New Drug Update 2009-2010 - LAFP

primary route of elimination.
Table 2. Comparison of the Pharmacokinetic Parameters for Duloxetine and Milnacipran
Parameter Duloxetine Milnacipran
T max
a
6 h 2 to 4 h
Bioavailability — 85% to 90%
Protein binding > 90% < 13%
Half-life 12 h 6 to 8 h
Elimination primary route Hepatic (CYP1A2, CYP2D6) Renal (55% as unchanged drug in the urine)
a T max = time to maximal plasma concentration.
COMPARATIVE EFFICACY:
Fibromyalgia
Milnacipran was assessed in a randomized, double-blind, placebo-controlled study enrolling 1,196
patients meeting the American College of Rheumatology criteria for fibromyalgia. The majority of patients
were women (96.2%) and white (93.5%), with a mean age of 50.2 years. Patients received milnacipran
100 mg/day (399 patients), milnacipran 200 mg/day (396 patients), or placebo (401 patients) for 15
weeks. Patients were required to discontinue all centrally acting fibromyalgia therapies, including
antidepressants, sedative-hypnotics, anticonvulsants, muscle relaxants, and centrally acting analgesics,
as well as transcutaneous electrical nerve stimulation, biofeedback, tender and trigger point injections,
acupuncture, and anesthetic or narcotic patches. Limited rescue doses of hydrocodone were permitted.
The primary efficacy end point for the “treatment of fibromyalgia” was a composite defining responders as
patients with at least 30% pain improvement as assessed by the change from baseline in 24-hour
morning recall pain collected from daily e-diary scores, a rating of “very much improved” or “much
improved” on the Patient Global Impression of Change (PGIC), and an at least 6-point improvement from
baseline in physical function (SF-36 Physical Component Summary score). The primary end point
measure for “treatment of pain of fibromyalgia” was a composite defining responders as patients
achieving at least 30% improvement in pain in 24-hour morning recall pain and rating themselves as “very
much improved” or “much improved” on the PGIC scale. Results were analyzed using baseline
observation carried forward (BOCF), for which any patients missing any primary end point data were
classified as nonresponders, as well as a last observation carried forward (LOCF) and a completer
analysis. Odds ratios for response compared with placebo are summarized in Table 3. At 15 weeks, there
were more “treatment of fibromyalgia” responders in the milnacipran groups than in the placebo group
(15% [P = 0.011] and 14% [P = 0.015] for 100 and 200 mg/day groups, respectively vs 9% for placebo).
Response rates for “treatment of pain of fibromyalgia” were also greater in the milnacipran groups (23%
[P = 0.0252] and 25% [P = 0.0037] for 100 and 200 mg/day groups, respectively, compared with 16% for
placebo). Pain improvements were reported to be evident as early as 1 week after initiation of
milnacipran. At 3 months, milnacipran was also reported to be associated with improvements in additional
pain measures (morning recall pain, weekly recall pain, real-time pain, paper visual analog scale [VAS]
measures), as well as the PGIC (both doses, P < 0.001). Discontinuation rates were 28% in the placebo
group, 34% in the milnacipran 100 mg/day group, and 35% in the milnacipran 200 mg/day group (Clin
Ther. 2008;30(11):1988-2004).
Table 3. Odds Ratios for Composite Response in Adults With Fibromyalgia Treated for 15 Weeks
With Placebo or Milnacipran
Parameter Milnacipran 100 mg/day Milnacipran 200 mg/day
Fibromyalgia treatment
BOCF 1.79 (95% CI, 1.14 to 2.8) a,b 1.75 (95% CI, 1.11 to 2.75) b
LOCF 1.82 (95% CI, 1.18 to 2.78) c 1.9 (95% CI, 1.24 to 2.91) c
60