Milnacipran

Pregnancy Category C.

Risk Summary

There are no adequate or well-controlled studies in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as milnacipran), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryo fetal and perinatal lethality in rats and the incidence of a minor skeletal variation in rabbits at doses below (rat) or approximately equal to (rabbit) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m² basis. No effects were seen in mice when treated with milnacipran during the period of organogenesis at doses up to 3 times the MHRD on a mg/m² basis. Because animal reproduction studies are not always predictive of human response, milnacipran should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Consideration

Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery and require prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Monitor neonates for reported clinical findings such as respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Animal Data

Studies were conducted in rats, rabbits and mice with dosing of milnacipran during the period of organogenesis. In rats, milnacipran was shown to increase embryo fetal lethality at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m² basis). In rabbits, dose-dependent increases in the incidence of the skeletal variation of an extra single rib were observed in several pups from multiple litters in the absence of maternal toxicity at 15 mg/kg/day (1.5 times the MRHD on a mg/m² basis). The clinical significance of this finding is unknown. In mice, no embryotoxic or teratogenic effects were seen at doses up to 125 mg/kg/day (3 times the MHRD on a mg/m² basis).

With peri- and postnatal exposure to oral milnacipran in rats, decreases in viability and body weight were observed on Postpartum Day 4 at a dose of 5 mg/kg/day (approximately 0.25 times the MRHD on a mg/m² basis). The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m² basis).

Milnacipran is present in the milk of lactating women treated with milnacipran tablet.

In a pharmacokinetic study, a single, oral dose of 50 mg milnacipran HCl tablet was administered to 8 lactating women who were at least 12 weeks postpartum and weaning their infants. The maximum estimated daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 5% of the maternal dose based on peak plasma concentrations. In most patients, peak concentrations of milnacipran in breast milk were seen within 4 hours after the maternal dose. Because of the limited data regarding infant exposure to milnacipran, caution should be exercised when milnacipran is administered to a nursing woman.

Carcinogenesis

Dietary administration of milnacipran to rats at doses of 50 mg/kg/day (2 times the MRHD on a mg/m² basis) for 2 years caused a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125 mg/kg/day.

Milnacipran did not induce tumors in Tg.rasH2 mice at any dose tested.

Mutagenesis

Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in the L5178Y TK +/- mouse lymphoma forward mutation assay. Milnacipran was also not clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo mouse micronucleus assay.

Impairment of Fertility

Although administration of milnacipran to male and female rats had no statistically significant effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m² basis), there was an apparent dose-related decrease in the fertility index at clinically relevant doses based on body surface area.

Milnacipran might diminish mental and physical capacities necessary to perform certain tasks such as operating machinery, including motor vehicles. Patients should be cautioned about operating machinery or driving motor vehicles until they are reasonably certain that milnacipran treatment does not affect their ability to engage in such activities.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patient Exposure

Milnacipran was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with milnacipran and 652 patients treated with placebo) for a treatment period up to 29 weeks.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with milnacipran 100 mg/day, 26% of patients treated with milnacipran 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥1% of patients in the milnacipran treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with milnacipran 200 mg/day compared to milnacipran 100 mg/day.

Most Common Adverse Reactions in Placebo Controlled Trials

In the placebo-controlled fibromyalgia patient trials, the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥5% and twice placebo) in patients treated with milnacipran were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension.

Table 4 lists all adverse reactions that occurred in at least 2% of patients treated with milnacipran at either 100 or 200 mg/day and at an incidence greater than that of placebo.

Table 4. Treatment-Emergent Adverse Reaction Incidence in Placebo Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Milnacipran-Treated Patients and Occurring More Frequently in Either Milnacipran Treatment Group Than in the Placebo Treatment Group):

Weight Changes

In placebo-controlled fibromyalgia clinical trials, patients treated with milnacipran for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the milnacipran 100 mg/day and the milnacipran 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients.

Genitourinary Adverse Reactions in Males

In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with milnacipran, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased.

Other Adverse Reactions Observed During Clinical Trials of milnacipran in Fibromyalgia

Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with milnacipran for periods up to 68 weeks. The listing does not include those events already listed in Table 4, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening.

Adverse reactions are categorized by body system and listed in order of decreasing frequency.

Gastrointestinal Disorders: diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension

General Disorders: fatigue, peripheral edema, irritability, pyrexia

Infections: urinary tract infection, cystitis

Injury, Poisoning, and Procedural Complications: contusion, fall

Investigations: weight decreased or increased

Metabolism and Nutrition Disorders: hypercholesterolemia

Nervous System Disorders: somnolence, dysgeusia

Psychiatric Disorders: depression, stress

Skin Disorders: night sweats

Postmarketing Experience

The following additional adverse reactions have been identified from spontaneous reports of milnacipran received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to milnacipran. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These events include:

Blood and Lymphatic System Disorders: leukopenia, neutropenia, thrombocytopenia

Cardiac Disorders: supraventricular tachycardia, Takotsubo cardiomyopathy

Eye Disorders: accommodation disorder

Endocrine Disorders: hyperprolactinemia

Gastrointestinal Disorders: acute pancreatitis

Hepatobiliary Disorders: hepatitis

Metabolism and Nutrition Disorders: anorexia, hyponatremia

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Nervous System Disorders: convulsions (including grand mal), loss of consciousness, Parkinsonism

Psychiatric Disorders: aggression, anger, delirium, hallucination, homicidal ideation

Renal and Urinary Disorders: acute renal failure

Reproductive System and Breast Disorders: galactorrhea

Skin Disorders: erythema multiforme, Stevens Johnson syndrome

Vascular Disorders: hypertensive crisis