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Drug Interactions between amitriptyline / perphenazine and phenytoin

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

phenytoin amitriptyline

Applies to: phenytoin and amitriptyline / perphenazine

MONITOR: Tricyclic antidepressants may increase serum phenytoin levels. In vitro studies suggest the mechanism may involve inhibition of CYP450 2C19-catalyzed phenytoin p-hydroxylation by tricyclic antidepressants, especially imipramine and amitriptyline. Phenytoin may induce the hepatic metabolism of desipramine resulting in decreased plasma concentrations. In addition, tricyclic antidepressants may lower the seizure threshold.

MANAGEMENT: Clinical monitoring of patient response, tolerance, and serum phenytoin concentrations is recommended. Patients should be advised to notify their doctor if they experience loss of seizure control or symptoms of phenytoin toxicity (drowsiness, visual disturbances, change in mental status, nausea, or ataxia). Phenytoin dosage may need to be adjusted.

References (9)
  1. Fogel BS, Haltzman S (1987) "Desipramine and phenytoin: a potential drug interaction of therapeutic relevance." J Clin Psychiatry, 48, p. 387-8
  2. Houghton GW, Richens A (1975) "Inhibition of phenytoin metabolism by other drugs used in epilepsy." Int J Clin Pharmacol, 12, p. 210-6
  3. Perucca E, Richens A (1977) "Interaction between phenytoin and imipramine." Br J Clin Pharmacol, 4, p. 485-6
  4. Shin JG, Park JY, Kim MJ, et al. (2002) "Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: mechanism of drug interaction between TCAs and phenytoin." Drug Metab Dispos, 30, p. 1102-7
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  6. Cerner Multum, Inc. "Australian Product Information."
  7. Agencia Española de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de información online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  8. Cerner Multum, Inc. (2015) "Canadian Product Information."
  9. Cerner Multum, Inc (2015) "ANVISA Bulário Eletrônico."
Moderate

phenytoin perphenazine

Applies to: phenytoin and amitriptyline / perphenazine

MONITOR: Concurrent use of phenothiazines and phenytoin may increase the effect of phenytoin and decrease the effect of the phenothiazine. The mechanism is unknown and clinical data have been inconsistent.

MANAGEMENT: Close monitoring for clinical and laboratory evidence of phenytoin toxicity is indicated. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.

References (5)
  1. Houghton GW, Richens A (1975) "Inhibition of phenytoin metabolism by other drugs used in epilepsy." Int J Clin Pharmacol, 12, p. 210-6
  2. Vincent FM (1980) "Phenothiazine-induced phenytoin intoxication." Ann Intern Med, 93, p. 56-7
  3. Haidukewych D, Rodin EA (1985) "Effect of phenothiazines on serum antiepileptic drug concentrations in psychiatric patients with seizure disorder." Ther Drug Monit, 7, p. 401-4
  4. Linnoila M, Viukari M, Vaisanen K, Auvinen J (1980) "Effect of anticonvulsants on plasma haloperidol and thioridazine levels." Am J Psychiatry, 137, p. 819-21
  5. Sands CD, Robinson JD, Salem RB, Stewart RB, Muniz C (1987) "Effect of thioridazine on phenytoin serum concentration: a retrospective study." Drug Intell Clin Pharm, 21, p. 267-72
Moderate

amitriptyline perphenazine

Applies to: amitriptyline / perphenazine and amitriptyline / perphenazine

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

References (16)
  1. Loga S, Curry S, Lader M (1981) "Interaction of chlorpromazine and nortriptyline in patients with schizophrenia." Clin Pharmacokinet, 6, p. 454-62
  2. Stadnyk AN, Glezos JD (1983) "Drug-induced heat stroke." Can Med Assoc J, 128, p. 957-9
  3. Bock JL, Nelson JC, Gray S, Jatlow PI (1983) "Desipramine hydroxylation: variability and effect of antipsychotic drugs." Clin Pharmacol Ther, 33, p. 322-8
  4. Gram LF, Overo KF (1972) "Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man." Br Med J, 1, p. 463-5
  5. El-Yousef MK, Manier DH (1974) "Tricyclic antidepressants and phenothiazines." JAMA, 229, p. 1419
  6. Hirschowitz J, Bennett JA, Zemlan FP, Garver DL (1983) "Thioridazine effect on desipramine plasma levels." J Clin Psychopharmacol, 3, p. 376-9
  7. Vandel S, Sandoz M, Vandel B, Bonin B, Allers G, Volmat R (1986) "Biotransformation of amitriptyline in man: interaction with phenothiazines." Neuropsychobiology, 15, p. 15-9
  8. Zelman S, Guillan R (1970) "Heat stroke in phenothiazine-treated patients: a report of three fatalities." Am J Psychiatry, 126, p. 1787-90
  9. Mann SC, Boger WP (1978) "Psychotropic drugs, summer heat and humidity, and hyperplexia: a danger restated." Am J Psychiatry, 135, p. 1097-100
  10. Warnes H, Lehmann HE, Ban TA (1967) "Adynamic ileus during psychoactive medication: a report of three fatal and five severe cases." Can Med Assoc J, 96, p. 1112-3
  11. Siris SG, Cooper TB, Rifkin AE, Brenner R, Lieberman JA (1982) "Plasma imipramine concentrations in patients receiving concomitant fluphenazine decanoate." Am J Psychiatry, 139, p. 104-6
  12. Johnson AL, Hollister LE, Berger PA (1981) "The anticholinergic intoxication syndrome: diagnosis and treatment." J Clin Psychiatry, 42, p. 313-7
  13. Lee BS (1986) "Possibility of hyperpyrexia with antipsychotic and anticholinergic drugs." J Clin Psychiatry, 47, p. 571
  14. Moreau A, Jones BD, Banno V (1986) "Chronic central anticholinergic toxicity in manic depressive illness mimicking dementia." Can J Psychiatry, 31, p. 339-41
  15. Hvizdos AJ, Bennett JA, Wells BG, Rappaport KB, Mendel SA (1983) "Anticholinergic psychosis in a patient receiving usual doses of haloperidol." Clin Pharm, 2, p. 174-8
  16. Maynard GL, Soni P (1996) "Thioridazine interferences with imipramine metabolism and measurement." Ther Drug Monit, 18, p. 729-31

Drug and food interactions

Moderate

phenytoin food

Applies to: phenytoin

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

References (16)
  1. Sandor P, Sellers EM, Dumbrell M, Khouw V (1981) "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther, 30, p. 390-7
  2. Holtz L, Milton J, Sturek JK (1987) "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr, 11, p. 183-6
  3. Sellers EM, Holloway MR (1978) "Drug kinetics and alcohol ingestion." Clin Pharmacokinet, 3, p. 440-52
  4. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  5. Doak KK, Haas CE, Dunnigan KJ, et al. (1998) "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy, 18, p. 637-45
  6. Rodman DP, Stevenson TL, Ray TR (1995) "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy, 15, p. 801-5
  7. Au Yeung SC, Ensom MH (2000) "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother, 34, p. 896-905
  8. Ozuna J, Friel P (1984) "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs, 16, p. 289-91
  9. Faraji B, Yu PP (1998) "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs, 30, p. 55-9
  10. Marvel ME, Bertino JS (1991) "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr, 15, p. 316-8
  11. Fleisher D, Sheth N, Kou JH (1990) "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr, 14, p. 513-6
  12. Haley CJ, Nelson J (1989) "Phenytoin-enteral feeding interaction." DICP, 23, p. 796-8
  13. Guidry JR, Eastwood TF, Curry SC (1989) "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med, 150, p. 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM (1987) "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia, 28, p. 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  16. Cerner Multum, Inc. "Australian Product Information."
Moderate

amitriptyline food

Applies to: amitriptyline / perphenazine

GENERALLY AVOID: Concomitant use of ethanol and a tricyclic antidepressant (TCA) may result altered TCA plasma levels and efficacy, and additive impairment of motor skills, especially driving skills. Acute ethanol ingestion may inhibit TCA metabolism, while chronic ingestion of large amounts of ethanol may induce hepatic TCA metabolism.

MANAGEMENT: Patients should be advised to avoid alcohol during TCA therapy. Alcoholics who have undergone detoxification should be monitored for decreased TCA efficacy. Dosage adjustments may be required.

References (7)
  1. Dorian P, Sellers EM, Reed KL, et al. (1983) "Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction." Eur J Clin Pharmacol, 25, p. 325-31
  2. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  3. Sandoz M, Vandel S, Vandel B, Bonin B, Allers G, Volmat R (1983) "Biotransformation of amitriptyline in alcoholic depressive patients." Eur J Clin Pharmacol, 24, p. 615-21
  4. Ciraulo DA, Barnhill JG, Jaffe JH (1988) "Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers." Clin Pharmacol Ther, 43, p. 509-18
  5. Seppala T, Linnoila M, Elonen E, Mattila MJ, Makl M (1975) "Effect of tricyclic antidepressants and alcohol on psychomotor skills related to driving." Clin Pharmacol Ther, 17, p. 515-22
  6. Ciraulo DA, Barnhill JG, Jaffe JH, Ciraulo AM, Tarmey MF (1990) "Intravenous pharmacokinetics of 2-hydroxyimipramine in alcoholics and normal controls." J Stud Alcohol, 51, p. 366-72
  7. Ciraulo DA, Alderson LM, Chapron DJ, Jaffe JH, Subbarao B, Kramer PA (1982) "Imipramine disposition in alcoholics." J Clin Psychopharmacol, 2, p. 2-7
Moderate

perphenazine food

Applies to: amitriptyline / perphenazine

GENERALLY AVOID: Concurrent use of ethanol and phenothiazines may result in additive CNS depression and psychomotor impairment. Also, ethanol may precipitate dystonic reactions in patients who are taking phenothiazines. The two drugs probably act on different sites in the brain, although the exact mechanism of the interaction is not known.

MANAGEMENT: Patients should be advised to avoid alcohol during phenothiazine therapy.

References (2)
  1. Lutz EG (1976) "Neuroleptic-induced akathisia and dystonia triggered by alcohol." JAMA, 236, p. 2422-3
  2. Freed E (1981) "Alcohol-triggered-neuroleptic-induced tremor, rigidity and dystonia." Med J Aust, 2, p. 44-5
Moderate

amitriptyline food

Applies to: amitriptyline / perphenazine

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

References (4)
  1. (2024) "Product Information. Cytisine (cytisinicline)." Consilient Health Ltd
  2. jeong sh, Newcombe D, sheridan j, Tingle M (2015) "Pharmacokinetics of cytisine, an a4 b2 nicotinic receptor partial agonist, in healthy smokers following a single dose." Drug Test Anal, 7, p. 475-82
  3. Vaughan DP, Beckett AH, Robbie DS (1976) "The influence of smoking on the intersubject variation in pentazocine elimination." Br J Clin Pharmacol, 3, p. 279-83
  4. Zevin S, Benowitz NL (1999) "Drug interactions with tobacco smoking: an update" Clin Pharmacokinet, 36, p. 425-38

Therapeutic duplication warnings

No 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.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor 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.
Unknown No interaction information available.

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