Milnacipran

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant that is used to treat chronic pain caused by fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸. Milnacipran was approved for use in the United States in 2009 to treat chronic pain caused by fibromyalgia ⁹. Milnacipran works by increasing the amount of serotonin and norepinephrine, natural neurotransmitters that help stop the movement of pain signals in your brain.

Milnacipran (Savella) comes as a 12.5 mg, 25 mg, 50 mg, and 100 mg mg tablets to be taken by mouth. Milnacipran is initiated at 12.5 mg daily, and the dose is increased by 12.5 mg every few weeks until reaching a maximum of 50 to 100 mg, taken once or twice daily. Clinical trials indicate an average effective dose of 100 mg/day. The recommended Milnacripran dosage is 50 mg twice daily after a 7 day titration schedule.

Milnacipran should be administered in two divided doses per day. The general titration table goes as follows: day 1: 12.5 mg once, days 2-3: 25 mg/day (12.5 mg twice daily), Day 4-7: 50 mg/day (50 mg twice daily), Day 7, and after 100 mg/day (50 mg twice daily) ¹⁰ The recommended dosage of 100 mg (50 mg twice daily) can be increased up to 200 mg/day depending on the individual patient ¹⁰.

The first dose of milnacipran is usually taken once on day 1 of therapy. After that, it is usually taken two times a day. Milnacipran may be taken with or without food, but taking it with food will decrease the chance that milnacipran will upset your stomach. Take milnacipran at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take milnacipran exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will start you on a low dose of milnacipran and gradually increase your dose during the first week of treatment.

Milnacipran may help control the symptoms of fibromyalgia, but will not cure it. It is important that your doctor check your progress at regular visits to allow for changes in your dose and to help reduce any side effects. Blood and urine tests may be needed to check for any unwanted effects.

Do not stop taking milnacipran without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking milnacipran, you may experience withdrawal symptoms such as mood changes, irritability, agitation, dizziness, numbness or tingling in the hands or feet, anxiety, confusion, headache, tiredness, difficulty falling asleep or staying asleep, ringing in the ears, abnormal excitement, or seizures. Tell your doctor if you experience any of these symptoms when your dose of milnacipran is decreased.

Common side effects of milnacipran include nausea, vomiting, constipation, headache, sweating, increased heart rate, palpitations, testicular pain, urinary hesitancy and erectile dysfunction. When used with other serotonin reuptake inhibitors, milnacipran can be associated with serotonin syndrome. Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin activity in your brain, often triggered by drug interactions or overdose, and characterized by a combination of mental, autonomic, and neuromuscular symptoms. Symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure and rapid heart rate. Get medical help right away if you have any of these symptoms. Severe serotonin syndrome can be life-threatening due to complications like seizures, hyperthermia (high body temperature), and organ damage. Serotonin syndrome happens most often when you take two medicines that both raise serotonin levels. This includes taking an serotonin and norepinephrine reuptake inhibitor (SNRI) with other antidepressants (selective serotonin reuptake inhibitors (SSRIs) + SNRIs), migraine medications (triptans), certain pain or headache medicines, the herbal supplement St. John’s wort or even some illicit drugs.

How does Milnacipran work?

Milnacipran is an selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that works by increasing the amount of serotonin and norepinephrine, natural neurotransmitters that help stop the movement of pain signals in your brain. Milnacipran is highly advantageous for fibromyalgia therapy as it does not interrupt the cytochrome P450 enzymes for drug metabolism. In mice studies, milnacipran has been shown to stimulate clonidine-aggressiveness in mice and activate the overexpression of alpha1-adrenoreceptor ¹¹. After continued exposure to treatment with milnacipran showed unresponsiveness of the serotonin 5HT2A receptors with their agonists and downregulation of the 5HT2A system ¹¹. For neurotransmitter receptors, it has been concluded that milnacipran does not show these neurological changes certainly in the alpha1-adrenergic and serotonin 5HT2A pathways ¹¹.

The ability of milnacipran to modify to serotonin 5HTA1 autoreceptors and postsynaptic serotonin 5HTA1 receptors has been elucidated in rats. As seen in an electrophysiological recording of the dorsal raphe nucleus, serotonin blocks the 5HT1A receptor antagonism ¹². Milnacipran only slightly knocked down the firing of the 5-HT system upon three days of administration but significantly did after 7 or 14 days of treatment ¹². Milnacipran also decreased the potency of the serotonin (5HT) system, unlike similar tricyclic antidepressants (TCAs) such as imipramine ¹². The CA1 potential in hippocampal slices of these rats were unchanged; therefore, milnacipran was demonstrated to deaden the somatodendritic 5HT1A receptors as opposed to the postsynaptic receptors ¹³.

The activity of the dorsal raphe neurons and locus coeruleus neurons can be measured in chloral hydrate anesthetized rats ¹⁴. Extracellular unitary recordings can measure the activity. Through 2,7, and 14-day treatments of milnacipran significantly tuned down the activity of norepinephrine neurons ¹⁴. The total level of norepinephrine is unaffected but by the alpha2-adrenergic effects. Following a similar treatment regimen with milnacipran, serotonin activity completely recovered by 14 days ¹⁴. Norepinephrine uptake in the hippocampal areas was decreased but not serotonin uptake. Through further studies in norepinephrine-denervated mice, milnacipran did not affect the dorsal raphe nucleus ¹⁴. Milnacipran allows serotonin recovery by some mechanism related to norepinephrine neurons.

Milnacipran uses

Milnacipran is an selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that is US Food and Drug Administration (FDA) approved to treat chronic pain caused by fibromyalgia (a medical condition that causes chronic pain in the muscles and joints) ¹⁵, ¹, ⁸. Milnacipran is initiated at 12.5 mg daily, and the dose is increased by 12.5 mg every few weeks until reaching a maximum of 50 to 100 mg, taken once or twice daily. Clinical trials indicate an average effective dose of 100 mg/day ⁸. Milnacipran has been shown to improve pain and fatigue levels in patients with fibromyalgia but can cause sleep problems and depressive symptoms ¹⁶. Milnacipran has a clinical benefit of improving 30% or more significant pain relief but not for 50% or greater ¹⁷. Milnacipran is intended to reduce pain levels, improve fibromyalgia, and ease physical activity.

Milnacipran is only approved for adults 18 years and older and is only available by prescription ¹⁵. Milnacipran is not approved for children. It can cause suicidal thoughts and ideations in some participants. Importantly, it is not used to treat depression and psychiatric conditions, but its mechanism of action is very similar to antidepressant medications. Milnacipran should never be taken with a monoamine oxidase inhibitor (MAOI) as it could cause potentially life-threatening serotonin syndrome side effects ¹⁵.

What to know before taking Milnacipran

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do.

Milnacipran may cause some teenagers and young adults to be agitated, irritable, or display other abnormal behaviors. Milnacipran may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, tell your doctor right away. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Do not take Milnacipran during 14 days after stopping a monoamine oxidase inhibitor (MAOI) (eg, isocarboxazid [Marplan], linezolid [Zyvox], methylene blue injection, phenelzine [Nardil], selegiline [Eldepryl], or tranylcypromine [Parnate]). Do not take an monoamine oxidase (MAO) inhibitor for at least 5 days after stopping Milnacipran. Talk to your doctor about this if you have questions.

Make sure your doctor knows if you are also using aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, naproxen, Advil, Aleve, Celebrex, Motrin), or a blood thinner (eg, warfarin, Coumadin). Milnacipran may increase your risk of bleeding problems when taken together with these medicines.

Milnacipran may cause a serious condition called serotonin syndrome when taken with certain medicines such as St. John’s wort, buspirone, fentanyl, lithium, tryptophan, amphetamines, other medicines to treat depression, or some pain or migraine medicines (eg, rizatriptan [Maxalt], sumatriptan [Imitrex], tramadol [Ultram], or zolmitriptan [Zomig]. Check with your doctor first before taking any other medicines. Check with your doctor right away if you have anxiety, restlessness, a fast heartbeat, fever, sweating, muscle spasms, twitching, nausea, vomiting, diarrhea, or see or hear things that are not there.

You will also need to have your blood pressure and pulse measured before starting and while you are using Milnacipran. If you notice any change to your recommended blood pressure or pulse rate, call your doctor right away. If you have questions about this, talk to your doctor.

Check with your doctor right away if you have clay-colored stools, dark urine, decreased appetite, fever, headache, itching, loss of appetite, nausea and vomiting, skin rash, stomach pain or tenderness, swelling of the feet or lower legs, unusual tiredness or weakness, or yellow eyes or skin. These may be symptoms of a serious liver problem.

Avoid drinking alcohol while you are using Milnacipran.

Milnacipran may cause some people to become less alert than they are normally. Do not drive or do anything else that could be dangerous until you know how Milnacipran affects you.

Milnacipran may cause hyponatremia (low sodium in the blood). This is more common in elderly patients, those who are taking diuretic medicines for high blood pressure, or those who have decreased amounts of fluid in the body due to severe diarrhea or vomiting. Check with your doctor right away if you have confusion, headache, memory problems, trouble concentrating, weakness, or feel unsteady when standing.

Check with your doctor right away if you have decreased interest in sexual intercourse, delayed or inability to have and orgasm in women, inability to have or keep an erection in men, or loss in sexual ability, desire, drive, or performance. These could be symptoms of sexual dysfunction.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John’s wort) or vitamin supplements.

The presence of other medical problems may affect the use of Milnacipran. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse
• Bleeding
• Depression
• Enlarged prostate
• Glaucoma, angle-closure
• Heart disease
• Heart rhythm problems (eg, tachyarrhythmia)
• Hypertension (high blood pressure)
• Hyponatremia (low sodium in the blood)
• Liver disease
• Mania
• Painful or difficult urination
• Seizures
• Urinary tract blockage: Use with caution. May make these conditions worse.
• End stage kidney disease: Use is not recommended in patients with this condition.
• Kidney disease, moderate or severe: Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to Milnacipran or any other medicines. Also tell your doctor if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children

Appropriate studies have not been performed on the relationship of age to the effects of milnacipran in the pediatric population. Safety and efficacy have not been established.

Elderly

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of milnacipran in the elderly. However, elderly patients are more likely to have hyponatremia (low sodium in the blood) and age-related kidney problems, which may require an adjustment in the dose for patients receiving milnacipran.

Pregnancy

Taking Milnacipran during pregnancy may cause serious lung problems or other complications in the baby. See your doctor right away if you become pregnant. Do not start or stop taking milnacipran during pregnancy without your doctor’s advice. If you are pregnant, your name may be listed on a pregnancy registry to track the effects of milnacipran on the baby.

Breastfeeding

Amounts of milnacipran in breastmilk are low and would not be expected to cause any adverse effects in breastfed infants ¹⁸. However, until more data become available, milnacipran should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant ¹⁸.

Eight lactating women who were at least 12 weeks following childbirth and weaning their infants received a single oral dose of milnacipran 50 mg. The average peak milk level of milnacipran was 262 mcg/L at an average of 4 hours and the average milk level was 122 mcg/L. The average relative infant dosage was estimated to be 2.8% of the weight-adjusted maternal dosage or 5% using the peak milk levels. Milnacipran was eliminated from milk with an average half-life of 7.5 hours ¹⁹, ¹⁵.

Galactorrhea (inappropriate lactation or milk production from the breast unrelated to pregnancy or lactation) is reported by the manufacturer to be a side effect of milnacipran ¹⁵. One woman who was being treated for depression took an intentional overdose of 950 mg of milnacipran orally. From day 5 to day 15 after the overdose, the patient noted a flow of milk from her left breast. The galactorrhea resolved without treatment ²⁰.

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking Milnacipran, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using Milnacipran with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Isocarboxazid
• Linezolid
• Methylene Blue
• Metoclopramide
• Ozanimod
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Tranylcypromine

Using Milnacipran with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Alfentanil
• Almotriptan
• Amifampridine
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Anileridine
• Apixaban
• Ardeparin
• Argatroban
• Aspirin
• Avitriptan
• Azathioprine
• Bemiparin
• Benperidol
• Benzhydrocodone
• Benzphetamine
• Betrixaban
• Bivalirudin
• Bromfenac
• Brompheniramine
• Bufexamac
• Buprenorphine
• Bupropion
• Buspirone
• Butorphanol
• Cangrelor
• Carbamazepine
• Celecoxib
• Certoparin
• Chlorpheniramine
• Choline Salicylate
• Plus many more not on this list.

Milnacipran Dosage

The dose of Milnacipran will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of Milnacipran. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (tablets)

• For treatment of fibromyalgia
  • Adults: At first, 12.5 milligrams (mg) once a day on Day 1. 12.5 mg 2 times a day on Days 2 to 3. 25 mg 2 times a day on Days 4 to 7. 50 mg 2 times a day after Day 7. Your doctor may adjust your dose as needed. However, the dose is usually not more than 200 mg per day.
  • Children: Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of Milnacipran, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Milnacipran Side Effects

Milnacipran may cause side effects. See your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• constipation
• stomach pain
• weight loss
• dry mouth
• feeling of extreme facial warmth and/or redness
• headache
• blurred vision
• extreme tiredness
• lack of energy
• loss of appetite
• sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation
• sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm
• pain or swelling of the testicles
• difficulty urinating
• rash
• itching

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING or SPECIAL PRECAUTIONS section, see your doctor immediately or get emergency medical treatment:

• fever, sweating, confusion, fast or irregular heartbeat, severe muscle stiffness or twitching, nausea, vomiting, or diarrhea
• hallucinations (seeing things or hearing voices that do not exist)
• confusion
• difficulty concentrating
• memory problems
• sweating or fever
• diarrhea
• dizziness
• uncontrollable shaking of a part of the body
• severe muscle stiffness
• weakness
• unsteady walking that may cause falling
• seizures
• fainting
• coma (loss of consciousness for a period of time)
• fast or irregular heartbeat
• difficulty breathing
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• dark colored urine
• unusual bleeding or bruising
• nosebleeds
• tiny red spots directly under the skin

Milnacipran may cause other side effects. Call your doctor if you have any unusual problems while you are taking milnacipran.

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