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Archive for July, 2010

The efficacy and tolerability of milnacipran

07 Jul

The efficacy and tolerability of milnacipran were evaluated in a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial of adults with FM. Patients received milnacipran 100 mg/day or 200 mg/day or placebo for 15 weeks.

Patients were eligible for enrollment if they:

  • were between 18 and 70 years of age.
  • had a diagnosis of primary FM, based on 1990 ACR criteria.
  • had withdrawn from centrally active therapies commonly used to treat FM.
  • had discontinued treatment using transcutaneous electrical nerve stimulation (TENS), biofeedback, acupuncture, anesthetic or narcotic patches, or injections for tender and trigger points.
  • had a raw score of 4 or higher on the physical function component of the Fibromyalgia Impact Questionnaire (FIQ) and 40 or more out of 100 on the mean VAS pain score.

Patients were excluded from the study if they:

  • had severe psychiatric illness.
  • displayed current major depressive illness based on the Mini-International Neuropsychiatric Interview or had a score higher than 25 on the Beck Depression Inventory.
  • exhibited a significant suicide risk.
  • were abusing alcohol, benzodiazepines, or other drugs.
  • had a history of behavior that prohibited compliance.
  • had coexisting cardiovascular, pulmonary, hepatic, renal, GI, or auto-immune disease (except for Hashimoto’s or Graves’ disease that has been stable for three months before screening).
  • had a systemic infection at the time.
  • currently had cancer (except for basal cell carcinoma), unstable endocrine disease, severe sleep apnea, prostate enlargement or other genitourinary disorder.
  • were pregnant or breast-feeding.

The study took place at 86 centers in the U.S. from November 2004 to December 2006. Before the trial, therapies that had the potential to interfere with pain symptoms of FM had to be discontinued. Of the 2,270 patients who were screened, 1,196 received milnacipran 100 mg/day, milnacipran 200 mg/day, or placebo, given as two daily doses.

Patients entered a one-week to four-week period for washout of prohibited medications, followed by a two-week baseline assessment period. Milnacipran-treated patients received 12.5 mg on day 1, 12.5 mg twice daily for two days, 25 mg twice daily for four days, and 50 mg twice daily for seven days. Patients receiving 200 mg/day received 100 mg twice daily for seven days; all other patients underwent a sham dose escalation to maintain blinding. After the escalation, the dosage was unchanged from week 3 to 15 (a total of 12 weeks). Any patient who was intolerant of the medication was dropped from the trial.

Baseline demographics in all treatment arms were similar. The primary efficacy measure was a composite response rate based on these endpoints:

  • pain improvement of 30% or more in VAS 24-hour morning recall
  • Patient Global Impression of Change (PGIC) ratings of “very much improved” or “much improved”
  • an improvement of 6 points or more on the Medical Outcome Short-Form 36 (SF-36) Physical Component Summary (PCS) score

After 15 weeks, a significantly greater number of patients receiving milnacipran 100 mg/day and 200 mg/day achieved the primary endpoints of meeting the three criteria for a FM composite response versus placebo (milnacipran doses of 100 mg/day, P = 0.01; milnacipran doses of 200 mg/day, P = 0.02). The number of patients experiencing more than a 30% improvement from baseline with 24-hour pain was highest with milnacipran 200 mg/day (39.9%), compared with 100 mg/day (37.3%) or placebo (28.7%).

The most frequently reported AE with the study drug was nausea, which occurred in 37.6% of patients taking 200 mg/day, in 34.3% of those taking 100 mg/day, and in 19.2% taking placebo. Other commonly reported AEs were dizziness, palpitations, hot flushes, hypertension, vomiting, tachycardia, hyperhidrosis, constipation, and migraines. Discontinuation rates attributable to AEs were higher with milnacipran than with placebo (23.7% with 200 mg/day, 19.5% with 100 mg/day, and 9.5% with placebo). Overall, milnacipran showed significant efficacy over placebo for treating FM; however, the higher dose of 200 mg/day was associated with more AEs.

 
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The efficacy of milnacipran

02 Jul

The efficacy of milnacipran for the treatment of patients with FM was evaluated in a phase 2, three-month, multi-center, randomized, double-blind comparative trial of the study drug and placebo. Adult patients received milnacipran once daily, milnacipran twice daily, or placebo for three months. This dose-escalation trial allowed maximum doses of milnacipran, up to 200 mg/day, to be tested. To be eligible for enrollment in the study, patients:

  • had to be between 18 and 70 years of age.
  • had to have a diagnosis of primary FM, based on the 1990 American College of Rheumatology (ACR) criteria.
  • had to have a pain score of 10 or higher on a 20-point Gracely scale at baseline.
  • had to have withdrawn from centrally active therapies commonly used to treat FM.

In addition, female participants were required to use contraception. Patients were excluded from the study if they:
were actively suicidal or psychotic.

  • had a substance abuse problem.
  • had any concurrent autoimmune, inflammatory, infectious, or malignant disorder; sleep apnea; or prostatic hypertrophy.
  • had abnormal baseline kidney and hepatic function test results.

The study consisted of a screening and washout phase, a baseline assessment, a dose-titration phase, and a stable-dose phase. The screening and baseline phases lasted four weeks. If patients met the criteria for entering the dose-titration phase, they were randomly assigned to one of the three study arms (milnacipran twice daily or once daily or placebo). Patients were randomly assigned by blocks of eight in a ratio of 3:3:2 for twice-daily/once-daily placebo dosing. The titration phase lasted for the first four weeks of the trial.
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All patients started with 25 mg/day at week 1. Each week following week 1, personnel at the study center called patients by telephone to advise them to remain with the current dose, to double the dose, or to discontinue therapy based on tolerability. At the end of the titration period, patients could reach a maximum target dose of 200 mg/day, or they could have remained with a lower dose if tolerability was a problem. Patients then continued to take the stable dose for another eight weeks after they completed the titration phase.

A total of 125 patients were enrolled in the study between March 20, 2002, and December 10, 2002. The primary efficacy endpoint evaluated was the average daily pain score in an electronic diary, as recorded by the patient. Secondary efficacy measures included weekly pain scores, as recorded in the e-diary, and pain assessments via a Visual Analogue Scale (VAS), the Gracely Pain Scale, and the McGill Pain Questionnaire.

Both milnacipran groups had reduced daily e-diary pain scores (−3.0 ± 3.5 for twice-daily dosing and −2.2 ± 2.3 for once-daily dosing). Although reductions in daily e-diary scores were higher than those reported for placebo (−1.86 ± 3.74), neither treatment group’s results were statistically significant in reducing daily pain scores when compared with placebo (P = 0.191 and P = 0.635 for twice-daily and once-daily dosing, respectively).

Twice-daily milnacipran, however, resulted in significantly lower pain scores and intensity in all secondary efficacy evaluations (P < 0.05) and in significantly lower weekly e-diary pain scores (−3.1 ± 3.5; P = 0.025) compared with placebo (−1.14 ± 3.79). The once-daily milnacipran dose did not result in a statistically significant reduction in pain scores in any primary or secondary evaluation. These observations are most likely attributed to the half-life of milnacipran.

A further analysis was conducted to determine whether comorbid depression influenced the treatment response, because milnacipran is an approved therapy in Europe for depression. Paradoxically, non-depressed patients showed significantly better improvement with milnacipran than the depressed patients did. These data are partially skewed, because most of the depressed patients with a co-morbidity received placebo (32%), compared with patients using once-daily milnacipran (7%) and twice-daily milnacipran (16%).
No unexpected hazardous side effects occurred in the treatment phases of the study. During the trial, 14.4% of patients discontinued therapy before the study’s completion. Of the 14.4% who withdrew, 3.6% of patients were receiving placebo, 21.7% were receiving once-daily milnacipran, and 13.7% were receiving twice-daily milnacipran. Tolerability was better with the twice-daily dose, suggesting that higher peaks levels of milnacipran were associated with increased AEs. Reasons for discontinuing the study drug were attributed primarily to headache and gastrointestinal (GI) upset.
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Overall, milnacipran was effective in reducing the pain of FM, but twice-daily dosing was necessary for tolerability and efficacy.

 
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