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Posts Tagged ‘Milnacipran’

Mease et al

10 Aug

Mease and colleagues performed a randomized, double-blind study to confirm the safety and efficacy of milnacipran in patients with FM. This 27-week study compared milnacipran 100 mg/day and 200 mg/day with placebo.
Eligibility requirements were as follows:

  • Female and male subjects were between 18 and 70 years of age.
  • Patients had a diagnosis of primary FM, based on 1990 ACR criteria.

Patients were excluded from the study if they:

  • had severe psychiatric illness, a current major depressive episode, or a risk of suicide.
  • were abusing alcohol or drugs.
  • had an autoimmune disease, a systemic infection, moderate-to-severe sleep apnea, an active peptic ulcer, or inflammatory bowel disease.
  • currently had cancer or were undergoing concurrent chemotherapy.
  • had a history of significant cardiovascular, respiratory, endocrine, genitourinary, liver, or kidney disease.

The 888 eligible patients from 59 centers in the U.S. were randomly assigned to receive milnacipran 100 mg/day, milnacipran 200 mg/day, or placebo in two divided doses for six months. The study involved four phases, beginning with a screening and washout phase of centrally acting therapies used for treating FM, followed by the baseline assessment phase. The next three weeks consisted of the dose-escalation phase, in which patients reached their assigned dose level. Sham dosing was implemented in the placebo patients and in the group receiving milnacipran 100 mg/day to maintain blinding. In the final phase, patients received stable doses for 24 weeks.
Baseline demographics were similar for all treatment arms. The primary efficacy measure for the treatment of FM pain was a composite response rate based on the following endpoints:

  • an improvement in pain of 30% or more in VAS 24-hour morning recall
  • Patient Global Impression of Change (PGIC) ratings of “very much improved” or “much improved”

At week 15, the midpoint of the study, more patients treated with milnacipran doses of 100 mg/day (27.2%; P = 0.056) and 200 mg/day (26.8%; P = 0.032) met the primary outcome criteria of FM pain responders compared with the placebo patients (19.3%). At the end of the study (at six months), more patients in both milnacipran groups met the criteria for response for treating FM pain (200 mg/day, 25.6%; 100 mg/day, 25.9%; and placebo, 18.4%).
Although the patients receiving milnacipran 100 mg/day had the highest composite response rate for the treatment of FM pain, there was only a trend toward reaching statistical significance (P = 0.072). Results for the 200-mg/day group differed significantly from those of the placebo group (P = 0.034).
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Improvements were observed during the study, but the rate of discontinuation associated with milnacipran use was extremely high. At week 27, 42.9% of patients receiving milnacipran 100 mg/day, 45.8% receiving 200 mg/day, and 35% of patients receiving placebo had discontinued therapy. Of the patients receiving milnacipran 200 mg/day, 27% withdrew from therapy because of AEs, compared with 19.6% taking milnacipran 100 mg/day and 10.3% receiving placebo.
Therapeutic failure was the second highest reason for discontinuing milnacipran; 11.1% of patients taking 200 mg/day stopped therapy, and 11.6% taking 100 mg/day withdrew. A higher percentage of patients receiving placebo (15.2%) experienced therapeutic failures.
Overall, milnacipran was associated with significant improvements in the treatment of pain associated with FM; however, higher doses were associated with more side effects.

 
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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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Adverse drug effects. Contraindications and precautions

30 Jun

Milnacipran is indicated for the management of fibromialgia in adults.

CONTRAINDICATIONS AND PRECAUTIONS

The use of milnacipran in patients with uncontrolled narrow-angle glaucoma is contraindicated. Milnacipran has been associated with an increased risk of mydriasis. Pupil dilation can restrict the flow of aqueous fluid, causing buildup behind the iris. If blockage occurs, a rapid rise in intraocular pressure can occur.

The concomitant use of milnacipran and MAO inhibitors is contraindicated because of the increased potential to cause serotonin syndrome and hypertensive crisis.

Milnacipran carries a boxed (black-box) warning for an increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults. This medication should not be prescribed to patients who are actively suicidal.
Reports suggest that selective serotonin reuptake inhibitors (SSRIs) and SNRIs, when used as monotherapy, can cause serotonin syndrome and neuroleptic malignant syndrome (NMS)–like reactions. Clinicians should be alert to any possible symptoms relating to either of these syndromes.

Increases in blood pressure (BP) and heart rate have been associated with milnacipran. The drug should be prescribed with caution if patients have uncontrolled, elevated BP and if they are taking other medications (e.g., psychostimulants) that can increase BP.
Milnacipran has also been associated with mild elevations in liver enzymes. Therapy should be discontinued if there is evidence of liver dysfunction.

ADVERSE DRUG EFFECTS

In placebo-controlled trials, the most commonly noted AE was nausea. Other frequently experienced side effects included constipation, hot flushes, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension. AEs leading to discontinuation of treatment doses of milnacipran in placebo-controlled trials consisted of nausea (6%), palpitations (3%), headache (2%), constipation (1%), increased heart rate (1%), hyperhidrosis (1%), vomiting (1%), and dizziness (1%).

In phase 3 trials, weight loss occurred at a greater rate in patients receiving milnacipran in comparison with placebo. A mean weight loss of approximately 0.8 kg was reported for milnacipran, compared with 0.2 kg for placebo.

DRUG INTERACTIONS

In clinical trials, hypertension was approximately doubled in patients who received milnacipran compared with those receiving placebo. Those patients in the 100-mg treatment group were more likely to become hypertensive (19.5%) than those receiving 200 mg/day (16.6%) or placebo (7.2%). Heart rate was also reported to be increased by an average of 7 to 8 bpm with milnacipran use.

Most of the milnacipran dose is metabolized predominantly through phase 2 conjugation, which reduces the possibility of interactions with drugs metabolized through CYP 450 enzymes.10 Although milnacipran is metabolized primarily through glucuronidation, the drug is a substrate and a weak inhibitor of CYP 3A4.12 This known inhibition is unlikely to produce any clinically relevant pharmacokinetic drug interactions.

Pharmacokinetic drug interactions involving CYP isoenzymes are not likely with milnacipran use, but several clinically important pharmacodynamic interactions must be considered. As previously mentioned, MAO inhibitors are contraindicated with milnacipran. Caution should be exercised with other agents such as antidepressants online, anti-psychotic drugs, and lithium, because these agents can precipitate 5-HT and NMS-like syndromes. Medications that increase BP and heart rate should also be used cautiously in patients receiving milnacipran because of its potential hypertensive effects.

 
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