In general, Periactin (cyproheptadine) should not be used at the same time as Benadryl (diphenhydramine) as they are both sedating antihistamines. Use of both together can cause additive sedative effects and increase the risk of other related side effects such as:

  • Dry mouth
  • Dry eyes
  • Constipation

In addition to its antihistamine effects, cyproheptadine also blocks serotonin receptors, making it beneficial for the treatment of variety of indications, including:

  • Anorexia (increases appetite)
  • Cushing's syndrome
  • Migraine prophylaxis

Benadryl (diphenhydramine) does not have serotonin effects, just antihistamine effects, so we aren't worried about any issues with serotonin in regard to use with cyproheptadine, just the additive antihistamine effects.

In terms of how long to space them, Benadryl has a duration of action around 4 to 6 hours while cyproheptadine lasts a little longer, around 6 to 8 hours per dose. Therefore, if Benadryl is dosed first, you should wait about 6 hours before dosing cyproheptadine. If cyproheptadine is dosed first, wait at least 8 hours.

In your situation, giving them 5 hours apart may increase sedation and drowsiness, but additional adverse reactions are unlikely unless there are other underlying health issues.