Drug Interactions

Paroxetine (Paxil®) Interactions

Taking Paroxetine with:

Paroxetine Drug Interactions:

Paroxetine is a potent inhibitor of cytochrome P450 2D6 (CYP2D6), but a very weak inhibitor of CYP3A4.

Use with caution and consider reducing dosage of concomitantly administered CYP2D6 substrate, particularly those with a narrow therapeutic index, such as tricyclic antidepressants, class IC antiarrhythmics, and phenothiazines.

Interactions with drugs metabolized by the CYP3A4 isoenzyme are unlikely.

  • Aspirin, NSAIDs, anticoagulants: increased risk of bleeding.
  • Cimetidine: may increase paroxetine concentrations.
  • Metoprolol: severe hypotension.
  • Monoamine oxidase (MAO) inhibitors: potentially serious or fatal serotonin syndrome; concurrent use is contraindicated, and at least 14 days should elapse between discontinuation of one drug and initiation of the other.
  • Serotonergics or other serotonin-enhancing drugs: increased risk of developing the serotonin syndrome, a rare but potentially fatal hyperserotonergic state.
  • Thioridazine and pimozide: potential for QTc prolongation, which is associated with serious ventricular arrhythmias and sudden death. Concurrent use is contraindicated.
  • Tryptophan: detrimental effects resembling serotonin syndrome.

Can you take Paroxetine and Aripiprazole (Abilify®)?

No adverse drug interactions expected. Paroxetine in combination with aripiprazole is used in the treatment of refractory major depressive disorder.

Can you take Paroxetine and Adderall®?

Adderall is a combination of amphetamine and dextroamphetamine. Paroxetine may decrease the metabolism of amphetamines resulting in raised plasma levels of the amphetamine. Concomitant use of paroxetine and Adderall® requires caution.

Can you take Paroxetine and Atomoxetine (Strattera®)?

Paroxetine noticably increases atomoxetine levels. Dosage adjustment and slower titration of atomoxetine may be necessary3.

Can you take Paroxetine and Amitriptyline?

Paroxetine inhibits hepatic cytochrome P450 enzyme CYP2D6 and may promote increased plasma levels of amitriptyline because amitriptyline is metabolized by enzyme CYP2D6. Therefore, use of paroxetine with amitriptyline (as well as with other tricyclic antidepressants nortriptyline, imipramine and desipramine) should be undertaken with caution and dosage adjustments may be necessary 1.

Can you take Paroxetine and Buspirone (Buspar®)?

Possible risk of serotonin syndrome4 as both paroxetine and buspirone have serotonergic effects. Concomitant use of paroxetine and buspirone is acceptable5 but requires some caution.

Can you take Paroxetine and Trazodone?

Concomitant use of paroxetine and trazodone is acceptable5. Theoretical risk of serotonin syndrome. Some degree of caution would be prudent if paroxetine is taken with trazodone.

Can you take Paroxetine and Alprazolam (Xanax®)?

No evidence for a significant interaction between paroxetine and alprazolam6.

Can you take Paroxetine and Diazepam (Valium®)?

There is no evidence of adverse effects when paroxetine is used in combination with diazepam7.

Can you take Paroxetine and Zaleplon (Sonata®)?

Generally, concomitant use of paroxetine with zaleplon is safe8.

Can you take Paroxetine and Zolpidem (Ambien®)?

Generally, concomitant use of paroxetine with zolpidem is safe1, 16. Several case reports suggest that interaction between zolpidem and SSRIs may lead to prolonged zolpidem-associated hallucinations9.
Combination of zolpidem with paroxetine may be effective for sleep maintenance and early morning awakenings16.

Can you take Paroxetine and Melatonin?

No evidence for a significant interaction between paroxetine and melatonin 1. It is safe to take paroxetine with melatonin.

Can you take Paroxetine and Benadryl®?

There are no reported drug interactions between paroxetine and diphenhydramine, an active ingredient in Benadryl® 1, 12. Concomitant use is considered to be safe.

Can you take Paroxetine and Tramadol?

Tramadol label has warning that concomitant therapy with paroxetine (CYP2D6 inhibitor) may reduce metabolism and clearance of tramadol increasing the risk of seizure and serotonin syndrome 10. Taking paroxetine along with tramadol is allowable under the supervision of your physician.

Can you take Paroxetine and Hydrocodone or other opioid analgesics?

There are no significant interactions between paroxetine and hydrocodone 1.

Paroxetine can inhibit the metabolism of the methadone thereby promoting its accumulation in the body 11. However, this the increase in methadone levels is unlikely to have clinical effects.

Can you take Paroxetine and Ibuprofen (Advil®)?

Taking paroxetine and ibuprofen at the same time is generally safe 14. Concomitant use may slightly increase the risk of bleeding 1.

Can you take Paroxetine and Topiramate (Topamax®)?

No major drug interactions 1. Paroxetine can be safely used along with topiramate15.

When you should NOT take Paroxetine?

  • Concomitant or recent (within 14 days) use of MAO inhibitors.
  • Concomitant use with thioridazine or pimozide.
  • Hypersensitivity to paroxetine.

Paroxetine during Pregnancy and lactation

Pregnancy Category D.
The data suggests that Paroxetine leads to increased rates of congenital malformations.

Some epidemiological studies suggest a small increased risk of cardiovascular malformation (e.g. ventricular and atrial septum defects) associated with the use of paroxetine during the first trimester. The risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is less than 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population.

Paroxetine is generally considered compatible (low risk to infant) while breast-feeding.


  • 1. U.S. FDA Paroxetine prescribing information
  • 2. Yoshimura R, Kishi T, Hori H, et al. Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Dec 3;39(2):355-7. PubMed
  • 3. Belle DJ, Ernest CS, Sauer JM, Smith BP, Thomasson HR, Witcher JW. Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J Clin Pharmacol. 2002 Nov;42(11):1219-27. PubMed
  • 4. Jägestedt M, von Bahr C. Combination of serotonergic agents resulted in severe adverse effects. Lakartidningen. 2004 Apr 29;101(18):1618-9. PubMed
  • 5. Fang Y, Yuan C, Xu Y, et al; OPERATION Study Team. A pilot study of the efficacy and safety of paroxetine augmented with risperidone, valproate, buspirone, trazodone, or thyroid hormone in adult Chinese patients with treatment-resistant major depression. J Clin Psychopharmacol. 2011 Oct;31(5):638-42. PubMed
  • 6. Calvo G, García-Gea C, Luque A, Morte A, Dal-Ré R, Barbanoj M. Lack of pharmacologic interaction between paroxetine and alprazolam at steady state in healthy volunteers. J Clin Psychopharmacol. 2004 Jun;24(3):268-76. PubMed
  • 7. Bannister SJ, Houser VP, Hulse JD, Kisicki JC, Rasmussen JG. Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin. Acta Psychiatr Scand Suppl. 1989;350:102-6. PubMed
  • 8. Darwish M. Overview of drug interaction studies with zaleplon. Poster presented at 13th Annual Meeting of Associated Professional Sleep Studies (APSS), Orlando, Florida, June 23rd, 1999.
  • 9. Katz SE. Possible paroxetine-zolpidem interaction. Am J Psychiatry (1995) 152, 1689.
  • 10. U.S. FDA Tramadol prescribing information
  • 11. Begré S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap CB. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol. 2002 Apr;22(2):211-5. PubMed
  • 12. Roth A, Akyol S, Nelson JC. Delirium associated with the combination of a neuroleptic, an SSRI, and benztropine. J Clin Psychiatry. 1994 Nov;55(11):492-5. PubMed
  • 14. Hersh EV, Pinto A, Moore PA. Adverse drug interactions involving common prescription and over-the-counter analgesic agents. Clin Ther. 2007;29 Suppl:2477-97. PubMed
  • 15. Hollander E, Dell'Osso B. Topiramate plus paroxetine in treatment-resistant obsessive-compulsive disorder. Int Clin Psychopharmacol. 2006 May;21(3):189-91. PubMed
  • 16. Yu ZH, Xu XH, Wang SD, Song MF, Liu Y, Yin Y, Mao HJ, Tang GZ. Effect and safety of paroxetine combined with zolpidem in treatment of primary insomnia. Sleep Breath. 2017 Jan 18 PubMed

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

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