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allergan, inc. - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 12.5 mg - savella is indicated for the management of fibromyalgia.  savella is not approved for use in pediatric patients [see use in specific populations ( 8.4 )] . the use of maois intended to treat psychiatric disorders with savella or within 5 days of stopping treatment with savella is contraindicated because of an increased risk of serotonin syndrome. the use of savella within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration ( 2.5 ), warnings and precautions ( 5.2 )] . starting savella in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration ( 2.6 ), warnings and precautions ( 5.2 )] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to savella during pregnancy.  physicians are advised to recommend that pregnant patients taking savella enroll in the savella pregnancy registry. enrollment is voluntary and may be initiated by pregnant patients or their healthcare providers by contacting the registry at 1-877-643-3010 or by email at pregnancyregistries@incresearch.com. data forms may also be downloaded from the registry website at www.savellapregnancyregistry.com. risk summary based on data from published observational studies, exposure to snris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions ( 5.2 )] . the available data on savella use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. there are risks associated with exposure to serotonin and norepinephrine reuptake inhibitors (snris) and selective-serotonin reuptake inhibitors (ssris), including savella, during pregnancy (see clinical considerations). animal reproduction studies have been performed in rats, rabbits and mice. milnacipran was shown to increase embryofetal 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 (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. clinical consideration maternal adverse reactions use of savella in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions ( 5.9 )]. fetal/neonatal   adverse reactions neonates exposed to snris or ssris, including savella, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. 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. these findings are consistent with either direct toxic effect of ssris and snris or possibly, a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see   warnings and precautions ( 5.2 , 5.7 )]. data 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 embryofetal 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). risk summary milnacipran is present in human milk [see data] . there are no reports on the effects of milnacipran on the breastfed child and on milk production/excretion. however, there are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to ssris or snris through breast milk (see clinical considerations). the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for savella and any potential adverse effects on the breastfed child from savella or from the underlying maternal conditions. clinical considerations monitor infants exposed to milnacipran for agitation, irritability, poor feeding and poor weight gain. data human data milnacipran is present in the milk of lactating women treated with milnacipran. in a lactation pharmacokinetic study with milnacipran, 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 milk/plasma auc ratio of milnacipran was 1.85 ± 0.38. the maximum estimated weight adjusted 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.   safety and effectiveness of savella in a fibromyalgia pediatric population below the age of 18 have not been established [see boxed warning , indications and usage ( 1 ),   and warnings and precautions ( 5.1 )] . the use of savella is not recommended in pediatric patients. in controlled clinical studies of savella, 402 patients were 60 years or older, and no overall differences in safety and efficacy were observed between these patients and younger patients. in view of the predominant excretion of unchanged milnacipran via kidneys and the expected decrease in renal function with age, renal function should be considered prior to use of savella in the elderly [see dosage and administration ( 2.2 )] . snris, ssris, and savella, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see warnings and precautions ( 5.8 )] . milnacipran is not a controlled substance. milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies. milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other snris and ssris. these withdrawal symptoms can be severe. thus, taper savella and do not abruptly discontinue after extended use [see warnings and precautions ( 5.7 )] .

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amneal pharmaceuticals llc - levomilnacipran hydrochloride (unii: 371u2zk31u) (levomilnacipran - unii:ugm0326txx) - levomilnacipran is indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies (14)] . limitation of use :  levomilnacipran extended-release capsules are not approved for the management of fibromyalgia. the efficacy and safety of levomilnacipran extended-release capsules for the management of fibromyalgia have not been established. levomilnacipran is contraindicated: - in patients with hypersensitivity to levomilnacipran, milnacipran hcl, or to any excipient in the formulation. - with the use of maois intended to treat psychiatric disorders with levomilnacipran or within 7 days of stopping treatment with levomilnacipran is contraindicated because of an increased risk of serotonin syndrome. the use of levomilnacipran within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.5) and warnings and precautions (5.2)] . starting levomilnacipran in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.6) and warnings and precautions (5.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants. risk summary based on data from published observational studies, exposure to snris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions (5.5) and clinical considerations] . the available data on levomilnacipran use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. there are risks associated with untreated depression in pregnancy and with exposure to snris and ssris, including levomilnacipran, during pregnancy (see clinical considerations). in animal reproduction studies, levomilnacipran was not associated with malformations in rats or rabbits when given during the period of organogenesis at doses up to 8 or 16 times the maximum recommended human dose (mrhd) of 120 mg on a mg/m2 basis, respectively. however, an increase in early post-natal rat pup mortality was seen at a dose equivalent to 5 times the mrhd given during pregnancy and lactation (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. maternal adverse reactions use of levomilnacipran in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.5)]. fetal/neonatal adverse reactions neonates exposed to snris or ssris, including levomilnacipran, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. 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. these findings are consistent with either direct toxic effect of ssris and snris or possibly, a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see warnings and precautions (5.2 and 5.10)]. data animal data no malformations were observed when levomilnacipran was administered to pregnant rats or rabbits during the period of organogenesis at oral doses up to 100 mg/kg/day. this dose is 8 and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (mrhd) of 120 mg on a mg/m2 basis. fetal body weights were reduced in rats, and skeletal ossification was delayed in both rats and rabbits at this dose; these effects were not observed in either species at doses up to 30 mg/kg/day, 2.4 times the mrhd in rats or 5 times the mrhd in rabbits on a mg/m2 basis. when levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 5 times the mrhd, during organogenesis and throughout pregnancy and lactation, there was an increase in early post-natal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the mrhd on a mg/m2 basis. among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 8 weeks of age; however, physical and functional development, including reproductive performance of the progeny, was not affected. the effects on body weight gain were not seen at 7 mg/kg/day, 0.6 times the mrhd on a mg/m2 basis. risk summary there are no available data on the presence of levomilnacipran in human milk; however, racemic milnacipran is present in human milk (see data). there are no reports on the effects of levomilnacipran or milnacipran on the breastfed infant or the effects on milk production. however, there are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to ssris or snris through breast milk (see clinical considerations) . the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levomilnacipran and any potential adverse effects on the breastfed child from levomilnacipran or from the underlying maternal conditions. clinical considerations infants exposed to levomilnacipran should be monitored for agitation, irritability, poor feeding and poor weight gain. data milnacipran, a racemic mixture that contains levomilnacipran (the 1s,2r -enantiomer of milnacipran), is present in the milk of lactating women treated with milnacipran. in a lactation pharmacokinetic study with milnacipran, 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 milk/plasma auc ratio of milnacipran was 1.85 ± 0.38. the maximum estimated weight-adjusted daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 ml/kg/day) was 5% of the maternal weight-adjusted dose based on peak plasma concentrations. the safety and effectiveness of levomilnacipran have not been established in pediatric patients for the treatment of major depressive disorder (mdd). the safety and efficacy of levomilnacipran were evaluated in two randomized, double-blind, placebo- and active-controlled 8-week trials in pediatric patients with mdd, one in patients 7 to 17 years of age (flexible-dose study) and the other in patients 12 to 17 years of age (fixed-dose study). the primary efficacy endpoint for both studies was the change from baseline to week 8 in the children’s depression rating scale-revised (cdrs-r) total score. the cdrs-r assesses the severity of depression and change in depressive symptoms in children and adolescents with depression. levomilnacipran was not superior to placebo in either study. the most commonly observed adverse reactions in pediatric patients 7 to 17 years of age randomized to levomilnacipran were similar to those observed in adults [see adverse reactions (6.1)] . levomilnacipran was associated with an increase in blood pressure in placebo-and active-controlled trials in pediatric patients with mdd. increases in blood pressure in pediatric patients treated with levomilnacipran led to a higher proportion of pediatric patients developing new-onset and sustained hypertension when compared to adults [see warnings and precautions (5.3)] . antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see boxed warning, warnings and precautions (5.1), and adverse reactions (6.1)]. juvenile animal toxicity data in a juvenile animal study, male and female rats were treated with 10, 35, or 120 mg/kg/day of levomilnacipran by oral gavage from post-natal day 21 to 90. at 120 mg/kg/day, there was a decrease in bone mineral density in both males and females and a decrease in mean tibia length in females. these effects were not completely resolved at the end of the recovery period. there was a delay in sexual maturation in females treated with 120 mg/kg/day; however, there was no effect on fertility. the no observed adverse effect level (noael) for all these findings was 35 mg/kg/day. no dose adjustment is recommended on the basis of age [see  clinical pharmacology (12.3)] . of the total number of patients in the 8-week clinical studies of levomilnacipran, 2.8% of patients were age 65 or older. because levomilnacipran is predominantly excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose [see dosage and administration (2.3)] . snris, including levomilnacipran, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see warnings and precautions (5.11)]. dose adjustment is not recommended in patients with mild (child-pugh score of 1 to 6), moderate (child-pugh score of 7 to 9), or severe (child-pugh score of 10 to 13) hepatic impairment [see clinical pharmacology (12.3) ] . renal excretion plays a predominant role in the elimination of levomilnacipran. levomilnacipran is not recommended for use in patients with end stage renal disease. dosing adjustment is recommended for patients with moderate (creatinine clearance of 30 ml/min to 59 ml/min) or severe (creatinine clearance of 15 ml/min to 29 ml/min) renal impairment [see dosage and administration (2.3)  and clinical pharmacology (12.3)] . dose adjustment is not recommended for patients with mild (creatinine clearance of 60 ml/min to 89 ml/min) renal impairment [see clinical pharmacology (12.3)] . levomilnacipran is not a controlled substance. levomilnacipran has not been systematically studied in animals or humans for its potential for abuse. there was no evidence suggestive of drug-seeking behavior in the clinical studies. it is not possible to predict on the basis of clinical experience the extent to which a cns active drug will be misused, diverted, and/or abused once marketed. consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of levomilnacipran (e.g., development of tolerance or drug-seeking behavior). levomilnacipran has not been systematically studied in animals or humans for its potential for dependence.

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allergan, inc. - levomilnacipran hydrochloride (unii: 371u2zk31u) (levomilnacipran - unii:ugm0326txx) - levomilnacipran 20 mg - fetzima® is indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies ( 14 )]. limitation of use: fetzima is not approved for the management of fibromyalgia. the efficacy and safety of fetzima for the management of fibromyalgia have not been established. fetzima is contraindicated: - in patients with hypersensitivity to levomilnacipran, milnacipran hcl, or to any excipient in the formulation. - with the use of maois intended to treat psychiatric disorders with fetzima or within 7 days of stopping treatment with fetzima is contraindicated because of an increased risk of serotonin syndrome. the use of fetzima within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration ( 2.5 ) and warnings and precautions ( 5.2 )] . starting fetzima in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [se

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unit dose services - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 25 mg - savella is indicated for the management of fibromyalgia. savella is not approved for use in pediatric patients [see use in specific populations (8.4)] . the use of maois intended to treat psychiatric disorders with savella or within 5 days of stopping treatment with savella is contraindicated because of an increased risk of serotonin syndrome. the use of savella within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.5), warnings and precautions (5.2)] . starting savella in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.6), warnings and precautions (5.2)] . 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 savella), or selective serotonin reuptake i

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cardinal health 107, llc - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 50 mg - savella is indicated for the management of fibromyalgia.  savella is not approved for use in pediatric patients [see use in specific populations (8.4)] . the use of maois intended to treat psychiatric disorders with savella or within 5 days of stopping treatment with savella is contraindicated because of an increased risk of serotonin syndrome. the use of savella within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.5), warnings and precautions (5.2)] . starting savella in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.6), warnings and precautions (5.2)] . 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 savella), or selective serotonin reuptake

United States - English - NLM (National Library of Medicine)

lake erie medical & surgical supply dba quality care products llc - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 50 mg - savella is indicated for the management of fibromyalgia. savella is not approved for use in pediatric patients [see use in specific populations (8.4)]. concomitant use of savella in patients taking monoamine oxidase inhibitors (maois) is contraindicated. in patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (maoi), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. these reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an maoi. some cases presented with features resembling neuroleptic malignant syndrome. the effects of combined use of savella and maois have not been evaluated in humans. therefore, it is recommended that savella should not be used in combination wit

United States - English - NLM (National Library of Medicine)

rebel distributors corp - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 25 mg - savella is indicated for the management of fibromyalgia. savella is not approved for use in pediatric patients [see use in specific populations (8.4) ]. concomitant use of savella in patients taking monoamine oxidase inhibitors (maois) is contraindicated. in patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (maoi), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. these reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an maoi. some cases presented with features resembling neuroleptic malignant syndrome. the effects of combined use of savella and maois have not been evaluated in humans. therefore, it is recommended that savella should not be used in combination wi

United States - English - NLM (National Library of Medicine)

stat rx usa llc - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 25 mg - savella is indicated for the management of fibromyalgia. savella is not approved for use in pediatric patients [see use in specific populations (8.4) ]. concomitant use of savella in patients taking monoamine oxidase inhibitors (maois) is contraindicated. in patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (maoi), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. these reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an maoi. some cases presented with features resembling neuroleptic malignant syndrome. the effects of combined use of savella and maois have not been evaluated in humans. therefore, it is recommended that savella should not be used in combination wi

United States - English - NLM (National Library of Medicine)

physicians total care, inc. - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hydrochloride 50 mg - savella is indicated for the management of fibromyalgia. savella is not approved for use in pediatric patients [see use in specific populations (8.4)]. concomitant use of savella in patients taking monoamine oxidase inhibitors (maois) is contraindicated. in patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (maoi), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. these reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an maoi. some cases presented with features resembling neuroleptic malignant syndrome. the effects of combined use of savella and maois have not been evaluated in humans. therefore, it is recommended that savella should not be used in combination wit

United States - English - NLM (National Library of Medicine)

amneal pharmaceuticals llc - milnacipran hydrochloride (unii: rnz43o5ww5) (milnacipran - unii:g56vk1hf36) - milnacipran hcl tablets are indicated for the management of fibromyalgia. milnacipran hcl tablets are not approved for use in pediatric patients [see use in specific populations (8.4)] . the use of maois intended to treat psychiatric disorders with milnacipran hcl or within 5 days of stopping treatment with milnacipran hcl is contraindicated because of an increased risk of serotonin syndrome. the use of milnacipran hcl within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.5), warnings and precautions (5.2)] . starting milnacipran hcl in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.6), warnings and precautions (5.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to milnacipran hcl during pregnancy. physicians