Milnacipran Hydrochloride (MIL) Uses in Medicine Essay

Milnacipran hydrochloride (MIL) is a selective serotonin and norepinephrine reuptake inhibitor. It was originally developed and manufactured by Pierre Fabre Medicament in France, and was approved in that country as an antidepressant in 1997 [1]. It has since been approved for this indication in multiple countries and currently marketed for this indication in over 45 countries worldwide including several European countries. Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for fibromyalgia purpose in the United States and Canadain 2003 from the manufacturer Pierre Fabre Laboratories [2-3]. Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

In January 2009 the U.S. Food and Drug Administration (FDA) approved MIL only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States [4].

Some of the drug information and properties are listed below:

2.1 Physical and chemical properties

Chemical name : MIL is chemically designated as (1R,2S)-rel-2(Amino-methyl)-N,N-diethyl-1-phenyl-cyclopropanecarboxamide hydrochloride and its structure is shown in Figure 2.1.

Synonyms : F-2207; Ixel; Toledomin; Dalcipran; Milnacipran Hydrochloride.

Empirical formula : C₁₅H₂₂N₂O. HCl

Molecular weight : 282.8

CAS No. : 101152-94-7

Melting point: 179°C

Physical description : MIL is a white to off-white, odourless, crystalline powder.

Dissociation constant (pKa) : 9.65

Permeability coefficient (Log P) : 1.42

Solubility : It is freely soluble in aqueous buffers over the entire physiological pH range. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether [5-6]. Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

BCS class : Class I, highly soluble and highly permeable drug.

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2.2 Pharmacological properties

Mechanism of Action

Milnacipran blocks 5-HT and norepinephrine (NE) reuptake into the neuron, thereby increasing 5-HT and NE extracellular concentrations. This activates 5-HT and NE auto and heteroreceptors culminating in a decreasing 5-HT and NE neuronal firing rates, synthesis, and release. On Chronic use MIL continues to block 5-HT and NE transporters without desensitization, but 5-HT and NE auto- and heteroreceptors are desensitized and thus, down regulated. Firing rates of 5-HT and NE return to normal, and the amount of 5-HT and NE released per nerve impulse is increased [7].

MIL has no significant affinity for α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, or γ-aminobutyric acid (GABA) receptors. MIL has no significant affinity for Ca²⁺, K⁺, Na⁺ and Cl^– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase [8-9].

One of the main differences between the various antidepressants and MIL is its equal preference and activity on the uptake of NE and 5-HT. The exact mechanism of the central pain inhibitory action and effectiveness in fibromyalgia symptom are unknown in Humans [10-11].

2.3 Therapeutic Indications

Treatment of depression

Major Depression, also known as major depressive disorder or unipolar depression, is a highly debilitating disorder that has been estimated to affect up to 21% of the world population [12]. It is a CNS disorder characterised by a combination of symptoms that interfere with a person’s ability to work, sleep, study, eat, and enjoy pleasurable activities [7,12].

Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects.Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.  These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas [12].

Management of Fibromyalgia

Fibromyalgia (FM) is a complex syndrome characterized by chronic musculoskeletal pain which is often accompanied by multiple other symptoms, including fatigue, sleep disturbances, decreased physical functioning, and dyscognition. Due to these multiple symptoms, as well as high rates of comorbidity with other related disorders, patients with FM have a reduced quality of life. The reduced serotonin and norepinephrine levels observed in patients with FM suggest that medications which increase the levels of these neurotransmitters, such as serotonin and norepinephrine reuptake inhibitors (SNRIs), may have clinically beneficial effects in FM and other chronic pain conditions. MIL is an SNRI that has been approved for the management of FM [8, 13]. MIL was viewed as a wonderful new weapon in the fight against both depression and pain.

Treatment of Lupus

Recent studies proved that MIL is also useful against lupus. Lupus is a chronic autoimmune disease in which the immune system turns against the body and harms healthy cells and tissues. It is a rheumatic disease which can affect many parts of the body including the joints, skin, kidneys, lungs, heart or brain. Some of the most common symptoms include extreme fatigue, painful or swollen joints, unexplained fever, skin rashes, and kidney problems. Scientific evidence indicates that lupus is caused by a combination of genetic and environmental factors. Lupus is characterized by periods of increased or intensified disease activity, called flares [14-15]. Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

Tolerability and side effects

MILhas demonstrated numerous adverse reactions in human clinical trials with tolerability decreasing with an increasing dose. In the placebo controlled trials in patients with fibromyalgia, the most frequent spontaneously reported adverse events were as follows: nausea, palpitations, headache, constipation, increased heart rate and hyperhidrosis, vomiting, and dizziness [16]. Discontinuation due to adverse reactions was generally more common among patients treated with 200 mg/day compared to 100 mg/day. The adverse effects can originate from the fluctuation in the plasma drug concentrations of an active substance following administration and subsequent metabolism and/or elimination from the body. Most of the reported adverse events were reduced or disappeared with the discontinuation of treatment [17].

2.4 Pharmacokinetics

The pharmacokinetic profile of MIL is as summarized in Table 2.1 [1,5].

Absorption

MIL is well-absorbed after oral administration. Absolute bioavailability is about 85-90 %. It is not affected by food intake. The peak plasma concentration is about 120 ng/ml achieved in 2 hours after a single 50 mg dose. Inter-subject variability is low. Plasma concentrations are linearly proportional with dose over the range of single acute doses of 25 to 200 mg as shown in Table 2.2 [1,2].

Distribution

Protein binding is low (13%) and not saturable. The volume of distribution of MIL is about 5 litre/kg with a total clearance of about 40 litre/hour. Renal and non-renal clearances are equivalent [1].

Metabolism

MIL is metabolized mainly by conjugation (Glucoronisation). Active metabolites have been found at very low levels without clinical relevance. Cytochrome P450 2D6 is involved in the metabolism of many psychotropic drugs and its inhibition is frequently a cause of drug-drug interactions. This enzyme has no impact on the metabolism of MIL and no oxidative metabolites of MIL have been detected in humans [1-3].

The pharmacokinetics of MIL are not modified in subjects who are deficient in the CYP2D6 isoenzyme (slow sparteine-like metabolisers). Furthermore, MIL does not interfere in-vivo with other isoenzymes of cytochrome P450 [1, 18].

Elimination

Plasma elimination half-life is about 8 hours. Elimination occurs mainly via the kidney with tubular secretion of the product in unchanged form. After repeated doses, MIL is totally eliminated in 2 to 3 days after termination of therapy. The liver and kidneys are both involved in the elimination of MIL as illustrated by renal and non-renal clearances with values of 23.8 ± 7.3 and 16.4 ± 3.1 l/h, respectively. Milnacipran Hydrochloride (MIL) Uses in Medicine Essay. This balance between renal and non-renal clearances may be an advantage in patients presenting with moderate renal insufficiency [3,5].

2.5 Dosage and administration

The recommended dose titration schedule for MIL is 12.5 mg once on Day 1, then 12.5 mg twice a day on Days 2-3, and then 25 mg twice a day on Days 4-7, and then 50 mg twice a day after Day 7. Recommended maintenance dose is 50 mg twice daily. In clinical trials, MIL was evaluated with a dose titration schedule. The daily dose may be increased to 200 mg (or 100 mg twice a day) based on individual response. Dosing should be adjusted in patients with severe renal impairment (CrCl < 29 ml/min) with a reduced maintenance dose to 25 mg twice a day. Following extended use, MIL should be tapered and not abruptly discontinued. MIL may be taken with or without food, but taking it with food may improve tolerability [4, 13].

2.6 Marketed formulations

There are various brands of MIL are available with dose of 12.5 mg, 25 mg, 50 mg and 100 mg immediate release tablets or capsules as shown in Table 2.3 [19-21].

ome young people have thoughts about suicide when first taking milnacipran. Stay alert to changes in your mood or symptoms.

Do not use milnacipran if you have used an MAO inhibitor in the past 14 days,such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine. After you stop taking milnacipran, you must wait at least 5 days before you start taking an MAOI. Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

Milnacipran is not approved for use by anyone younger than 18 years old.

Before taking this medicine

You should not use milnacipran if you are allergic to it.

Do not use milnacipran if you have used an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, and tranylcypromine. After you stop taking milnacipran, you must wait at least 5 days before you start taking an MAOI.

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Milnacipran should not be given to a child younger than 18 years old.

Tell your doctor if you have ever had:

• liver disease;
• kidney disease;
• heart disease, high blood pressure;
• seizures or epilepsy;
• bipolar disorder (manic depression);
• bleeding problems;
• low levels of sodium in your blood;
• if you drink alcohol; or
• if you take a blood thinner such as warfarin (Coumadin, Jantoven). Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

Be sure your doctor knows if you also take stimulant medicine, opioid medicine, herbal products, or medicine for depression, mental illness, Parkinson’s disease, migraine headaches, serious infections, or prevention of nausea and vomiting. These medicines may interact with milnacipran and cause a serious condition called serotonin syndrome.  Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

Some young people have thoughts about suicide when first taking milnacipran. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

Taking this medicine during pregnancy may cause serious lung problems or other complications in the baby. Tell your doctor right away if you become pregnant. Do not start or stop taking this medicine 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.

It may not be safe to breastfeed while using this medicine. Ask your doctor about any risk.

How should I take milnacipran?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed. Tell your doctor if you feel an increased urge to take more of milnacipran.

You may take medicine with or without food, but food may help you tolerate the medicine better.

Your blood pressure and heart rate will need to be checked often.

Do not stop using milnacipran suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using milnacipran.

Store at room temperature away from moisture and heat. Milnacipran Hydrochloride (MIL) Uses in Medicine Essay.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.