Milnacipran Hydrochloride - Uses, Dosage, and Side Effects

Overview:

Milnacipran hydrochloride is one of the three approved drugs by the U.S. Food and Drug Administration (FDA) for treating fibromyalgia. The other two drugs are Pregabalin and Duloxetine. Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It was only approved in The United States for fibromyalgia cases in 2009.

It is similar to other drugs used in depression and other psychiatric disorders but is not marketed as an antidepressant. Milnacipran is present in many countries for the use of depression, but it is not an opioid. Instead, it is a non-narcotic drug with low-risk rates.

What Is Fibromyalgia?

Fibromyalgia is a chronic illness with musculoskeletal pain that affects muscles and joints. In addition, it may also cause fatigue, sleep, and memory issues. The pain associated with the condition keeps on coming and going. Although there are no known causes of fibromyalgia, it can occur due to genetic or other factors like anxiety, depression, and viral infections. It usually affects middle-aged women, but men and young adults can also be affected.

What Are the Symptoms of Fibromyalgia?

Symptoms associated with fibromyalgia are:

• Widespread muscle and joint pain.

• Anxiety or depression.

• Diarrhea or constipation.

• Headaches.

• Memory issues.

• Numbness in hand.

• Facial pain.

• Difficulty in falling asleep.

How Is Fibromyalgia Diagnosed?

There are no definitive tests to diagnose fibromyalgia. The diagnosis of fibromyalgia is entirely based on clinical examination. Although basic blood tests to define the blood amount and infection in the blood are performed. The diagnosis is dependent upon the patient's symptoms and medical history. However, the presence of widespread pain for at least three months and 11 tender points with 18 anatomic sites is the criteria used by the American College of Rheumatology for the diagnosis of fibromyalgia.

What Happens in the Body in Fibromyalgia?

It is a central nervous system disorder that increases pain sensitivity. The pain perception is due to excessive spinal nerve signaling to higher cortical pain regions and a decrease in descending cortical mechanism. These pathways are channelized by multiple neurotransmitters, including serotonin and epinephrine. Thus, abnormal functioning of serotonin and epinephrine in ascending and descending pathways leads to painful fibromyalgia symptoms.

How Does Milnacipran Hydrochloride Work for Fibromyalgia?

Milnacipran hydrochloride increases the neurotransmitters serotonin and norepinephrine levels, which are usually low in fibromyalgia patients. It increases the level of norepinephrine more than serotonin. It works by increasing the amount of serotonin, norepinephrine, and natural substances that help stop the movement of pain signals in the brain.

Dosage Restrictions:

Route of Administration - oral.

Dosage Strength - 12.5 mg, 25 mg, 50 mg,100 mg tablets.

Dose form - Off-white crystalline powder, film-coated tablets, or dose-titration pack.

Recommendation for Dose

• The first dose of Milnacipran is taken once on day one.

• Afterward, it is taken twice a day.

• It can be taken with or without food.

• Taking the dosage at the same time every day is recommended.

Pharmacokinetics of Milnacipran

Absorption and Distribution

• Bioavailability - 85 to 90 percent.

• The volume of distribution is 400 liters.

• Peak concentration- 2 hours to 4 hours after dose intake.

• Plasma protein concentration - 13 percent.

Metabolism and Elimination

• Half-life - 6 hours to 8 hours.

• Excreted by kidneys through urine.

Use of Milnacipran Hydrochloride

Milnacipran hydrochloride is only used for the condition of fibromyalgia.

Uses of Milnacipran Hydrochloride Under Special Considerations

Renal Insufficiency

Mild renal insufficiency patients do not require dose adjustments. However, caution is needed for moderate renal impairment patients. The patient with severe renal insufficiency requires a maintenance dose reduced up to 50 percent with 25 mg divided doses. It is not advised for end-stage patients.

Hepatic Impairments

No dosage adjustments are used in hepatic impairment patients. But still, a caution check is required.

Elderly Patients

Older patients are those above 60 years of age. Milnacipran is safely used in elderly patients with depression. However, fewer side effects like nausea can appear, but better results than other drugs.

Pregnant Women and Breastfeeding Mothers

No cases have been reported using Milnacipran in pregnant and breastfeeding mothers. Therefore, Milnacipran can be used in pregnant women only if it is beneficial and not risky for the fetus. The use of Milnacipran in breastfeeding mothers is not recommended because Milnacipran can be excreted in the mother's milk and hence affects the baby.

Pediatric Patients

The use of Milnacipran in the child population is not being done, and no evidence has been found for the safety of the pediatric population.

Contraindications of Milnacipran Hydrochloride

• The use of Milnacipran hydrochloride is prohibited in cases of narrow-angle glaucoma. It can cause mydriasis and further pupil dilation, leading to a limited flow of aqueous humor and even increasing intraocular pressure.

• Milnacipran is contraindicated in patients already taking monoamine oxidase (MAO) inhibitors.

• Milnacipran can cause high blood pressure and heart rate, so it is used cautiously in patients with hypertension.

• Milnacipran can elevate liver enzymes, so regular checking of liver functioning is necessary with Milnacipran.

• It is contraindicated in the patient who is allergic to Milnacipran.

• Contraindicated for pregnant women and breastfeeding mothers.

• Contraindicated for the patient with an increased risk for suicidal activity as it affects the thinking and behaviors of the patient.

• Contraindicated for the pediatric population under 17 years of age.

For Patients

What Is Milnacipran Hydrochloride?

Milnacipran hydrochloride is the medicine used in the treatment of fibromyalgia. Fibromyalgia is a chronic illness with severe muscle and joint pains, fatigue, and stress. The use of Milnacipran hydrochloride in fibromyalgia has helped to ease pain and fatigue and improve sleep.

Why Is It Prescribed in Fibromyalgia Cases?

It increases the amount of serotonin and epinephrine, which are usually low in fibromyalgia cases. The increased level of serotonin helps stop the pain signals going to the brain. It is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It further controls the pain in joints and muscles, leading to better results and sound sleep.

How Should It Be Used?

It is taken in tablet form by mouth. The dose of Milnacipran should be increased slowly; it is not recommended to start abruptly with a high dose of 100 mg. The first dose of Milnacipran (12.5 mg) is taken once on day one. Afterward, it is taken twice a day by increasing the dose up to 100 mg in the following days.

What Are the Precautions Taken While Having Milnacipran Hydrochloride?

Precautions are:

• It can be taken with or without food, but usually with food so that it does not upset the stomach.

• Taking medicine every day at the same time.

• Taking the dose as recommended by the doctor.

• Start with a low dose and increase it gradually.

• Do not abruptly stop taking medicine; ask the doctor; the doctor will gradually decrease the dose.

What Should You Inform Your Doctor Before He Suggests Milnacipran?

Before starting milnacipran hydrochloride, inform the doctor before he suggests the Milnacipran to you.

• If Milnacipran is allergic to you, inform the doctor.

• Inform the doctor if you are taking other medications like blood thinners.

• Do inform the doctor if you take any nutritional supplements.

• Inform the doctor about your medical conditions like high blood pressure or seizures.

• If you are an alcoholic, do let the doctor know.

• Inform your pregnancy or if you are planning to be pregnant.

• Let your dentist know about the Milnacipran dose if any dental surgery is required.

• If the patient is suffering from glaucoma, then Milnacipran hydrochloride is contraindicated.

• Milnacipran is also not suggested to the patient on monoamine oxidase (MAO) medicine; the doctor will not allow you to take both medications together. He will recommend waiting for 14 days after MAO withdrawal and Milnacipran starting.

What Are the Side Effects of Milnacipran?

Side effects of Milnacipran are,

• Nausea.

• Vomiting.

• Constipation.

• Stomach pain.

• Weight loss.

• Dry mouth.

• Headache.

• Blurred vision.

• Tiredness.

• Lack of energy.

• Facial warmth or sometimes redness over the face.

• Loss of appetite.

• Sexual problems in both males and females like decreased sex drive.

• Difficulty in urination.

• Rashes.

• Itchiness.

• Pain and swelling of testicles.

What Are the Warning Signs of Milnacipran?

Warning signs are the side effects that can be serious. If you have any of it, consult your doctor as soon as possible.

Warning signs are:

• Fever with sweating and irregular heartbeat.

• Severe muscle stiffness.

• Nausea and vomiting.

• Diarrhea.

• Hallucinations.

• Confusions.

• Memory issues.

• Dizziness.

• Difficulty while concentrating.

• Weakness.

• Falling while walking.

• Shaking body parts.

• Seizures.

• Fainting.

• Coma-like state (temporary unconsciousness).

• Irregular heartbeat.

• Difficulty in breathing.

• Pain in the upper right part of the stomach.

• Unusual bruising.

• Unusual bleeding.

• Red spots under the skin.

What if You Missed a Milnacipran Dose?

If you missed a Milnacipran dose on routine and timings, take the missed dose as soon as you remember. However, if the timing of the next dose is almost near, take the next dose and skip the previous one. Do not take both doses together.

What Diet Should You Take Along With Milnacipran Medicine?

The diet should be regular and continued as it was before the Milnacipran. But if your doctor recommends you to have another supplement diet, you can have that only if your doctor says.

How to Store Milnacipran Medicine?

The Milnacipran medicine is stored in tightly closed containers. And store it at room temperature. The medicine should keep away from excess heat and moisture.

How to Dispose of the Milnacipran Medicine?

The medicine should be disposed of appropriately; there is a certain medicine take-back program to dispose of it. The FDA provides special instructions for the safe disposal of medication to dispose of the medicine. The medicine should not be flushed out of the toilet. All these instructions and take-back programs are performed so that no pet, child, or other person unknowingly consumes the medicine.

What Are the Important Points Regarding the Use of Medicine?

Important points are:

• Do not let any other person or pet take your medicine.

• Do let the doctor know your symptoms after using it.

• Do visit the doctor on regular follow-up visits.

• Do inform the doctor about other medications or supplements you take.

• Do not stop the medicine on your own; inform your doctor before withdrawal so that that doctor can prescribe better ways of withdrawal. Otherwise, it can show withdrawal symptoms like mood changes, dizziness, numbness of hands, anxiety, headache, confusion, and tiredness with sleep difficulty.

Does Milnacipran Medicine Cure Fibromyalgia?

No, Milnacipran does not cure fibromyalgia. However, it can help to control the symptoms of fibromyalgia. In addition, it helps ease pain and fatigue and improves the patient's sleep.

For Doctor

What Are the Chemical and Physical Properties of Milnacipran Hydrochloride?

Chemical Properties:

• The chemical name of Milnacipran hydrochloride is 2-(amino-methyl)-N, N-diethyl-1-phenyl cyclophane-carboxamide HCL.

• Its empirical formula is C15H23CIN20.

• The molecular weight is 282.8 g/mol.

• It is an off-white crystalline powder.

• Its melting point is 179-degree Celsius.

• It is soluble in water, methanol, ethanol, chloroform, and methylene chloride.

• It is sparingly soluble in diethyl ether.

Physical Properties :

• It is taken orally.

• It is present in tablet form in 12.5 mg, 25 mg, 50 mg, and 100 mg.

• It should store between 59-degree Celsius to 86-degree Celsius.

Pharmacology of Milnacipran Hydrochloride:

Milnacipran hydrochloride is a serotonin and norepinephrine reuptake inhibitor (SNRI) that inhibits serotonin and norepinephrine reuptake. It has a mild affinity for inhibiting N-methyl-D-aspartate (NMDA). Its mechanism is unknown till now, but it is clear that it affects the noradrenergic and serotonergic pathways. It does not affect the uptake of dopamine and Benzodiazepine.

Pharmacokinetics of Milnacipran:

Absorption

After oral intake, the drug is rapidly absorbed and expresses maximum concentration at two to four hours. Milnacipran has a high bioavailability of approximately 85 to 90 percent. Therefore, its first-pass mechanism is limited.

Distribution

Milnacipran has low plasma protein binding of nearly 13 percent. As it has low protein binding, it is free to diffuse and is distributed all over the body from 0.4 liter/kilogram to 5.3 liter/kilogram.

Metabolism

Glucuronidation pathways metabolize Milnacipran. As going through phase 2 conjugation, Milnacipran forms inactive metabolites. The metabolites formed are L-milnacipran carbamoyl-O-glucuronide and D-milnacipran carbamoyl-O-glucuronide. They constitute nearly 20 percent of the excreted drug. The parent drug Milnacipran goes for therapeutic effects. The drug also goes for N-dealkylation by cytochrome P450 enzyme, but only 8 percent of the drug goes.

Elimination

The kidneys eliminate Milnacipran and its inactive metabolites. As a result, about 50 to 60 percent of the initial drug dose is excreted in the urine. The half-life of Milnacipran is between six to eight hours and forms a stable level of the dose that appears in the blood in 36 hours to 48 hours.

Recommended Dosage for Milnacipran

The Milnacipran dose starts slowly with a lower dose and gradually increases. The dose keeps on varying within a week.

The seven-day schedule for the milnacipran dose is as follows:

• Day 1 - The dose is started with 12.5 mg once daily.

• Day 2 to 3 - the dose is increased to 25 mg daily but taken twice daily as 12.5 mg.

• Day 4 to 6 - the dose is again increased to 50 mg daily, but taken twice a day as 25 mg.

• Day 7 - the dose is increased to 100 mg daily but taken twice a day as 50 mg.

• The dose can be increased to 200 mg twice daily, taken as 100 mg at once.

The dosage should adjust for each patient, and the patient should not discontinue the drug intake abruptly as it can cause withdrawal symptoms.

Special Considerations:

Renal Insufficiency

The patient with mild effects on kidneys can take the dose as other regular patients. But then, moderate renal insufficiency patients should cautiously use the drug. Patients with severe renal insufficiency should intake 25 mg daily (50 percent reduced to 50 mg). Patients with renal failure end stage are not advised to use Milnacipran.

Hepatic Insufficiency

Patients with hepatic issues can take the dose prescribed for regular patients, but caution is essential in these cases.

Geriatric Patients

Patients with ages more than sixty come under geriatric. Milnacipran can be used in older patients as the effects are lesser than other drugs. However, dry mouth and nausea are a few side effects probably visible in them.

Pregnancy

If the patient is pregnant, Milnacipran should be used cautiously. Milnacipran should be used if the drug has more benefits than the fetus's risks.

Lactating Mothers

Lactating mothers are not advised to have the Milnacipran drug as the mother's milk can excrete the Milnacipran, which the baby can take up.

Pediatric Patients

Drug safety has not been justified in the pediatric population. Hence children below 17 years of age are not recommended for the Milnacipran drug.

Indication of Milnacipran:

Milnacipran is indicated in cases of fibromyalgia. It helps to control the symptoms of fibromyalgia and soothes the patient to live pain-free. However, it does not cure fibromyalgia completely.

Contraindications of Milnacipran:

• It is not used in cases of narrow-angle glaucoma as Milnacipran may result in mydriasis and further dilated pupils, which would restrict the passage of aqueous and possibly raise intraocular pressure.

• Combining monoamine oxidase inhibitors and Milnacipran is not recommended as it can cause serotonin syndrome and hypertensive crisis.

• Individuals with suicidal tendencies are not advised to have Milnacipran, as the drug may increase the risk of developing suicidal ideation and thoughts.

Cautious Use of Milnacipran:

• The reports have been seen in cases with selective serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI). When used can cause neuroleptic malignant syndrome (NMS), so the doctor should watch out if any symptoms appear.

• Milnacipran is used cautiously in patients with hypertension and elevated heart rate.

• Milnacipran can develop a mild increase in liver enzymes. If the doctor notices any liver dysfunction symptoms, he should start withdrawing the drug.

Adverse Effects of Milnacipran

Adverse effects and discontinuing symptoms are almost similar to the Milnacipran drug. They are:

• Nausea

• Constipation.

• Hot flushes.

• Hyperhidrosis (excessive sweating).

• Vomiting.

• Palpitation.

• Increased heart rate.

• Dry mouth.

• Hypertension.

• Weight loss.

Drug Interactions of Milnacipran

• Milnacipran interaction with the CYP450 enzymes on going through phase 2 conjugation reduces its chances of interacting with CYP isoenzymes.

• Monoamine oxidase (MAO) inhibitors are drug interactions that are contraindicated.

• Other agents like antidepressants, antipsychotic drugs, and lithium are prohibited along with Milnacipran because they can form 5-HT and neuroleptic malignant syndrome-like symptoms.

• Medicine that increases the blood pressure and heart rate should be used cautiously in a patient who is taking Milnacipran because Milnacipran can also cause high blood pressure.

Clinical Efficacy of Milnacipran

• It was done to check the efficacy of Milnacipran in fibromyalgia cases. It was performed by Gendreau et al. in 2002. It was completed in phase 2, for three months at multicenter, with the randomized and double-blind trial study of drug and placebo. One hundred twenty-five patients were selected from march 2002 to December 2002. The adults took drugs once daily, Milnacipran twice daily, or a placebo for three months.

For the study, the patient selected was:

• The patients should be Between 18 to 70 years of age.

• Has American College of Rheumatology criteria for diagnosing fibromyalgia.

• Have a pain score of 10.

• Have gone through other therapies for treating fibromyalgia.

The study has a screening, a washout phase, a baseline assessment, a dose-titration phase, and a stable-dose phase.

Primary Endpoint Efficacy

The efficacy evaluated was the patient's average daily pain score in electronic dairy.

Secondary Endpoint Efficacy

The secondary efficacy includes weekly pain scores by e-dairy and pain assessments by visual analog or Gracely pain scale.

Results

Both the Milnacipran groups with once-daily and twice-daily doses have reduced daily pain scores, and pain reports for the placebo were higher than those. However, results of twice-daily Milnacipran have significantly lower pain scores and intensity in all the secondary efficacy evaluations (P<0.05) and significantly lower weekly e-dairy pain scores (-3.1+3.5; P=0.025) as compared to placebo (-1.14+3.79). The once-daily dose does not result in a statistically significant reduction in pain scores in the primary and secondary evaluations. Overall, Milnacipran effectively reduced the pain of fibromyalgia, but twice-daily dosing was necessary for efficacy and tolerability.

• The study was done by Clauw et al. for the efficacy and tolerability of Milnacipran evaluation within 15 weeks, the multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial of adults with fibromyalgia. The patient is made to take a Milnacipran drug dose of 100 mg per day or 200 mg per day or a placebo for 15 weeks. The study was performed at 86 centers in the U.S. from November 2004 to December 2006. One thousand one hundred ninety-six patients were chosen for the Milnacipran dose.

The patient selected for the study are:

• The patient should be between 18 to 70 years.

• Should have fibromyalgia according to criteria.

• The patient has undergone other treatments for fibromyalgia.

• Have discontinued treatment for trigger points or narcotic patches, or acupuncture.

• The fibromyalgia impact questionnaire should have a raw score of 4 or higher.

Milnacipran patients received 12.5 mg on day 1, 12.5 mg twice on day 2, 25 mg twice for four days, and 50 mg twice a day on day 7. The patient with 200 mg received 100 mg twice daily for seven days.

Primary Endpoints

• The number of patients experiencing more than 30 percent improvement from the baseline with 24-hour pain was highest, with Milnacipran 200 mg per day compared to 100 mg per day.

Results

Results showed an improvement in pain score in the patient with 200 mg per day and 100 mg per day. 200 mg per day of Milnacipran has improved 30 percent more than 100 mg daily. But discontinuation of the drug has expressed some adverse effects in the patients having Milnacipran than placebo. Adverse effects were attributed as 23.7 percent in 200 mg per day, 19.5 percent in 100 mg per day, and 9.5 percent in placebo. Overall, Milnacipran showed significant efficacy over a placebo for treating fibromyalgia. However, higher doses of 200 mg are associated with more adverse effects.

• Another study was performed by Mease et al. as a randomized, double-blind to confirm the safety and efficacy of Milnacipran in fibromyalgia cases. It was a 27-week study with milnacipran 100 mg/day and 200 mg/day with placebo. Eight hundred eighty-eight patients were selected from 59 centers in the U.S. to receive Milnacipran 100 mg/day, Milnacipran 200 mg/day, and placebo in two divided doses for six months. The study has four phases: screening, washout, baseline, and dose-escalation phase. In the final phase, the patient receives stable doses for 24 weeks. The patient selection criteria were similar to the previous clinical trial.

Primary Endpoint

At the end of the study, more patients in both Milnacipran groups met the criteria for a response for treating fibromyalgia pain.

Results

Although the results with the Milnacipran were good, as improvements were significantly observed during the study, the rate of discontinuation with Milnacipran was extremely high. Nearly at week 27, 42.9 percent of patients with 100 mg/day, 45.8 percent with 200 mg/day, and 35 percent of patients with placebo had discontinued therapy. Therapeutic failure was the second reason for discontinuing Milnacipran. For example, 11.1 percent of patients taking 200 mg/day stopped, and 11.6 percent of 100 mg/day withdrew. And a higher percentage of 15.2 percent suffer therapeutic failure with a placebo. So, overall, Milnacipran improves the patient's pain but causes side effects with higher dosages.