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Drug Interactions between fluvoxamine and timolol

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

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Interactions between your drugs

Moderate

timolol fluvoxaMINE

Applies to: timolol and fluvoxamine

MONITOR: Limited clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may potentiate the pharmacologic effects of some beta-blockers. There have been case reports of patients stabilized on beta-blocker therapy who developed bradycardia, hypotension, and complete heart block following the addition of a SSRI, subsequently requiring discontinuation of one or both agents and/or institution of a permanent pacemaker. The interaction is also corroborated by data from in vitro and clinical studies involving paroxetine and metoprolol conducted by one group of investigators. The proposed mechanism is SSRI inhibition (competitive and/or noncompetitive) of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of beta-blockers such as carvedilol, labetalol, metoprolol, nebivolol, propranolol, and timolol. Paroxetine and norfluoxetine (the active metabolite of fluoxetine), in particular, are potent inhibitors of CYP450 2D6 and may be more likely than other SSRIs to cause the interaction. On the other hand, fluvoxamine is a potent inhibitor of CYP450 1A2 and may significantly interact with propranolol, which is a substrate of both CYP450 2D6 and 1A2.

MANAGEMENT: During concomitant therapy with SSRIs, a lower initial dosage and more cautious titration of the beta-blocker may be appropriate. Cardiac function should be closely monitored and the beta-blocker dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of SSRI in patients who are stabilized on their beta-blocker regimen. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine. To avoid the interaction, use of beta-blockers that are primarily eliminated by the kidney such as atenolol, acebutolol, betaxolol, carteolol, and nadolol may be considered.

References

  1. Walley T, Pirmohamed M, Proudlove C, Maxwell D (1993) "Interaction of metoprolol and fluoxetine." Lancet, 341, p. 967-8
  2. Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM (1993) "Inhibition by fluoxetine of cytochrome P450 2D6 activity." Clin Pharmacol Ther, 53, p. 401-9
  3. Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S (1993) "Fluvoxamine is a potent inhibitor of cytochrome P4501A2." Biochem Pharmacol, 45, p. 1211-4
  4. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  5. Drake WM, Gordon GD (1994) "Heart block in a patient on propranolol and fluoxetine." Lancet, 343, p. 425-6
  6. Perucca E, Gatti G, Spina E (1994) "Clinical pharmacokinetics of fluvoxamine." Clin Pharmacokinet, 27, p. 175-90
  7. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1992) "The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes." Br J Clin Pharmacol, 34, p. 262-5
  8. (2001) "Product Information. Luvox (fluvoxamine)." Solvay Pharmaceuticals Inc
  9. Riesenman C (1995) "Antidepressant drug interactions and the cytochrome p450 system: a critical appraisal." Pharmacotherapy, 15, s84-99
  10. Nemeroff CB, Devane CL, Pollock BG (1996) "Newer antidepressants and the cytochrome p450 system." Am J Psychiatry, 153, p. 311-20
  11. Ereshefsky L (1996) "Treating depression: potential drug-drug interactions: commentary." J Clin Psychopharmacol, 16 (suppl, s50-3
  12. Richelson E (1998) "Pharmacokinetic interactions of antidepressants." J Clin Psychiatry, 59, p. 22-6
  13. Kashuba ADM, Nafziger AN, Kearns GL, Leeder JS, Gotschall R, Rocci ML, Kulawy RW, Beck DJ, Bertino JS (1998) "Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping." Clin Pharmacol Ther, 64, p. 257-68
  14. Hemeryck A, Lefebvre RA, DeVriendt C, Belpaire FM (2000) "Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers." Clin Pharmacol Ther, 67, p. 283-91
  15. Amchin J, Ereshefsky L, Zarycranski W, Taylor K, Albano D, Klockowski PM (2001) "Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe." J Clin Pharmacol, 41, p. 443-51
  16. Hemeryck A, DeVriendt CA, Belpaire FM (2001) "Metoprolol-paroxetine interaction in human liver microsomes: Stereoselective aspects and prediction of the in vivo interaction." Drug Metab Disposition, 29, p. 656-63
View all 16 references

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Drug and food interactions

Moderate

fluvoxaMINE food

Applies to: fluvoxamine

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
View all 4 references

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Moderate

timolol food

Applies to: timolol

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

References

  1. Sternbach H (1991) "Fluoxetine-associated potentiation of calcium-channel blockers." J Clin Psychopharmacol, 11, p. 390-1
  2. Shook TL, Kirshenbaum JM, Hundley RF, Shorey JM, Lamas GA (1984) "Ethanol intoxication complicating intravenous nitroglycerin therapy." Ann Intern Med, 101, p. 498-9
  3. Feder R (1991) "Bradycardia and syncope induced by fluoxetine." J Clin Psychiatry, 52, p. 139
  4. Ellison JM, Milofsky JE, Ely E (1990) "Fluoxetine-induced bradycardia and syncope in two patients." J Clin Psychiatry, 51, p. 385-6
  5. Rodriguez de la Torre B, Dreher J, Malevany I, et al. (2001) "Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients." Ther Drug Monit, 23, p. 435-40
  6. Cerner Multum, Inc. "Australian Product Information."
  7. Pacher P, Kecskemeti V (2004) "Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?" Curr Pharm Des, 10, p. 2463-75
  8. Andrews C, Pinner G (1998) "Postural hypotension induced by paroxetine." BMJ, 316, p. 595
View all 8 references

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Moderate

timolol food

Applies to: timolol

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

References

  1. Kirch W, Schafer-Korting M, Axthelm T, Kohler H, Mutschler E (1981) "Interaction of atenolol with furosemide and calcium and aluminum salts." Clin Pharmacol Ther, 30, p. 429-35

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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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