There is limited clinical experience with milnacipran overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg daily were reported with none being fatal ^F3925. In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with milnacipran only ^F3925. The most common signs and symptoms of overdose included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes F3919, F3922, F3925.

There are no adequate and well-controlled studies in pregnant women F3919, F3922, F3925. In fact, milnacipram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus F3919, F3922, F3925.

Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding F3919, F3922, F3925. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying F3919, F3922, F3925. These features are consistent with either a direct toxic effect of SNRI class drugs like milnacipran or, possibly, a drug discontinuation syndrome F3919, F3922, F3925. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome F3919, F3922, F3925.

The effect of milnacipran on labor and delivery in humans is unknown F3919, F3922, F3925. Milnacipran should be used during labor and delivery only if the potential benefits outweigh the potential risks F3919, F3922, F3925.

There are no adequate and well-controlled studies in nursing mothers F3919, F3922, F3925. It is not known if milnacipran is excreted in human milk F3919, F3922, F3925. Studies have shown that levomilnacipran is excreted into the milk of lactating rats F3919, F3922, F3925. Subsequently, possible excretion into human milk possesses the potential for serious adverse reactions in nursing infants F3919, F3922, F3925. As a consequence, breastfeeding by women treated with levomilnacipran should be considered only if the potential benefits outweigh the potential risks to the child F3919, F3922, F3925.

Milnacipran is not indicated for use in children under 18 years of age due to concerns over the potential for agitation-type emotional and behavioral changes, as well as suicidal ideation and/or behavior F3919, F3922, F3925.

SNRIs like milnacipran have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event F3919, F3922, F3925.

Levomilnacipran was not mutagenic when evaluated in vitro in a bacterial mutagenicity study (Ames test) and not genotoxic in a mouse lymphoma study F3919, F3922, F3925. It was not clastogenic in an in vivo micronucleus assay in rats F3919, F3922, F3925.

The potential effects of levomilnacipran on gonadal function, mating behavior, reproductive performance and early pregnancy were evaluated in rats at oral doses of 0, 10, 30, or 100 mg/kg/day F3919, F3922, F3925. The NOAEL was 100 mg/kg/day based on reductions in body weight gain and food consumption F3919, F3922, F3925. There were no levomilnacipran effects on male and female fertility parameters F3919, F3922, F3925.

In the rat and rabbit embryo/fetal development studies, decreases in maternal body weight gain and food consumption were noted F3919, F3922, F3925. In the fetuses, increases in the incidence of ossification anomalies were noted but were of no toxicological significance F3919, F3922, F3925. In both species, the NOAEL was determined to be 100 mg/kg/day, a dose which represents a rat or rabbit animal-to-human exposure margin of 9-fold and 4-fold, respectively relative to the human exposure from 120 mg/day of levomilnacipran F3919, F3922, F3925.

Material safety data for milnacipran has documented the LD50 oral value in the rat model as being 213 mg/kg MSDS.