Milnacipran has low potential for drug-drug interaction

Milnacipran, a norepinephrine and serotonin reuptake inhibitor (NRSI) under investigation for the treatment of fibromyalgia syndrome (FMS), was shown to significantly reduce pain and improve other FMS-associated symptoms in several clinical trials. Because many FMS patients suffer from comorbid disorders and currently take medications to treat these disorders as well as their multiple symptoms associated with FMS, the drug-drug interactions of milnacipran are an important aspect of its safety profile. Results from in vitro/in vivo studies indicate milnacipran has minimal hepatic metabolism, therefore, has relative lack of interference with the CYP450 liver enzyme system. Drug-drug interaction studies were conducted in healthy subjects receiving single- or multiple-doses of milnacipran (daily 50, 100, or 200 mg). The pharmacokinetics of milnacipran were not altered in subjects who were poor metabolizers of sparteine (CYP2D6 deficiency) or mephenytoin (CYP2C19 deficiency) compared to extensive metabolizers. No pharmacokinetic interactions or interaction-related adverse events (AEs) were found with digoxin or warfarin. Milnacipran pharmacokinetics was not altered by either of these drugs. No pharmacokinetic changes were observed with coadministration of either lorazepam or lithium. No clinically significant pharmacokinetic alterations occurred with carbamazepine and levomepromazine. In a study in which healthy subjects switched from fluoxetine to milnacipran without washout, there were no changes in milnacipran pharmacokinetics after single or multiple dosing. In a similar study with clomipramine, the AE profile changed suggesting that patients be monitored when treatment is switched without washout. Finally, milnacipran did not increase motor skill impairment caused by alcohol; alcohol did not affect milnacipran pharmacokinetics. Overall, data from these studies indicate that milnacipran has a low potential for drug-drug interactions and can be safely used with concomitant medications commonly used to treat FMS patients. Supported by Forest Laboratories and Cypress Bioscience.