Drug Interaction Report
6 potential interactions and/or warnings found for the following 2 drugs:
- Ifex (ifosfamide)
- Margesic (acetaminophen / butalbital / caffeine)
Interactions between your drugs
acetaminophen butalbital
Applies to: Margesic (acetaminophen / butalbital / caffeine), Margesic (acetaminophen / butalbital / caffeine)
MONITOR: Barbiturates may increase the hepatotoxic potential of acetaminophen and decrease its therapeutic effects. The mechanism may be related to accelerated CYP450 metabolism of acetaminophen with consequent increase in hepatotoxic metabolites. This interaction is of greatest concern in cases of acetaminophen overdose.
MANAGEMENT: Monitoring for altered efficacy and safety is recommended. Prolonged use or high doses of acetaminophen should be avoided by patients on barbiturate therapy.
References
- Pirotte JH (1984) "Apparent potentiation by phenobarbital of hepatotoxicity from small doses of acetaminophen." Ann Intern Med, 101, p. 403
- Douidar SM, Ahmed AE (1987) "A novel mechanism for the enhancement of acetaminophen hepatotoxicity by phenobarbital." J Pharmacol Exp Ther, 240, p. 578-83
- Wright N, Prescott LF (1973) "Potentiation by previous drug therapy of hepatotoxicity following paracetamol overdose." Scott Med J, 18, p. 56-8
- Bock KW, Wiltfang J, Blume R, Ullrich D, Bircher J (1987) "Paracetamol as a test drug to determine glucuronide formation in man: effects of inducers and of smoking." Eur J Clin Pharmacol, 31, p. 677-83
ifosfamide butalbital
Applies to: Ifex (ifosfamide), Margesic (acetaminophen / butalbital / caffeine)
MONITOR: Centrally-acting agents such as antiemetics, sedatives, narcotics, or antihistamines may add to the neurotoxic effects of ifosfamide. Administration of ifosfamide can cause CNS toxicity, which necessitates careful monitoring of the patient. Neurologic manifestations include somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma. There have also been reports of peripheral neuropathy. Ifosfamide neurotoxicity may occur within a few hours to a few days after initial administration and typically resolves within 48 to 72 hours of ifosfamide discontinuation. However, symptoms may persist for longer periods of time, and recovery has occasionally been incomplete. Fatal outcomes have been reported. There have also been reports of recurrence of CNS toxicity after several uneventful treatment courses.
MANAGEMENT: Due to the potential for additive effects, centrally-acting agents should be used with caution in combination with ifosfamide. Patients should be advised to avoid driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them. If ifosfamide-induced encephalopathy occurs, both ifosfamide and non-essential concomitant CNS agents should be discontinued. Supportive therapy should be initiated and maintained until complete resolution of neurotoxicity.
References
- Simonian NA, Gilliam FG, Chiappa KH (1993) "Ifosfamide causes a diazepam-sensitive encephalopathy." Neurology, 43, p. 2700-2
- (2001) "Product Information. Ifex (ifosfamide)." Bristol-Myers Squibb
Drug and food interactions
acetaminophen food
Applies to: Margesic (acetaminophen / butalbital / caffeine)
GENERALLY AVOID: Chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, which has included rare cases of fatal hepatitis and frank hepatic failure requiring liver transplantation. The proposed mechanism is induction of hepatic microsomal enzymes during chronic alcohol use, which may result in accelerated metabolism of acetaminophen and increased production of potentially hepatotoxic metabolites.
MANAGEMENT: In general, chronic alcoholics should avoid regular or excessive use of acetaminophen. Alternative analgesic/antipyretic therapy may be appropriate in patients who consume three or more alcoholic drinks per day. However, if acetaminophen is used, these patients should be cautioned not to exceed the recommended dosage (maximum 4 g/day in adults and children 12 years of age or older).
References
- Kaysen GA, Pond SM, Roper MH, Menke DJ, Marrama MA (1985) "Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen." Arch Intern Med, 145, p. 2019-23
- O'Dell JR, Zetterman RK, Burnett DA (1986) "Centrilobular hepatic fibrosis following acetaminophen-induced hepatic necrosis in an alcoholic." JAMA, 255, p. 2636-7
- Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB (1986) "Acetaminophen hepatotoxicity in alcoholics." Ann Intern Med, 104, p. 399-404
- Thummel KE, Slattery JT, Nelson SD (1988) "Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen." J Pharmacol Exp Ther, 245, p. 129-36
- McClain CJ, Kromhout JP, Peterson FJ, Holtzman JL (1980) "Potentiation of acetaminophen hepatotoxicity by alcohol." JAMA, 244, p. 251-3
- Kartsonis A, Reddy KR, Schiff ER (1986) "Alcohol, acetaminophen, and hepatic necrosis." Ann Intern Med, 105, p. 138-9
- Prescott LF, Critchley JA (1983) "Drug interactions affecting analgesic toxicity." Am J Med, 75, p. 113-6
- (2002) "Product Information. Tylenol (acetaminophen)." McNeil Pharmaceutical
- Whitcomb DC, Block GD (1994) "Association of acetaminopphen hepatotoxicity with fasting and ethanol use." JAMA, 272, p. 1845-50
- Bonkovsky HL (1995) "Acetaminophen hepatotoxicity, fasting, and ethanol." JAMA, 274, p. 301
- Nelson EB, Temple AR (1995) "Acetaminophen hepatotoxicity, fasting, and ethanol." JAMA, 274, p. 301
- Zimmerman HJ, Maddrey WC (1995) "Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure." Hepatology, 22, p. 767-73
butalbital food
Applies to: Margesic (acetaminophen / butalbital / caffeine)
GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.
MANAGEMENT: The combination of ethanol and barbiturates should be avoided.
References
- Gupta RC, Kofoed J (1966) "Toxological statistics for barbiturates, other sedatives, and tranquilizers in Ontario: a 10-year survey." Can Med Assoc J, 94, p. 863-5
- Misra PS, Lefevre A, Ishii H, Rubin E, Lieber CS (1971) "Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats." Am J Med, 51, p. 346-51
- Saario I, Linnoila M (1976) "Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving." Acta Pharmacol Toxicol (Copenh), 38, p. 382-92
- Stead AH, Moffat AC (1983) "Quantification of the interaction between barbiturates and alcohol and interpretation of fatal blood concentrations." Hum Toxicol, 2, p. 5-14
- Seixas FA (1979) "Drug/alcohol interactions: avert potential dangers." Geriatrics, 34, p. 89-102
ifosfamide food
Applies to: Ifex (ifosfamide)
GENERALLY AVOID: Grapefruit and/or grapefruit juice may reduce the efficacy of ifosfamide, whose anticancer effect is dependent on its activation to the 4-hydroxyifosfamide metabolite via CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4 metabolism by certain compounds present in grapefruit. There are no data available about the effects of grapefruit on ifosfamide. However, in a small study, 8 patients with incurable malignancies received ifosfamide 3 g/m2 by infusion with the potent CYP450 3A4 inhibitor ketoconazole 200 mg orally twice daily for 4 days starting 1 day before the ifosfamide infusion. Ketoconazole decreased the clearance of ifosfamide by 11%, decreased systemic exposure (AUC) of the active metabolite 4-hydroxyifosfamide by 30%, and increased the AUC of the inactive but potentially neurotoxic metabolite 2-dechloroethylifosfamide by 23%, as compared to control. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.
GENERALLY AVOID: Alcohol may potentiate the neurotoxic effects of ifosfamide. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills. In addition, ifosfamide therapy may cause gastrointestinal disorders and alcohol consumption may increase nausea and vomiting.
MANAGEMENT: Given the potential for reduced efficacy of ifosfamide and increased risk of neurotoxicity and nephrotoxicity it may be advisable for patients to avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with ifosfamide. In addition, patients receiving ifosfamide should be warned of the increased risk of neurotoxicity, nausea and vomiting when used in combination with alcohol. Patients should avoid or limit the consumption of alcohol during treatment with ifosfamide.
References
- (2019) "Product Information. Ifosfamide (ifosfamide)." Hikma USA (formerly West-Ward Pharmaceutical Corporation)
- Kerbusch T, jansen rlh, mathot raa, huitema adr, Jansen RNM, Rijswijk REN, Beijen JH (2001) "Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin" Clin Pharmacol and Therapeutic, 70, p. 132-141
- (2018) "Product Information. Ifex (ifosfamide)." Baxter Pharmaceutical Products, Inc
- (2018) "Product Information. Holoxan (iFOSFamide)." Baxter Healthcare Pty Ltd
- (2022) "Product Information. Ifosfamide (ifosfamide)." Baxter Healthcare Ltd
- (2018) "Product Information. Ifex (ifosfamide)." Baxter Corporation
caffeine food
Applies to: Margesic (acetaminophen / butalbital / caffeine)
The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.
References
- (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
- Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WR (1996) "Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics." Pharmacotherapy, 16, p. 1046-52
Therapeutic duplication warnings
No duplication warnings were found for your selected drugs.
Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.
Drug Interaction Classification
Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. | |
Moderately clinically significant. Usually avoid combinations; use it only under special circumstances. | |
Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan. | |
No interaction information available. |
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