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Drug Interactions between alprazolam and Leader Heartburn Relief

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

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Interactions between your drugs

Moderate

cimetidine ALPRAZolam

Applies to: Leader Heartburn Relief (cimetidine) and alprazolam

MONITOR: Administration of cimetidine with benzodiazepines may increase systemic exposure to benzodiazepines. The mechanism may be related to inhibition of CYP450 3A4 hepatic metabolism by cimetidine, a moderate inhibitor of this isoenzyme. This interaction has been reported for alprazolam, diazepam, triazolam, midazolam and chlordiazepoxide, but may also occur with other benzodiazepines. In one pharmacokinetic study, two groups of healthy subjects (n=8) were administered cimetidine (1 g daily) for 2 weeks, with the addition of either alprazolam (0.5 mg three times a day) or triazolam (0.5 mg nightly) during the second week of cimetidine administration. Concomitant administration with cimetidine led to statistically significant alterations in some of the pharmacokinetic parameters of the benzodiazepines. Alprazolam systemic exposure, (AUC [0 to infinity]) and Cmax increased by 73% and 82%, respectively, and clearance (L/h) decreased by 42%. Triazolam systemic exposure (AUC [0 to infinity]) and Cmax increased by 120% and 51%, respectively, half-life increased by 68%, and clearance (L/h) decreased by 55%. This interaction appears to be minimal with lorazepam, oxazepam, and temazepam. Ranitidine may increase or decrease benzodiazepine plasma levels; however, the effects are not expected to be clinically significant. This interaction has not been noted with other H2 antagonists.

MANAGEMENT: The US manufacturers of alprazolam, estazolam and triazolam recommend consideration of a dose reduction when these medicines are co-administered with cimetidine. The authors of the abovementioned pharmacokinetic study suggest either a reduction to the alprazolam dose by one-third or an increase to the dosage interval to twice daily when used concomitantly with cimetidine. Use of H2 antagonists and benzodiazepines that are not reported to interact may also be considered. Patients should be advised to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Gough PA, Curry SH, Araujo OE, Robinson JD, Dallman JJ "Influence of cimetidine on oral diazepam elimination with measurement of subsequent cognitive change." Br J Clin Pharmacol 14 (1982): 739-42
  2. Parker WA, MacLachlan RA "Prolonged hypnotic response to triazolam-cimetidine combination in an elderly patient." Drug Intell Clin Pharm 18 (1984): 980-1
  3. Klotz U, Arvela P, Rosenkranz B "Effect of single doses of cimetidine and ranitidine on the steady-state plasma levels of midazolam." Clin Pharmacol Ther 38 (1985): 652-5
  4. Desmond PV, Patwardhan RV, Schenker S, Speeg KV "Cimetidine impairs elimination of chlordiazepoxide ( librium) in man." Ann Intern Med 93 (1980): 266-8
  5. Klotz U, Reimann I "Delayed clearance of diazepam due to cimetidine." N Engl J Med 302 (1980): 1012-4
  6. Klotz U, Reimann I "Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam." Eur J Clin Pharmacol 18 (1980): 517-20
  7. Patwardhan RV, Johnson RF, Sinclair AP, Schenker S, Speeg KV "Lack of tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide (librium) elimination." Gastroenterology 81 (1981): 547-51
  8. Greenblatt DJ, Abernethy DR, Morse DS, Harmatz JS, Shader RI "Clinical importance of the interaction of diazepam and cimetidine." N Engl J Med 310 (1984): 1639-43
  9. Ruffalo RL, Thompson JF, Segal J "Cimetidine-benzodiazepine drug interaction." Am J Hosp Pharm 38 (1981): 1365-6
  10. Klotz U, Reimann IW, Ohnhaus EE "Effect of ranitidine on the steady state pharmacokinetics of diazepam." Eur J Clin Pharmacol 24 (1983): 357-60
  11. Andersson T, Andren K, Cederberg C, Edvardsson G, Heggelund A, Lundborg P "Effect of omeprazole and cimetidine on plasma diazepam levels." Eur J Clin Pharmacol 39 (1990): 51-4
  12. Sanders LD, Whitehead C, Gildersleve CD, Rosen M, Robinson JO "Interaction of H2-receptor antagonists and benzodiazepine sedation. A double-blind placebo-controlled investigation of the effects of cimetidine and ranitidine on recovery after intravenous midazolam." Anaesthesia 48 (1993): 286-92
  13. Britton ML, Waller ES "Central nervous system toxicity associated with concurrent use of triazolam and cimetidine." Drug Intell Clin Pharm 19 (1985): 666-8
  14. Pourbaix S, Desager JP, Hulhoven R, Smith RB, Harvengt C "Pharmacokinetic consequences of long term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects." Int J Clin Pharmacol Ther Toxicol 23 (1985): 447-51
  15. Abernethy DR, Greenblatt DJ, Divoll M, Moschitto LJ, Harmatz JS, Shader RI "Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam." Psychopharmacology (Berl) 80 (1983): 275-8
  16. Greenblatt DJ, Locniskar A, Scavone JM, Blyden GT, Ochs HR, Harmatz JS, Shader RI "Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam." Anesth Analg 65 (1986): 176-80
  17. Wilson CM, Robinson FP, Thompson EM, Dundee JW, Elliott P "Effect of pretreatment with ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone. A clinical study." Br J Anaesth 58 (1986): 483-6
  18. Salonen M, Aantaa E, Aaltonen L, Kanto J "Importance of the interaction of midazolam and cimetidine." Acta Pharmacol Toxicol (Copenh) 58 (1986): 91-5
  19. Wrighton SA, Ring BJ "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res 11 (1994): 921-4
View all 19 references

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Drug and food interactions

Moderate

ALPRAZolam food

Applies to: alprazolam

GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

References

  1. "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn PROD (2002):
  2. "Product Information. Valium (diazepam)." Roche Laboratories PROD (2002):
  3. "Product Information. Halcion (triazolam)." Pharmacia and Upjohn PROD (2001):
  4. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
  5. Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther 58 (1995): 20-8
  6. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther 58 (1995): 127-31
  7. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther 68 (2000): 468-77
View all 7 references

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Minor

cimetidine food

Applies to: Leader Heartburn Relief (cimetidine)

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

References

  1. Feely J, Wood AJ "Effects of cimetidine on the elimination and actions of ethanol." JAMA 247 (1982): 2819-21
  2. Hansten PD "Effects of H2-receptor antagonists on blood alcohol levels." JAMA 267 (1992): 2469

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Minor

cimetidine food

Applies to: Leader Heartburn Relief (cimetidine)

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

References

  1. "Product Information. Tagamet (cimetidine)." SmithKline Beecham PROD (2001):
  2. Broughton LJ, Rodgers HJ "Decreased systenuc clearance of caffeine due to cimetidine." Br J Clin Pharmacol 12 (1981): 155-9

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Minor

cimetidine food

Applies to: Leader Heartburn Relief (cimetidine)

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.

References

  1. Bendayan R, Sullivan JT, Shaw C, Frecker RC, Sellers EM "Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans." Eur J Clin Pharmacol 38 (1990): 165-9

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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.

Further information

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