Brand Name:  Savella®

Generic Name:  Milnacipran

Manufacturer:  Forest Laboratories/Cypress Bioscience®

Drug Class:   Selective serotonin and norepinephrine reuptake inhibitor (SNRI)¹

Uses: 

Labeled: Indicated for the treatment of fibromyalgia¹

Off-label: Depression²               

Mechanism of Action:

Milnacipran selectively inhibits the reuptake of serotonin and norepinephrine. The exact mechanism by which it improves fibromyalgia symptoms is unknown.¹

Pharmacokinetics:^1,2,3

Metabolism²: Metabolized by the liver via glucuronidation, extent unknown. Not shown to be metabolized by the CYP450 system

Elimination²: Milnacipran and its metabolites are primarily eliminated renally.  Approximately 55% excreted unchanged in urine.

Efficacy: 

Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG.  A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Human Psychopharmacology. 2004. 19. S27-S35

Study Design: A double-blind, placebo-controlled, randomized multi-center study

Description of Study:  A total of 125 patients were randomized to receive either milnacipran as a single daily dose, twice daily doses, or placebo.  Doses were titrated to 50 mg on week 2, 100 mg week 3, and 200 mg thereafter for a total of 12 weeks.  The primary outcome measure was improvement of symptoms from baseline.  Adverse events and vital signs were reported at monthly clinic visits.  14.4% of all patients dropped out of the study, most due to adverse events.  Improvements in pain reached statistical significance for twice daily milnacipran in all but one measure, whereas once daily milnacipran reached statistical significance in only 3 of 10 measures.  Twice daily milnacipran was significantly more effective than once daily milnacipran.  Over 70% of all patients who took milnacipran improved on the global impression of change scale, compared to 38% for placebo (p = 0.003 for total milnacipran vs placebo).

Limitations: The power of the study was not stated and the sample size was small.  The authors did not disclose any conflicts of interest.  Blinding was not measured during the study.  Patients were allowed to take NSAIDS and acetaminophen during the study, which may have altered the pain results for each group.  The majority of patients in each treatment group were female (96% and 98%), which limit the conclusions that can be made about milnacipran in the male population. 

Conclusions:  The study would have been stronger if patients who utilized OTC pain relievers were asked to record how often and what medications they were using.  Study would have improved if the exclusion method of drop outs was used as well as the intent-to-treat analysis to determine if the number of drop outs significantly affected the results. Due to the low sample size, more studies are needed before recommending milnacipran for the treatment of fibromyalgia.

Clauw DJ,  Mease, P, Palmer RH, Gendreau M, Wang Y. Milnacipran for the treatment of fibromyalgia in adults. A 15 week multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial.  Clinical Therapeutics 2008. 30(11).  pp 1988-2004

Study Design: Randomized, double-blind, placebo-controlled trial. 

Description of Study: 1196 patients were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401) for a 15 week study. The majority of patients were female (96.2%) and white (93.5%).  Significantly greater numbers of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004), than those in the placebo group. Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points.  Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 mg and 200 mg/d, respectively, compared with 9.5% of placebo recipients. In adults with fibromyalgia, both doses of milnacipran (100 mg/d and 200 mg/d) were associated with significant improvements in pain and other symptoms. 

Limitations: Several authors have financial associations with or are employed by the manufacturer of Savella.  Success of blinding was not determined.  Most of the subjects recruited were female and Caucasian, which limits the generalizability of the results to other patient populations.  Patients who required extra pain control were allowed to take up to 60 mg/d of hydrocodone to control their symptoms.  The study lasted for only 15 weeks, so further studies looking into the long term effects are needed

Conclusions: This was the first adequately-powered clinical trial that showed milnacipran to be efficacious in treating fibromyalgia symptoms.  This drug also showed that milnacipran is relatively safe and without serious adverse events.  The conclusions based on the data in the trial are applicable to Caucasian females, but extrapolating the data to males and other races should be done cautiously, if at all.  Other studies are needed to determine the effectiveness of milnacipran in other populations.    

Hindmarch I, Rigney U, Stanley N, Briley M. Pharmacodynamics of milnacipran in young and elderly volunteers. Journal of Clinical Pharmacology. 2000. 49. pp 118-125

Study Design: Randomized, double-blinded, crossover study

Description of Study:  A series of psychometric tests were done on the subjects pre and post dose in 2 separate groups.  In the first group 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose.  The second group compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo in healthy volunteers aged over 65 years.  The test battery was administered at baseline and at 2, 10 and 24 h post dose.  The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short-term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ).  In the elderly, milnacipran significantly increased CFF scores (P<0.05) compared to placebo, but had no significant effects on any other measures.  Milnacipran had no significant dose-related effects in young volunteers.  On the other hand, amitriptyline significantly decreased the CFF threshold, increased error on the CTT, and lengthened the CRT.  Amitriptyline also increased the values in the LARS and LSEQ.

Limitations: Small sample size was an obvious issue in the study.  Power was not mentioned in the study.  Patients were only required to refrain from alcohol, caffeine, and nicotine for 24hr prior to each study day and during the study day.  Amitriptyline dose was lower than the clinically recommended dose for treatment of depression.  The second study used milnacipran doses of 75 mg/d (below the normal dose of 100 mg/d) while the first study group used doses varying from 12.5 mg to 100 mg per day.  

Conclusions: The authors concluded that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from side effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers.  Due to the small sample size, this study is only a start when determining the pharmacodynamic differences in young and elderly patients taking milnacipran.  Many variables could have interfered with the results on the test battery, including diet, exercise, alcohol or tobacco use, or concomitant use of prescription or OTC medications.  In addition, the elderly were not exposed to the same maximum dose of 100 mg like they younger populations was.          

Black Box Warning:

Milnacipran is an SNRI, which is similar to other medications used to treat depression and other psychiatric disorders.  Antidepressants carry a risk of increasing suicidal ideation and behavior in children and adolescents younger than 24 years old.  These patients must be monitored closely during therapy by their physicians.  In addition, family members are encouraged to learn the signs and symptoms of worsening depression, and suicidality.

Contraindications:²   

Use of milnacipran is contraindicated in patients currently taking monoamine oxidase inhibitors (MAOI), or those who have taken MAOI’s in the past 14 days.  In addition, those patients with uncontrolled narrow-angle glaucoma are put at greater risk of mydriasis if started on milnacipran; therefore use is contraindicated in these patients.

Precautions:^{1, 2}

• Suicidal behavior/thoughts, worsening depression, changes in behavior. Monitoring is recommended during first few months of therapy and after dosage adjustments.
• Abnormal bleeding may occur, increased risk if taking drugs that affect coagulation status (NSAIDS, aspirin, warfarin, etc)
• Severe withdrawal symptoms have been reported, and doses should be gradually reduced instead of abrupt withdrawal
• Concomitant use of alcohol may precipitate or worsen liver disease; recommend avoidance of alcohol
• Concomitant use of IV digoxin should be avoided
• Use of serotonin precursors and serotonin-effecting drugs (triptans, tryptophan, etc) should be avoided due to the risk of developing serotonin syndrome.
• Prior history of dysuria, prostatic hypertrophy, prostatitis, urinary obstructive disorders may put patients at greater risk for urinary adverse effects.
• Heart rate increases, monitoring or dose reduction is recommended if symptoms develop
• Hepatotoxicity, increased ALT and AST. Discontinue in patients who become jaundice or develop liver failure
• Hypertension has been reported, use caution in patient with current or past history of hypertension or other cardiac disease.
• Hyponatremia and SIADH have been reported. Elderly patients and those who are volume-depleted or on diuretics are at greater risk.
• History of mania, patients may experience worsening symptoms when started on milnacipran.
• Controlled narrow-angle glaucoma.
• Renal impairment, dosage reduction necessary for severe impairment (CrCl 5-29 ml/min). Use not recommended in patients with end stage renal disease.
• History of seizures
• Milnacipran contains tartrazine, may cause allergic reactions in patients sensitive to tartrazine.
• Patients should not operate heavy machinery until they know how milnacipran affects them

Adverse Effects:²

• Increased blood pressure, (2%-19.5%)
• Increased heart rate, (6%-8%)
• Palpitations, (7%)
• Tachycardia, (2%)
• Diaphoresis, (9%)
• Flushing, (3%)
• Hot Sweats, (12%)
• Steven-Johnson syndrome has been reported, incidence unknown
• Hyponatremia
• Constipation, (16%)
• Nausea, (37%)
• Xerostomia, (5%)
• Abnormal bleeding
• ALT elevation, (6%-7%)
• AST elevation, (3%-5%)
• Dizziness, (10%)
• Headache, (18%)
• Insomnia, (12%)
• Migraine, (5%)
• Seizures
• Serotonin Syndrome
• Acute renal failure
• Urinary tract infection
• Shivering, (2%) 

Drug Interactions:^{1, 2}

• Level 1 (severe) interactions

Dexfenfluramine - potential risk of serotonin syndrome

Fenfluramine - potential risk of serotonin syndrome

Monoamine oxidase inhibitors (MAOIs) - Concurrent use of milnacipran with MAOIs may be associated with serotonin syndrome 

• Level 2 (major) interactions

Amphetamine- potential risk of serotonin syndrome

Buspirone - potential risk of serotonin syndrome

Clonidine - milnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and   other pharmacologic effects of clonidine

Cocaine - potential risk of serotonin syndrome

Desvenlafaxine - potential risk of serotonin syndrome

Dexmethylphenidate - potential risk of serotonin syndrome

Dextroamphetamine - potential risk of serotonin syndrome

Dextromethorphan - potential risk of serotonin syndrome

Digoxin - Postural hypotension and tachycardia have occurred during concurrent use of intravenous digoxin and milnacipran

Duloxetine - potential risk of serotonin syndrome

Epinephrine - hypertension and arrhythmias may occur during concurrent use of epinephrine or norepinephrine

Furazolidone - Caution is advisable during use of other drugs with MAOI-activity, risk of serotonin syndrome       

Linezolid - Caution is advisable during concurrent use of other drugs with MAOI-activity, risk of serotonin syndrome

Melatonin - may potentially interact with medications the inhibit serotonin reuptake

Meperidine - potential risk of serotonin syndrome

Methylphenidate - potential risk of serotonin syndrome

Nefazodone - potential risk of serotonin syndrome

Norepinephrine - hypertension and arrhythmias may occur during concurrent use of epinephrine or norepinephrine

Phentermine - hypertension and arrhythmias may occur

Procarbazine - Caution is advisable during use of other drugs with MAOI-activity, risk of serotonin syndrome

Selective serotonin reuptake inhibitors (SSRIs) - potential risk of serotonin syndrome

Serotonin receptor agonists - potential risk of serotonin syndrome

Sibutramine - potential risk of serotonin syndrome

St. John’s Wort - potential risk of serotonin syndrome

Tramadol - potential risk of serotonin syndrome

Trazodone - potential risk of serotonin syndrome

Tricyclic Antidepressants - potential risk of serotonin syndrome

Tryptophan - potential risk of serotonin syndrome

Venlafaxine - potential risk of serotonin syndrome 

• Level 3 (moderate) interactions

Anticoagulants - Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of bleeding

Antihypertensive agents - The effectiveness of antihypertensive agents may be diminished during concomitant use of milnacipran

Aspirin - Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication

Kava Kava - The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with kava kava.  These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.

Lithium - potential risk of serotonin syndrome

NSAIDS - Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication

Platelet inhibitors - Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of bleeding

Salicylates - Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of bleeding

Thrombolytic agents - Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of bleeding

Valerian - The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with valerian.  These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.

Zolpidem - In some patients taking serotonergic medications like milnacipran, zolpidem has been associated with rare reports of disorientation, delusions, or hallucinations

Dosing/Administration ²:

Usual dose: Upon initiating therapy for the treatment of fibromyalgia, a 7-day titration is necessary.  12.5 mg orally once daily on day 1, 12.5 mg twice daily on days 2 and 3, and 25 mg twice daily on days 4-7. For maintenance therapy following the 7-day titration the recommended dose is 50 mg twice daily.  Dosage may be increased based on tolerability to a maximum daily dosage of 100 mg twice daily.  Milnacipran should never be abruptly discontinued.  Milnacipran should be gradually reduced, especially after extended therapy.             

Pediatric dose: Safety and efficacy of milnacipran has not been studied in pediatric patients less than 17 years of age.  Milnacipran is not recommended for use in the pediatric population.

Renal Impairment:

Mild renal impairment (CrCl 50-80 ml/min) – no dosage adjustments necessary

Moderate renal impairment (CrCl 30-49 ml/min) – caution is advised but no dosage adjustments needed

Severe renal impairment (CrCl 5-29 ml/min) – maintenance dose should be reduced by 50% to 25 mg twice daily, with a maximum dose of 50 mg twice daily.

Hepatic Insufficiency: no dosage adjustments necessary

Geriatric Population: no dosage adjustments necessary

Use in Special Circumstances ³:

Pregnancy: Milnacipran is pregnancy category C.  There are no adequate, well-controlled studies in pregnant women.  Milnacipran should only be used in pregnant women if the benefit of therapy outweighs all the potential risk to the women and the fetus.  Neonates exposed to SNRIS or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can appear immediately after delivery. Clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These symptoms may be characteristic of the drug class or symptoms of withdrawal. 

Lactation: There have been no adequate studies done on breastfeeding mothers taking milnacipran.  It is unknown if milnacipran          is secreted into human milk.  Studies have shown that milnacipran and its metabolites are excreted into milk during       studies in animals.  Nursing while taking milnacipran is discouraged.                      

Conclusion: 

While its exact place in therapy is unclear given the various treatment options available to treat fibromyalgia, milnacipran is another option that appears to be effective.  Despite the positive findings on milnacipran’s efficacy in treating the various symptoms of fibromyalgia, studies will need to be done to compare its effectiveness to other drugs approved for fibromyalgia, such as pregabalin, amitriptyline, and fluoxetine.  Milnacipran does have a prescribing advantage over pregabalin, since it is not a controlled substance.  In addition, milnacipran has a better side effect and tolerability profile than the tricyclic antidepressants (TCA), so those who experience adverse events to TCAs could benefit from milnacipran.  It is unclear whether milnacipran has any benefit over the other SNRIs available to treat fibromyalgia, such as venlafaxine and duloxetine.  Studies are needed to compare the effectiveness of these medications when treating fibromyalgia before conclusions can be made.

Recommended References:

1. Milnacipran. Clinical Pharmacology. [Internet database]. Gold Standard, Inc. 2009. Available at http://www.clinicalpharmacology.com. Accessed: March 11^th, 2009.
2. Milnacipran. In: MICROMEDEX® [Internet database]. Greenwood Village, Colo: Thomson® Micromedex. Updated periodically. Accessed March 11^th, 2009.
3. Savella Full Prescribing Information [package insert]. Forest Pharmaceuticals, Inc. St Louis, Mo. Updated January 2009. Available at http://www.savella.com
4. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG.  A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Human Psychopharmacology. 2004. 19. S27-S35
5. Clauw DJ,  Mease, P, Palmer RH, Gendreau M, Wang Y. Milnacipran for the treatment of fibromyalgia in adults. A 15 week multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial.  Clinical Therapeutics 2008. 30(11).  pp 1988-2004
6. Hindmarch I, Rigney U, Stanley N, Briley M. Pharmacodynamics of milnacipran in young and elderly volunteers. Journal of Clinical Pharmacology. 2000. 49. pp 118-125 

Pepared by: Sean Lamont, Doctor of Pharmacy Candidate