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Acetaminophen / dextromethorphan / diphenhydramine Side Effects

For the Consumer

Applies to acetaminophen / dextromethorphan / diphenhydramine: liquid

Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; excitability (especially in children); headache; loss of appetite; nausea; nervousness or anxiety; upset stomach; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur while taking acetaminophen / dextromethorphan / diphenhydramine:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); dark urine or pale stools; difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, drowsiness, lightheadedness, or headache; severe or persistent loss of appetite; stomach pain; tremor; trouble sleeping; unusual fatigue; vision changes; yellowing of the skin or eyes.

For Healthcare Professionals

Applies to acetaminophen / dextromethorphan / diphenhydramine: oral liquid


Two cases hypotension have been reported following the administration of acetaminophen. Both patients experienced significant decreases in blood pressure. One of the two patients required pressor agents to maintain adequate mean arterial pressures. Neither episode was associated with symptoms of anaphylaxis. Neither patient was rechallenged after resolution of the initial episode.[Ref]

Cardiovascular side effects of acetaminophen have included two cases of hypotension.

Cardiovascular side effects of diphenhydramine have included hypotension, tachycardia, and palpitations.[Ref]


Gastrointestinal side effects of diphenhydramine have been usually mild and included nausea and dry mouth.

Gastrointestinal side effects of dextromethorphan have included stomach upset.[Ref]


Genitourinary side effects of diphenhydramine have included urinary retention and dysuria as a result of the anticholinergic effects of diphenhydramine.[Ref]


Hematologic side effects of acetaminophen have included rare cases of thrombocytopenia. Methemoglobinemia with resulting cyanosis has also been observed in the setting of acute overdose.

Hematologic side effects of diphenhydramine have included rare reports of hemolytic anemia, thrombocytopenia, and agranulocytosis.[Ref]


Most commonly, hypersensitivity to diphenhydramine has manifested itself in patients receiving systemic drug after being sensitized to it by topical application. Sensitization with systemic administration has also been reported.[Ref]

Hypersensitivity side effects of diphenhydramine have included rash, pruritus and eczema. Photosensitivity reactions have also been reported.

Hypersensitivity side effects of dextromethorphan have included rare reports of fixed-drug eruptions.[Ref]

Nervous system

The CNS depressant effect of diphenhydramine parallels its plasma concentrations. The plasma concentration threshold for sedation is 30 to 42 ng/mL, and to cause mental impairment is 58 to 74 ng/mL. Patients should be warned against driving while taking diphenhydramine. Dystonic reactions have been accompanied by dizziness, mental confusion, rigidity, lip and tongue protrusion, trismus, torticollis, and swallowing difficulties and generally resolve spontaneously. Toxic encephalopathy has been reported in a child with chicken pox treated generously with topical diphenhydramine. Delirium has been reported in elderly patients with mild dementia following a small oral dose of diphenhydramine.[Ref]

Nervous system side effects of diphenhydramine have included frequent reports of depression with drowsiness and sedation. Motor skills may be impaired. Dystonic reactions have been reported after single doses of diphenhydramine.

Nervous system side effects of dextromethorphan have included drowsiness and dizziness. Other side effects such as excitation, mental confusion, and opioid like respiratory depression have been rare and occurred at higher dosages. In some cases of abuse, patients experienced euphoria, hyperactivity, mania, and auditory and visual hallucinations.[Ref]


Ocular side effects of diphenhydramine have included blurred vision, diplopia, and dry eyes due to anticholinergic effects.[Ref]


Dermatologic side effects acetaminophen have included rare reports of erythematous skin rashes. Acetaminophen associated bullous erythema and purpura fulminans have been reported. One case of toxic epidermal necrolysis associated with acetaminophen administered to a pediatric patient has been reported. Acetaminophen has been associated with a risk of rare but potentially fatal serious skin reactions known as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).[Ref]


Alcoholic patients may develop hepatotoxicity after even modest doses of acetaminophen. In healthy patients, approximately 15 grams of acetaminophen is necessary to deplete liver glutathione stores by 70% in a 70 kg person. However, hepatotoxicity has been reported following smaller doses. Glutathione concentrations may be repleted by the antidote N-acetylcysteine. One case report has suggested that hypothermia may also be beneficial in decreasing liver damage during overdose.

In a recent retrospective study of 306 patients admitted for acetaminophen overdose, 6.9% had severe liver injury but all recovered. None of the 306 patients died.

One study has suggested that acetaminophen may precipitate acute biliary pain and cholestasis. The mechanism of this effect may be related to inhibition of prostaglandin and alterations in the regulation of the sphincter of Oddi.

Cases of acute pancreatitis have been reported rarely.

A 19-year-old female developed hepatotoxicity, reactive plasmacytosis and agranulocytosis followed by a leukemoid reaction after acute acetaminophen toxicity.[Ref]

Hepatic side effects of acetaminophen have included severe and sometimes fatal dose dependent hepatitis in alcoholic patients. Hepatotoxicity has been increased during fasting.[Ref]


Renal side effects of acetaminophen have included rare reports of acute renal failure, acute tubular necrosis, and interstitial nephritis. Adverse renal effects are most often observed after overdose, after chronic abuse (often with multiple analgesics), or in association with acetaminophen-related hepatotoxicity.[Ref]

Acute tubular necrosis usually occurs in conjunction with liver failure, but has been observed as an isolated finding in rare cases. A possible increase in the risk of renal cell carcinoma has been associated with chronic acetaminophen use as well.

One case-control study of patients with end-stage renal disease suggested that long term consumption of acetaminophen may significantly increase the risk of end-stage renal disease particularly in patients taking more than two pills per day.

However, a recent cohort study of analgesia use of initially healthy men concluded that moderate use of analgesics including acetaminophen was not associated with increased risk of renal disease.[Ref]


Metabolic side effects of acetaminophen have included metabolic acidosis following a massive overdose of acetaminophen.[Ref]

In the case of metabolic acidosis, causality is uncertain as more than one drug was ingested. The case of metabolic acidosis followed the ingestion of 75 grams of acetaminophen, 1.95 grams of aspirin, and a small amount of a liquid household cleaner The patient also had a history of seizures which the authors reported may have contributed to an increased lactate level indicative of metabolic acidosis.[Ref]


Respiratory side effects of acetaminophen have included a case of eosinophilic pneumonia.[Ref]


1. Brown G "Acetaminophen-induced hypotension." Heart Lung 25 (1996): 137-40

2. Knowles SR, Weber E "Dextromethorphan anaphylaxis." J Allerg Clin Immunol 102 (1998): 316-7

3. "Product Information. Benadryl (diphenhydramine)." Parke-Davis, Morris Plains, NJ.

4. Schuller DE, Turkewitz D "Adverse effects of antihistamines." Postgrad Med 79 (1986): 75-86

5. Lee WM "Acute liver failure." Am J Med 96 (1994): 3-9

6. Whitcomb DC, Block GD "Association of acetaminopphen hepatotoxicity with fasting and ethanol use." JAMA 272 (1994): 1845-50

7. Cheung L, Meyer KC "Acetaminophen poisoning and liver function." N Engl J Med 331 (1994): 1311-2

8. Minton NA, Henry JA, Frankel RJ "Fatal paracetamol poisoning in an epileptic." Hum Toxicol 7 (1988): 33-4

9. Rumore MM, Blaiklock RG "Influence of age-dependent pharmacokinetics and metabolism on acetaminophen hepatotoxicity." J Pharm Sci 81 (1992): 203-7

10. Block R, Jankowski JA, Lacoux P, Pennington CR "Does hypothermia protect against the development of hepatitis in paracetamol overdose?" Anaesthesia 47 (1992): 789-91

11. Kumar S, Rex DK "Failure of physicians to recognize acetaminophen hepatotoxicity in chronic alcoholics." Arch Intern Med 151 (1991): 1189-91

12. McJunkin B, Barwick KW, Little WC, Winfield JB "Fatal massive hepatic necrosis following acetaminophen overdose." JAMA 236 (1976): 1874-5

13. Covington TR, Lawson LC, Young LL, eds. "Handbook of Nonprescription Drugs. 10th ed." Washington, DC: American Pharmaceutical Association (1993):

14. Zimmerman HJ, Maddrey WC "Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure." Hepatology 22 (1995): 767-73

15. Mofenson HC, Caraccio TR, Nawaz H, Steckler G "Acetaminophen induced pancreatitis." Clin Toxicol 29 (1991): 223-30

16. Bonkovsky HL "Acetaminophen hepatotoxicity, fasting, and ethanol." JAMA 274 (1995): 301

17. Wong V, Daly M, Boon A, Heatley V "Paracetamol and acute biliary pain with cholestasis." Lancet 342 (1993): 869

18. Singer AJ, Carracio TR, Mofenson HC "The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction." Ann Emerg Med 26 (1995): 49-53

19. Keays R, Harrison PM, Wendon JA, et al "Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial." BMJ 303 (1991): 1026-9

20. Hartleb M "Do thyroid hormones promote hepatotoxicity to acetaminophen?" Am J Gastroenterol 89 (1994): 1269-70

21. O'Dell JR, Zetterman RK, Burnett DA "Centrilobular hepatic fibrosis following acetaminophen-induced hepatic necrosis in an alcoholic." JAMA 255 (1986): 2636-7

22. Kaysen GA, Pond SM, Roper MH, Menke DJ, Marrama MA "Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen." Arch Intern Med 145 (1985): 2019-23

23. Block R "Liver failure induced by paracetamol." BMJ 306 (1993): 457

24. Bonkovsky HL, Kane RE, Jones DP, Galinsky RE, Banner B "Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition - evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency." Hepatology 19 (1994): 1141-8

25. Bray GP "Liver failure induced by paracetamol." BMJ 306 (1993): 157-8

26. Nelson EB, Temple AR "Acetaminophen hepatotoxicity, fasting, and ethanol." JAMA 274 (1995): 301

27. Cheung L, Potts RG, Meyer KC "Acetaminophen treatment nomogram." N Engl J Med 330 (1994): 1907-8

28. Johnson GK, Tolman KG "Chronic liver disease and acetaminophen." Ann Intern Med 87 (1977): 302-4

29. Baraka OZ, Truman CA, Ford JM, Roberts JC "The effect of propranolol on paracetamol metabolism in man." Br J Clin Pharmacol 29 (1990): 261-4

30. Whitcomb DC "Acetaminophen poisoning and liver function." N Engl J Med 331 (1994): 1311

31. Smilkstein MJ, Douglas Dr, Daya MR "Acetaminophen poisoning and liver function." N Engl J Med 331 (1994): 1310-1

32. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB "Acetaminophen hepatotoxicity in alcoholics." Ann Intern Med 104 (1986): 399-404

33. Keaton MR "Acute renal failure in an alcoholic during therapeutic acetaminophen ingestion." South Med J 81 (1988): 1163-6

34. Brotodihardjo AE, Batey RG, Farrell GC, Byth K "Hepatotoxicity from paracetamol self-poisoning in Western Sydney: a continuing challenge." Med J Aust 157 (1992): 382-5

35. Wolfe TR, Caravati EM "Massive dextromethorphan ingestion and abuse." Am J Emerg Med 13 (1995): 174-6

36. Lee WM "Medical progress: drug-induced hepatotoxicity." N Engl J Med 333 (1995): 1118-27

37. Shoenfeld Y, Shaklai M, Livni E, Pinkhas J "Thrombocytopenia from acetaminophen." N Engl J Med 303 (1980): 47

38. Heine A "Diphenhydramine: a forgotten allergen?" Contact Dermatitis 35 (1996): 311-2

39. Stubb S, Reitamo S "Fixed-drug eruption due to dextromethorphan ." Arch Dermatol 126 (1990): 970-1

40. Yamada S, Tanaka M, Kawahara Y, Inada M, Ohata Y "Photoallergic contact dermatitis due to diphenhydramine hydrochloride." Contact Dermatitis 38 (1998): 282

41. Lawrence CM, Byrne JP "Eczematous eruption from oral diphenhydramine." Contact Dermatitis 7 (1981): 276-7

42. Settipane RA, Stevenson DD "Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma." J Allergy Clin Immunol 84 (1989): 26-33

43. Davenport PM, Wilhelm RE "An unusual vasculitis due to diphenhydramine. Cutaneous and central nervous system involvement." Arch Dermatol 92 (1965): 577-80

44. Doan T "Acetaminophen hypersensitivity and other analgesics - response." Ann Allergy 72 (1994): 285

45. Kalyoncu AF "Acetaminophen hypersensitivity and other analgesics." Ann Allergy 72 (1994): 285

46. Coskey RJ "Contact dermatitis caused by diphenhydramine hydrochloride." J Am Acad Dermatol 8 (1983): 204-6

47. Horio T "Allergic and photoallergic dermatitis from diphenhydramine." Arch Dermatol 112 (1976): 1124-6

48. Leung R, Plomley R, Czarny D "Paracetamol anaphylaxis." Clin Exp Allergy 22 (1992): 831-3

49. Emmett EA "Diphenhydramine photoallergy." Arch Dermatol 110 (1974): 249-52

50. Kawada A, Hiruma M, Noguchi H, Ishibashi A "Fixed drug eruption induced by acetaminophen in a 12-year-old girl." Int J Dermatol 35 (1996): 148-9

51. Doan T, Greenberger PA "Nearly fatal episodes of hypotension, flushing, and dyspnea in a 47- year-old woman." Ann Allergy 70 (1993): 439-44

52. Van Diem L, Grilliat JP "Anaphylactic shock induced by paracetamol." Eur J Clin Pharmacol 38 (1990): 389-90

53. Halevi A, BenAmitai D, Garty BZ "Toxic epidermal necrolysis associated with acetaminophen ingestion." Ann Pharmacother 34 (2000): 32-4

54. Barranco P, LopezSerrano MC, MorenoAncillo A "Anaphylactic reaction due to diphenhydramine." Allergy 53 (1998): 814

55. Borbely AA, Youmbi-Balderer G "Effect of diphenhydramine on subjective sleep parameters and on motor activity during bedtime." Int J Clin Pharmacol Ther Toxicol 26 (1988): 392-6

56. Vuurman EFPM, Vanveggel LMA, Sanders RL, Muntjewerff ND, Ohanlon JF "Effects of semprex-d and diphenhydramine on learning in young adults with seasonal allergic rhinitis." Ann Allergy Asthma Immunol 76 (1996): 247-52

57. Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T "Tolerance to daytime sedative effects of h1 antihistamines." J Clin Psychopharmacol 22 (2002): 511-5

58. Simons FER, Fraser TG, Reggin JD, Simons KJ "Comparison of the central nervous system effects produced by six h-1-receptor antagonists." Clin Exp Allergy 26 (1996): 1092-7

59. Hall RC, Beresford TP, Stickney SK, Nasdahl CS, Coleman JH "Psychiatric reactions produced by respiratory drugs." Psychosomatics 26 (1985): 605-8,616-7

60. Helfer J, Kim OM "Psychoactive abuse potential of Robitussin-DM." Am J Psychiatry 147 (1990): 672-3

61. Bostwick JM "Dextromethorphan-induced manic symptoms in a bipolar patient on lithium." Psychosomatics 37 (1996): 571-2

62. Jones B, Lal S "Tardive dyskinesia uncovered after ingestion of Sominex, an over-the- counter drug." Can J Psychiatry 30 (1985): 370-1

63. Murray S, Brewerton T "Abuse of over-the-counter dextromethorphan by teenagers." South Med J 86 (1993): 1151-3

64. Filloux F "Toxic encephalopathy caused by topically applied diphenhydramine." J Pediatr 108 (1986): 1018-20

65. Lavenstein BL, Cantor FK "Acute dystonia: an unusual reaction to diphenhydramine." JAMA 236 (1976): 291

66. Tejera CA, Saravay SM, Goldman E, Gluck L "Diphenhydramine-induced delirium in elderly hospitalized patients with mild dementia." Psychosomatics 35 (1994): 399-402

67. Polles A, Griffith JL "Dextromethorphan-induced mania." Psychosomatics 37 (1996): 71-4

68. Ramaekers JG, Ohanlon JF "Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dosing." Eur J Clin Pharmacol 47 (1994): 261-6

69. Sexton JD, Pronchik DJ "Diphenhydramine induced psychosis with therapeutic doses." Am J Emerg Med 15 (1997): 548-9

70. Roila F, Donati D, Basurto C, Del Favero A "Diphenhydramine and acute dystonia ." Ann Intern Med 111 (1989): 92-3

71. Carruthers SG, Shoeman DW, Hignite CE, Azarnoff DL "Correlation between plasma diphenhydramine level and sedative and antihistamine effects." Clin Pharmacol Ther 23 (1978): 375-82

72. Gengo F, Gabos C, Miller JK "The pharmacodynamics of diphenhydramine-induced drowsiness and changes in mental performance." Clin Pharmacol Ther 45 (1989): 15-21

73. Brait KA, Zagerman AJ "Dyskinesias after antihistamine use ." N Engl J Med 296 (1977): 111

74. Etzel JV "Diphenhydramine-induced acute dystonia." Pharmacotherapy 14 (1994): 492-6

75. Burns M, Moskowitz H "Effects of diphenhydramine and alcohol on skills performance." Eur J Clin Pharmacol 17 (1980): 259-66

76. Santora J, Rozek S, Samie MR "Diphenhydramine-induced dystonia ." Clin Pharm 8 (1989): 471

77. Seedor JA, Lamberts D, Bergmann RB, Perry HD "Filamentary keratitis associated with diphenhydramine hydrochloride (Benadryl)." Am J Ophthalmol 101 (1986): 376-7

78. Hopfenbeck JR, Cowley DS, Radant A, Greenblatt DJ, Roybyrne PP "Effects of diphenhydramine on human eye movements." Psychopharmacology (Berl) 118 (1995): 280-6

79. Guccione JL, Zemtsov A, Cobos E, Neldner KH "Acquired purpura fulminans induced by alcohol and acetaminophen - successful treatment with heparin and vitamin-k." Arch Dermatol 129 (1993): 1267-9

80. Thomas RH, Munro DD "Fixed drug eruption due to paracetamol." Br J Dermatol 115 (1986): 357-9

81. Filipe PL, Freitas JP, Decastro JC, Silva R "Drug eruption induced by acetaminophen in infectious mononucleosis." Int J Dermatol 34 (1995): 220-1

82. Gursoy M, Haznedaroglu IC, Celik I, Sayinalp N, Ozcebe OI, Dundar SV "Agranulocytosis, plasmacytosis, and thrombocytosis followed by a leukemoid reaction due to acute acetaminophen toxicity." Ann Pharmacother 30 (1996): 762-5

83. McCredie M, Stewart JH, Day NE "Different roles for phenacetin and paracetamol in cancer of the kidney and renal pelvis." Int J Cancer 53 (1993): 245-9

84. Goldberg M "Analgesic nephropathy in 1981: which drug is responsible?" JAMA 247 (1982): 64-5

85. Vanchieri C "Australian study links certain analgesics to renal cancers." J Natl Cancer Inst 85 (1993): 262-3

86. Boyer TD, Rouff SL "Acetaminophen-induced hepatic necrosis and renal failure." JAMA 218 (1971): 440-1

87. Drenth JP, Frenken LA, Wuis EW, Van der Meer JW "Acute renal failure associated with paracetamol ingestion in an alcoholic patient." Nephron 67 (1994): 483-5

88. Duchene A, Chadenas D, Marneffe-Lebrequier H "Insuffisance renale aigue isolee apres intoxication volontaire par le paracetamol." Presse Med 20 (1991): 1684-5

89. Curry RW, Robinson JD, Sughrue MJ "Acute renal failure after acetaminophen ingestion." JAMA 247 (1982): 1012-4

90. Kleinman JG, Breitenfield RV, Roth DA "Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breast-feeding." Clin Nephrol 14 (1980): 201-5

91. Segasothy M, Suleiman AB, Puvaneswary M, Rohana A "Paracetamol: a cause for analgesic nephropathy and end-stage renal disease." Nephron 50 (1988): 50-4

92. Perneger TV, Whelton PK, Klag MJ "Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs." N Engl J Med 331 (1994): 1675-79

93. Eguia L, Materson BJ "Acetaminophen-related acute renal failure without fulminant liver failure." Pharmacotherapy 17 (1997): 363-70

94. Koulouris Z, Tierney MG, Jones G "Metabolic acidosis and coma following a severe acetaminophen overdose." Ann Pharmacother 33 (1999): 1191-4

95. Kondo K, Inoue Y, Hamada H, Yokoyama A, Kohno N, Hiwada K "Acetaminophen-induced eosinophilic pneumonia." Chest 104 (1993): 291-2

Not all side effects for acetaminophen / dextromethorphan / diphenhydramine may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

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