Levomilnacipran (Fetzima) Patient Guide: Benefits, Dosing, and Side Effects Explained

This guide is adapted from the clinician guide authored by Sebastián Malleza, M.D., M.Sc. at the Psychopharmacology Institute. For the complete clinical resource, visit: Levomilnacipran Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

What is Levomilnacipran?

Levomilnacipran (brand name Fetzima) is a medication used to treat major depressive disorder (MDD). It belongs to a group of medications called SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors). Levomilnacipran may be particularly helpful for people experiencing depression with symptoms of fatigue and low energy.[1,3,4]

How Does This Medication Work?

Levomilnacipran works by regulating two important brain chemicals called serotonin and norepinephrine.[1] These chemicals help regulate your mood, energy levels, and other functions in your body.

What makes levomilnacipran different from some other antidepressants is that it has a stronger effect on norepinephrine than serotonin (in a 2:1 ratio).[1] This may help improve energy levels and reduce fatigue alongside treating depression symptoms.[3,4]

Unlike some other medications in the same class, levomilnacipran affects both chemicals simultaneously at all doses, which may provide more consistent benefits.[2]

How to Take This Medication

Levomilnacipran comes as an extended-release capsule that you take once daily, with or without food.[6] The typical dosing schedule is:

• Starting dose: 20 mg once daily for 2 days
• Usual next step: Increase to 40 mg once daily
• Your doctor may gradually increase the dose in 40 mg increments as needed
• Maximum dose: 120 mg once daily

Important instructions:

• Swallow the capsule whole. Do not crush, chew, or split the capsule.[6]
• Take it at approximately the same time each day.
• If you miss a dose, take it as soon as you remember. If it’s almost time for your next dose, skip the missed dose and continue with your regular schedule. Do not take two doses to make up for a missed one.

Common Side Effects

Many side effects improve over time as your body adjusts to the medication. Common side effects include:

Digestive system effects:

• Nausea (occurs in about 17% of people)[6]
• Dry mouth (10%)[6]
• Constipation (9%)[6]
  • Increasing fluid and fiber intake may help with constipation[13,14]
• Vomiting (5%)[6]
• Decreased appetite (3%)[6]

Other common side effects:

• Increased heart rate (6%)[6]
• Increased sweating (9%)[6]
• Dizziness (8%)[6]
• Urinary hesitation or difficulty urinating (4-6%)[21]
• Sexual effects, more common in men (5-10%)[21]
• Insomnia or sleep problems (5%)[6]

Levomilnacipran is generally weight-neutral, meaning most people don’t experience significant weight changes while taking it.[15-20]

Important Safety Information

Do Not Take Levomilnacipran If:

• You are taking or have recently taken (within 14 days) medications called MAOIs (monoamine oxidase inhibitors)[6]
• You have end-stage kidney disease[6]

Talk to Your Doctor Before Taking Levomilnacipran If You Have:

• High blood pressure or heart problems[6,21]
• Kidney problems[6]
• Urinary retention or difficulty urinating[21]
• History of seizures[6]
• Bipolar disorder[6]
• Glaucoma (increased pressure in the eye)[27,28]
• Bleeding problems or if you take blood thinners[29,30]
• Low sodium levels[6,31]
• If you are pregnant, planning to become pregnant, or breastfeeding[6,32,33]

Avoid While Taking Levomilnacipran:

• Alcohol (it can affect how the medication is released in your body)[6]
• Other medications that increase serotonin levels without talking to your doctor first
• Driving or operating machinery until you know how this medication affects you

When to Contact Your Doctor Immediately

Contact your healthcare provider right away if you experience:

• Unusual changes in behavior, thoughts of suicide, or worsening depression
• Signs of serotonin syndrome: agitation, hallucinations, rapid heart rate, fever, excessive sweating, shivering, muscle stiffness or twitching, trouble with coordination, nausea, vomiting, or diarrhea[6]
• Difficulty urinating[21]
• Unusual bleeding or bruising[29,30]
• Severe headache, significant increase in blood pressure[21]
• Vision changes or eye pain[27,28]
• Severe allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing

Starting and Stopping the Medication

Starting: It may take several weeks before you notice the full benefits of this medication.

Stopping: Do not stop taking levomilnacipran suddenly without talking to your doctor. A gradual reduction in dose over 2-4 weeks is typically recommended to reduce the risk of discontinuation symptoms.[25,26]

Possible discontinuation symptoms include:

• Dizziness
• Nausea
• Headache
• Irritability
• Fatigue
• Insomnia

Special Considerations

Pregnancy and Breastfeeding

• Limited information is available about the safety of levomilnacipran during pregnancy.[6,32]
• The medication may pass into breast milk. Talk to your doctor about the risks and benefits if you are breastfeeding.[33]

Older Adults

No special dosage adjustments are needed for older adults, but your doctor will monitor you more closely for side effects like low sodium levels.[6,31]

Kidney Problems

If you have kidney problems, your doctor may prescribe a lower dose.[6]

References

1. Sansone, R. A., & Sansone, L. A. (2014 Mar-Apr). Serotonin Norepinephrine Reuptake Inhibitors: A Pharmacological Comparison. Innovations in Clinical Neuroscience, 11(3–4), 37.
2. Kasper, S., & Pail, G. (2010). Milnacipran: A unique antidepressant? Neuropsychiatric Disease and Treatment, 6, 23–31.
3. Gautam, M., Kaur, M., Jagtap, P., & Krayem, B. (2019). Levomilnacipran: More of the Same? The Primary Care Companion for CNS Disorders, 21(5), 27423.
4. Thase, M. E., Gommoll, C., Chen, C., Kramer, K., & Sambunaris, A. (2016). Effects of levomilnacipran extended-release on motivation/energy and functioning in adults with major depressive disorder. International Clinical Psychopharmacology, 31(6), 332–340.
5. Food, U. S., & Administration, D. (2024). FETZIMA® (levomilnacipran) extended-release capsules – Prescribing information.
6. Anti, M., Pignataro, G., Armuzzi, A., Valenti, A., Iascone, E., Marmo, R., Lamazza, A., Pretaroli, A. R., Pace, V., Leo, P., Castelli, A., & Gasbarrini, G. (1998). Water supplementation enhances the effect of high-fiber diet on stool frequency and laxative consumption in adult patients with functional constipation. Hepato-Gastroenterology, 45(21), 727–732.
7. Markland, A. D., Palsson, O., Goode, P. S., Burgio, K. L., Busby-Whitehead, J., & Whitehead, W. E. (2013). Association of Low Dietary Intake of Fiber and Liquids With Constipation: Evidence From the National Health and Nutrition Examination Survey. American Journal of Gastroenterology, 108(5), 796–803.
8. Asnis, G. M., Bose, A., Gommoll, C. P., Chen, C., & Greenberg, W. M. (2013). Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: A phase 3, randomized, double-blind, placebo-controlled study.
9. Sambunaris, A., Bose, A., Gommoll, C. P., Chen, C., Greenberg, W. M., & Sheehan, D. V. (2014). A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder.
10. Bakish, D., Bose, A., Gommoll, C., Chen, C., Nunez, R., Greenberg, W. M., Liebowitz, M., & Khan, A. (2014). Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: A phase III, randomized, double-blind, fixed-dose, placebo-controlled study.
11. Gommoll, C. P., Greenberg, W. M., & Chen, C. (2014). A randomized, double-blind, placebo-controlled study of flexible doses of levomilnacipran ER (40-120 mg/day) in patients with major depressive disorder.
12. Mago, R., Forero, G., Greenberg, W. M., Gommoll, C., & Chen, C. (2013). Safety and tolerability of levomilnacipran ER in major depressive disorder: Results from an open-label, 48-week extension study.
13. Shiovitz, T., Greenberg, W. M., Chen, C., Forero, G., & Gommoll, C. P. (2014). A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder.
14. Asnis, G. M., & Henderson, M. A. (2015). Levomilnacipran for the treatment of major depressive disorder: A review.
15. Horowitz, M. A., Framer, A., Hengartner, M. P., Sørensen, A., & Taylor, D. (2023). Estimating Risk of Antidepressant Withdrawal from a Review of Published Data. CNS Drugs, 37(2), 143–157.
16. Perahia, D. G., Kajdasz, D. K., Desaiah, D., & Haddad, P. M. (2005). Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. Journal of Affective Disorders, 89(1–3), 207–212.
17. Narayanan, V. (2019). Ocular Adverse Effects of Antidepressants – Need for an Ophthalmic Screening and Follow up Protocol. Ophthalmology Research: An International Journal, 1–6.
18. Wiciński, M., Kaluzny, B. J., Liberski, S., Marczak, D., Seredyka-Burduk, M., & Pawlak-Osińska, K. (2019). Association between serotonin-norepinephrine reuptake inhibitors and acute angle closure: What is known? Survey of Ophthalmology, 64(2), 185–194.
19. McFarland, D., Merchant, D., Khandai, A., Mojtahedzadeh, M., Ghosn, O., Hirst, J., Amonoo, H., Chopra, D., Niazi, S., Brandstetter, J., Gleason, A., Key, G., & di Ciccone, B. L. (2023). Selective Serotonin Reuptake Inhibitor (SSRI) Bleeding Risk: Considerations for the Consult-Liaison Psychiatrist. Current Psychiatry Reports, 25(3), 113–124.
20. Rahman, A. A., Platt, R. W., Beradid, S., Boivin, J.-F., Rej, S., & Renoux, C. (2024). Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding. JAMA Network Open, 7(3), e243208.
21. Gheysens, T., Van Den Eede, F., & De Picker, L. (2024). The risk of antidepressant-induced hyponatremia: A meta-analysis of antidepressant classes and compounds. European Psychiatry, 67(1), e20.
22. Jiang, H., Xu, L., Li, Y., Deng, M., Peng, C., & Ruan, B. (2016). Antidepressant use during pregnancy and risk of postpartum hemorrhage: A systematic review and meta-analysis. Journal of Psychiatric Research, 83, 160–167.
23. Sriraman, N. K., Melvin, K., Meltzer-Brody, S., & the Academy of Breastfeeding Medicine. (2015). ABM Clinical Protocol #18: Use of Antidepressants in Breastfeeding Mothers. Breastfeeding Medicine, 10(6), 290–299.