5. Levomilnacipran

Levomilnacipran, a (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide derivative, is the levo-enantiomer (1S, 2R-milnacipran) of racemate milnacipran, approved in 2009 for the treatment of fibromyalgia [53, 54]. It was discovered by Pierre Fabre Laboratories, France, and coproduced by Forest Laboratories, Inc. (Fetzima™), being approved by the FDA to be used for the treatment of MDD in adult patients in the United States and Japan in July 2013 and in Canada in May 2015 [55, 56]. It is not available on the market in the European Union and Australia.

The drug is available as extended-release capsules for oral administration, which contain

New Antidepressant Medication: Benefits Versus Adverse Effects

http://dx.doi.org/10.5772/intechopen.72003

137

Short-term safety clinical trials revealed that most patients with MDD have well responded and tolerated and did not experience important side effects to levomilnacipran [62, 65]. The most common side effects of levomilnacipran were nausea, vomiting, hyperhidrosis, heart rate increase, tachycardia, palpitations, urinary hesitation, erectile dysfunction, and ejaculate dis-

Long-term clinical studies documented that levomilnacipran manifested acceptable tolerability compared to placebo. Severe adverse reactions, such as nausea, vomiting, headache, tachycardia, hypertension, extrasystoles, and convulsion, observed in long-term trials of 48 weeks in patients treated with levomilnacipran, generally lead to discontinuation of the treatment. The other side effects of the levomilnacipran were related to the drug-drug interactions (inhibitors of CYP3A4 such as clarithromycin, ketoconazole, or itraconazole will increase its blood level) or to a concomitant hepatic, renal, and cardiac pathology. On the contrary, the association of levomilnacipran with the inducers of CYP3A4, such as rifampicin or carbamazepine, may

80 mg extended-release capsule with pink cap and white body

Dosage Initial dosage of 20 mg in a unique daily administration for 2 days, then increasing the dose to

is converted primarily to two inactive metabolites: desethyl levomilnacipran and p-hydroxylevomilnacipran with a minor involvement of CYP2C8, CYP2C19, CYP2D6, and CYP2J2

levomilnacipran hydrochloride (Table 4).

determine a diminution of its plasma concentration [66, 67].

Administration Orally, once daily, with or without food

6–8 hours

21–29 L/hour

Elimination 58% of uncharged drug is excreted in the urine

Absorption Not influenced by food intake

22%

Metabolism Hepatic (primarily by CYP3A4);

Table 4. Pharmacological aspects of levomilnacipran [55, 56].

T1/T2 Approximately 12 hours

Time to maximum concentration

Protein-binding percentage

Mean apparent total

clearance

Bioavailability 92%

Volume of distribution 387–473 L

40 mg per day;

Dosage forms 20 mg, extended-release capsule with yellow cap and white body 40 mg, extended-release yellow-opaque capsule

120 mg, pink-opaque extended-release capsule

the maximum accepted daily dose is 120 mg

5.2. Side effects of levomilnacipran

orders in men (Table 5) [56].

The researches performed in laboratory animals showed that levomilnacipran is the pharmacologically more active enantiomer of the racemic mixture milnacipran, having 50, respectively, and 13 times more intense inhibitory activity on the norepinephrine and serotonin reuptake pumps, a higher peak blood concentration and a prolonged elimination half-life compared with the other enantiomer 1S,2R-milnacipran (coded F2696) [56–59].

Currently, it is under clinical research as a therapy of anxiety, bipolar disorders, post-traumatic stress diseases, vasomotor symptoms associated with menopause, peripheral neuropathy (especially associated with diabetes mellitus), and chronic musculoskeletal pain. Levomilnacipran has also been investigated for the treatment of fibromyalgia and phantom limb syndrome but was not approved to be used for these purposes [56].

### 5.1. Pharmacological properties

In vitro studies revealed that levomilnacipran determines the strong and selective inhibition of serotonin and norepinephrine reuptake transporters (two times more potent and selective for norepinephrine than for serotonin), with a consequent increasing of these mediator concentration in the central nervous system [60]. It proved to have a more balanced reuptake of both serotonin and norepinephrine compared to other known SNRIs [56, 61]. Due to this difference in the selectivity action on these neurotransmitters, it was postulated that levomilnacipran may be beneficial in MDD related to the norepinephrine deficiency, with the demonstrated improvement of core symptoms and, consequently, the patient social and occupational activities [62–64]. It may also be useful in refractory depression or in the cases susceptible to potential increase of weight gain during chronic therapy with other antidepressant drugs [61].

Levomilnacipran provides a "two and a half" action, the inhibition of the norepinephrine transporter facilitating the action of dopamine, as long as this mediator diffuses through the synapses, without requiring the presence of a transporter. No important activity on dopamine, serotonin (5-HT1–5-HT7), muscarine, histamine, and alpha- or beta-adrenergic and opioid receptors and no inhibitory effects on the monoamino oxidase were evidenced. The lack of affinity on the sodium, potassium, chloride, or calcium ion channels was also observed [56].

Recent researches highlighted the inhibitory action of levomilnacipran on the beta-site amyloid precursor protein cleaving enzyme-1, known to be responsible for the formation of β-amyloid plaque, thus arguing its possible use in the treatment of Alzheimer's disease [64].

The drug is available as extended-release capsules for oral administration, which contain levomilnacipran hydrochloride (Table 4).
