier, 1988

    Google Scholar 

  48. Jaeger RW, DeCastro FJ, Barry RC. Radiopacity of drugs and plants in vivo — limited usefulness. Vet Hum Toxicol 1981; 23: 2–4

    PubMed  CAS  Google Scholar 

  49. Anon. Radiopaque agents. In: Gelman CR, Rumack BH, editors. Poisindex information systems. Denver: Micromedex Inc, 1994

    Google Scholar 

  50. Robins JB, Turnbull JA, Robertson C. Gastric perforation after acute aspirin overdose. Hum Toxicol 1985; 4: 527–8

    Article  PubMed  CAS  Google Scholar 

  51. Farrand RJ, Green JH, Haworth C. Enteric coated aspirin overdose and gastric perforation. BMJ 1975; 4: 85–6

    Article  PubMed  CAS  Google Scholar 

  52. Hamblin JE, Martin CA. Transdermal patch poisoning. Pediatrics 1987 Jan; 79(1): 161

    PubMed  CAS  Google Scholar 

  53. Sennhauser FH, Schwarz HP. Toxic psychosis from transdermal scopolamine in a child. Lancet 1986 Nov 1; 2(8514): 1033

    Article  PubMed  CAS  Google Scholar 

  54. Ehrenpreis ED, Young MA, Leikin JB. Symptomatic nitroglycerin toxicity from erroneous use of topical nitroglycerin. Vet Hum Toxicol 1989 Aug; 31: 362

    Google Scholar 

  55. Engel CJ, Parmentier AH. Suicide attempts and the nicotine patch [letter]. JAMA 1993 July 21; 270(3): 323–4

    Article  PubMed  CAS  Google Scholar 

  56. Howarth DM, Dawson AH, Smith AJ, et al. Calcium channel blocking drug overdose. An Australian series. Hum Exp Toxicol 1994; 13: 161–6

    Article  PubMed  CAS  Google Scholar 

  57. McGuigan MA. Death due to salicylate poisoning in Ontario. Can Med Assoc J 1986; 135(8): 891–4

    CAS  Google Scholar 

  58. Albertson TE, Derlet RW, Foulke GE, et al. Superiority of activated charcoal alone compared with ipecac and activated charcoal in the treatment of acute toxic ingestions. Ann Emerg Med 1989 Jan; 18(1): 56–9

    Article  PubMed  CAS  Google Scholar 

  59. Curtis RA, Barone J, Giacona N. Efficacy of ipecac and activated charcoal/cathartic. Arch Intern Med 1984 Jan; 144: 48–52

    Article  PubMed  CAS  Google Scholar 

  60. Underhill TJ, Greene MK, Dove AF. A comparison of the efficacy of gastric lavage, ipecacuanha and activated charcoal in the emergency management of paracetamol overdose. Arch Emerg Med 1990; 7: 148–54

    PubMed  CAS  Google Scholar 

  61. Kulig K, Bar-Or D, Cantrill SV, et al. Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985 Jun; 14(6): 562–7

    Article  PubMed  CAS  Google Scholar 

  62. Merigian KS, Woodward M, Hedges JR. Prospective evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med 1990; 8: 479–83

    Article  PubMed  CAS  Google Scholar 

  63. Bartecchi CE. Removal of gastric drug masses. N Engl J Med 1977 Feb 3; 296(5): 282–3

    PubMed  CAS  Google Scholar 

  64. Soni N, Baines D, Pearson IY. Cardiovascular collapse and propranolol overdose. Med J Aust 1983; 2: 629–30

    PubMed  CAS  Google Scholar 

  65. Palatnick W, Tenenbein M. Activated charcoal in the treatment of drug overdose. Drug Saf 1992; 7(1): 3–7

    Article  PubMed  CAS  Google Scholar 

  66. Pond SM. Role of repeated oral doses of activated charcoal in clinical toxicology. Med Toxicol 1986; 1(1): 3–11

    PubMed  CAS  Google Scholar 

  67. Minton NA, Henry JA, Rolls LJ, et al. Prevention of drug absorption following simulated overdose of sustained-release theophylline. Proceedings of the British Pharmacological Society. Br J Clin Pharmacol 1990; 29(5): 605P–6P

    Google Scholar 

  68. Keller RE, Schwab RA, Krenzelok EP. Contribution of sorbitol combined with activated charcoal in prevention of salicylate absorption. Ann Emerg Med 1990 Jun; 19(6): 654–6

    Article  PubMed  CAS  Google Scholar 

  69. Berlinger WG, Spector R, Goldberg MJ, et al. Enhancement of theophylline clearance by oral activated charcoal. Clin Pharmacol Ther 1983 March: 33(3): 351–4

    Article  PubMed  CAS  Google Scholar 

  70. Pond S, Jacobs M, Marks J, et al. Treatment of digitoxin overdose with oral activated charcoal [letter]. Lancet 1981 Nov 21; 2(8256): 1177–8

    Article  PubMed  CAS  Google Scholar 

  71. Levy G. Gastrointestinal clearance of drugs with activated charcoal. N Engl J Med 1982 Sept; 307: 676–8

    Article  PubMed  CAS  Google Scholar 

  72. Berg MJ, Berlinger WG, Goldberg MJ, et al. Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med 1982 Sept: 307(11): 642–4

    Article  PubMed  CAS  Google Scholar 

  73. Filippone GA, Fish SS, Lacouture PG, et al. Reversible adsorption (desorption) of aspirin from activated charcoal. Arch Intern Med 1987 Aug; 147: 1390–2

    Article  PubMed  CAS  Google Scholar 

  74. Goldberg MJ, Spector R, Park GD, et al. The effect of sorbitol and activated charcoal on serum theophylline concentrations after slow-release theophylline. Clin Pharmacol Ther 1987 Jan; 41: 108–11

    Article  PubMed  CAS  Google Scholar 

  75. Henderson A, Salm P, Pond SM. Rapid rise in serum theophylline concentration after overdose with sustained release theophylline. Med J Aust 1992 Sept; 157(7): 354–6

    PubMed  CAS  Google Scholar 

  76. Ilkhanipour K, Yealy DM, Krenzelok EP. The comparative efficacy of various multiple-dose activated charcoal regimens. Am J Emerg Med 1992 July; 10: 298–300

    Article  PubMed  CAS  Google Scholar 

  77. Tenenbein M, Cohen S, Sitar DS. Whole bowel irrigation as a decontamination procedure after acute drug overdose. Arch Intern Med 1987 May; 147: 905–7

    Article  PubMed  CAS  Google Scholar 

  78. Tenenbein M. Whole bowel irrigation in iron poisoning. J Pediatr 1987 Jul; 111(1): 142–5

    Article  PubMed  CAS  Google Scholar 

  79. Tenenbein M. Whole bowel irrigation as a gastrointestinal decontamination procedure after acute poisoning. Med Toxicol 1988; 3: 77–84

    CAS  Google Scholar 

  80. Tenenbein M. Whole bowel irrigation and activated charcoal. Ann Emerg Med 1989 Jun; 18(6): 707–8

    Article  PubMed  CAS  Google Scholar 

  81. Laggner AN, Kaik G, Lenz K, et al. Treatment of severe poisoning with slow release theophylline. BMJ 1984 May 19; 288: 1497

    Article  PubMed  CAS  Google Scholar 

  82. Tenenbein M. Whole bowel irrigation for toxic ingestions. Clin Toxicol 1985; 23(2–3): 177–84

    Article  CAS  Google Scholar 

  83. Lenz K, Mörz R, Kleinberger G, et al. Effect of gut lavage on phenobarbital elimination in rats. Clin Toxicol 1983; 20(2): 147–57

    Article  CAS  Google Scholar 

  84. Mayer AL, Sitar DS, Tenenbein M. Multiple-dose charcoal and whole-bowel irrigation do not increase clearance of absorbed salicylate. Arch Intern Med 1992 Feb; 152: 393–6

    Article  PubMed  CAS  Google Scholar 

  85. Laine K, Kivisto KT, Neuvonen PJ. The effect of activated charcoal on the absorption and elimination of astemizole. Hum Exp Toxicol 1994 Jul; 13(7): 502–5

    Article  PubMed  CAS  Google Scholar 

  86. Burkhart KK, Wuerz RC, Donovan JW. Whole-bowel irrigation as adjunctive treatment for sustained-release theophylline overdose. Ann Emerg Med 1992 Nov; 21: 1316–20

    Article  PubMed  CAS  Google Scholar 

  87. Kirshenbaum LA, Mathews SC, Sitar DS, et al. Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals. Clin Pharmacol Ther 1989 Sept; 46: 264–71

    Article  PubMed  CAS  Google Scholar 

  88. Rosenberg P, Livingstone D, McLellan BA. Whole bowel irrigation and activated charcoal [letter]. Ann Emerg Med 1989 Jun; 18: 708

    Article  Google Scholar 

  89. Buckley NA, Dawson AH. Whole bowel irrigation for theophylline overdose. Ann Emerg Med 1993; 22(11): 1774

    Article  PubMed  CAS  Google Scholar 

  90. Kirshenbaum LA, Sitar DS, Tenenbein M. Interaction between whole-bowel irrigation solution and activated charcoal: implications for the treatment of toxic ingestions. Ann Emerg Med 1990 Oct; 19(10): 1129–32

    Article  PubMed  CAS  Google Scholar 

  91. Landsman I, Bricker JT, Reid BS. Emergency gastrotomy treatment of choice for iron bezoar. J Paediatr Surg 1987; 22: 184–5

    Article  CAS  Google Scholar 

  92. Schwartz HS. Acute meprobamate poisoning with gastrotomy and removal of a drug-containing mass. N Engl J Med 1976; 295: 1177–8

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Discipline of Clinical Pharmacology, University of Newcastle, Newcastle, New South Wales, Australia

    Nicholas A. Buckley

  2. Department of Clinical Toxicology and Pharmacology, Mater Misericordiae Hospital, Newcastle, New South Wales, Australia

    Andrew H. Dawson & David A. Reith

  3. Department of Clinical Pharmacology and Toxicology, Newcastle Mater Misericordiae Hospital, Locked Bag 7, Hunter Regional Mail Centre, New South Wales, 2310, Australia

    Nicholas A. Buckley

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Buckley, N.A., Dawson, A.H. & Reith, D.A. Controlled Release Drugs in Overdose. Drug-Safety 12, 73–84 (1995). https://doi.org/10.2165/00002018-199512010-00006

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