Drug Interactions

Fluoxetine (Prozac®) Interactions

Taking Fluoxetine with:

Fluoxetine Drug Interactions

Fluoxetine is an inhibitor of CYP2D6 enzymes.

  • MAO Inhibitors: combination may lead to serious, possibly fatal, serotonin syndrome. Discontinue MAO inhibitor at least 14 days before starting fluoxetine; discontinue fluoxetine at least 5 weeks before starting MAO inhibitor.
  • NSAIDs: increased risk of GI bleeding.
  • Pimozide: a case of life-threatening sinus bradycardia has been reported.
  • Serotonergic agents, tryptophan: potential for serotonin syndrome, caution is advised when fluoxetine is administered with other drugs that may affect serotonergic neurotransmission.
  • Thioridazine: concurrent use is contraindicated because of risk of prolongation of QTc interval and development of serious ventricular arrhythmias (eg, torsades de pointes) and sudden death.
  • Tricyclic antidepressants: increased plasma concentration of tricyclic antidepressant.
  • Warfarin: the anticoagulant effects of warfarin may be increased, possibly because of displaced protein binding.

Can you take Fluoxetine and Adderall®?

Adderall (amphetamine and dextroamphetamine) is a combination of amphetamine salts. Fluoxetine may decrease the metabolism of amphetamines, resulting in increased amphetamine levels and sympathetic hyperstimulation2. The concomitant use of fluoxetine and Adderall® requires caution.

Can you take Fluoxetine and Phentermine?

Fluoxetine potentiates both the anorectic and dopamine neurotoxic effects of phentermine, possibly by increasing phentermine brain levels3. Concomitant use of paroxetine and phentermine is acceptable under the supervision of the physician.

Can you take Fluoxetine and Amitriptyline?

There are several reports of serotonin syndrome following concurrent use of the SSRIs and tricyclic antidepressants. Concomitant use of fluoxetine and amitriptyline may result in increased plasma levels of amitriptyline accompanied by toxicity if these drugs are used without reducing the dosage of amitriptyline. The pharmacokinetics of fluoxetine is not affected by amitriptyline5.

If used carefully at proper doses fluoxetine plus amitriptyline combination is safe and effective4.

Can you take Fluoxetine and Mirtazapine (Remeron®)?

Mirtazapine is increasingly used as an augmentation antidepressant with SSRIs10. In fact, low-dose mirtazapine may be very beneficial and well-tolerated in patients with SSRI-induced sexual dysfunction9.

Restless legs syndrome has been reported in 3 patients taking fluoxetine and mirtazapine11.

So fluoxetine and mirtazapine can be taken at the same time, but some caution is also needed.

Can you take Fluoxetine and Trazodone?

The combination of fluoxetine plus trazodone has been successfully used for certain conditions13, 15. Fluoxetine is activating in some patients, and trazodone is frequently used for treating antidepressant-induced sleep disturbances14.

However, fluoxetine modestly increases trazodone levels12, and some patients may develop increased side effects, particularly excessive sedation13, irritability, anger, anxiety23.

Concurrent use of fluoxetine and trazodone at proper doses is usually safe16, but monitoring of possible increased side effects is recommended.

Can you take Fluoxetine and Buspirone (Buspar®)?

Possible risk of serotonin syndrome, seizures 20. Concomitant use of fluoxetine with buspirone is a common practice, but requires some caution.

The combination of buspirone and fluoxetine can be effective for treatment-resistant depression21 and obsessive-compulsive disorder22.

Can you take Fluoxetine and Alprazolam (Xanax®)?

There is evidence that fluoxetine may reduce the clearance of alprazolam and increase its plasma levels and as a result increased psychomotor impairment 6. Caution would be prudent if alprazolam is taken simultaneously with fluoxetine.

Can you take Fluoxetine and Diazepam (Valium®)?

Fluoxetine can decrease the metabolism of diazepam, though this effect is not of clinical significance 7. Some caution would be prudent if diazepam is taken simultaneously with fluoxetine.

Can you take Fluoxetine and Lorazepam (Ativan®)?

There are no reported drug interactions between fluoxetine and lorazepam, concurrent use is considered safe 1.

Can you take Fluoxetine and Benadryl®?

There are no drug interactions between fluoxetine and diphenhydramine (an active ingredient in Benadryl®)1.

Can you take Fluoxetine and Ibuprofen (Advil®)?

Generally, concomitant use of fluoxetine and ibuprofen is safe. Theoretically NSAIDs potentiate the risk of gastrointestinal or other bleeding1.

Can you take Fluoxetine and Tramadol?

Both tramadol and fluoxetine are serotonergic drugs, so concomitant use may cause serotonin syndrom1, 8. These medications can be used at the same time under strict medical supervision.

Can you take Fluoxetine and Melatonin?

There are no drug interaction between fluoxetine and melatonin17, 18. Both medications can be take at the same time.

Can you take Fluoxetine and Topiramate (Topamax®)?

There are no significant drug interaction between fluoxetine and topiramate 1. Topiramate augmentation may potentiate fluoxetine efficacy in treatment of resistant depression 19.

When you should NOT take Fluoxetine?

  • Hypersensitivity to fluoxetine. During premarketing testing of more than 5600 patients given fluoxetine, approximately 4% developed a rash or urticaria.
  • MAOI. Not to be used with an MAOI or within 14 days of discontinuing MAOI therapy.

Pregnancy & Lactation

Pregnancy Category C.
Neonates exposed to fluoxetine and other SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization and supportive care. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers
Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.


  • 1. U.S. FDA Fluoxetine Prescribing Information
  • 2. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction. Psychopharmacology (Berl). 1999 Feb;141(4):421-7. PubMed
  • 3. Callahan BT, Yuan J, Ricaurte GA. Fluoxetine increases the anorectic and long-term dopamine-depleting effects of phentermine. Synapse. 2000 Dec 15;38(4):471-6. PubMed
  • 4. Krymchantowski AV, Silva MT, Barbosa JS, Alves LA. Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache. 2002 Jun;42(6):510-4. PubMed
  • 5. El-Yazigi A, Chaleby K, Gad A, Raines DA. Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone. J Clin Pharmacol. 1995 Jan;35(1):17-21. PubMed
  • 6. Hall J, Naranjo CA, Sproule BA, Herrmann N. Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol. 2003 Aug;23(4):349-57. PubMed
  • 7. Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther. 1988 Apr;43(4):412-9. PubMed
  • 8. Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med. 1999 Sep;92(9):474-5. PubMed
  • 9. Atmaca M, Korkmaz S, Topuz M, Mermi O. Mirtazapine Augmentation for Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction. Psychiatry Investig. 2011 Mar;8(1):55-7. PubMed
  • 10. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010 Mar;167(3):281-8. PubMed
  • 11. Prospero-Garcia KA, Torres-Ruiz A, Ramirez-Bermudez J, et al. Fluoxetine-mirtazapine interaction may induce restless legs syndrome: report of 3 cases from a clinical trial. J Clin Psychiatry. 2006 Nov;67(11):1820. PubMed
  • 12. Maes M, Westenberg H, Vandoolaeghe E, Demedts P, Wauters A, Neels H, Meltzer HY. Effects of trazodone and fluoxetine in the treatment of major depression: therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine. J Clin Psychopharmacol. 1997 Oct;17(5):358-64. PubMed
  • 13. Nierenberg AA, Cole JO, Glass L. Possible trazodone potentiation of fluoxetine: a case series. J Clin Psychiatry. 1992 Mar;53(3):83-5. PubMed
  • 14. Nierenberg AA1, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry. 1994 Jul;151(7):1069-72. PubMed
  • 15. Swerdlow NR, Andia AM. Trazodone-fluoxetine combination for treatment of obsessive-compulsive disorder. Am J Psychiatry. 1989 Dec;146(12):1637.
  • 16. Prapotnik M, Waschgler R, König P, Moll W, Conca A. Therapeutic drug monitoring of trazodone: are there pharmacokinetic interactions involving citalopram and fluoxetine? Int J Clin Pharmacol Ther. 2004 Feb;42(2):120-4. PubMed
  • 17. Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry. 1998 Aug;155(8):1119-21. PubMed
  • 18. Grunhaus L, Hirschman S, Dolberg OT, Schreiber S, Dannon PN. Coadministration of melatonin and fluoxetine does not improve the 3-month outcome following ECT. J ECT. 2001 Jun;17(2):124-8. PubMed
  • 19. Mowla A, Kardeh E. Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):970-3. PubMed
  • 20. Grady TA, Pigott TA, L'Heureux F, Murphy DL. Seizure associated with fluoxetine and adjuvant buspirone therapy. J Clin Psychopharmacol. 1992 Feb;12(1):70-1. PubMed
  • 21. Bakish D. Fluoxetine potentiation by buspirone: three case histories. Can J Psychiatry. 1991 Dec;36(10):749-50. PubMed
  • 22. Markovitz PJ, Stagno SJ, Calabrese JR. Buspirone augmentation of fluoxetine in obsessive-compulsive disorder. Am J Psychiatry. 1990 Jun;147(6):798-800. PubMed
  • 23. Amin R. Fluoxetine and Trazodone Combination Pharmacotherapy Resulting in Severe Irritability, Anger, Anxiety, and Anorexia: Probable Adverse Drug Interaction. Prim Care Companion CNS Disord. 2016 Aug 11;18(4).

By HealthyStock Research Group, September 2009
Medical resources reviewed: August 2018

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