Fetzima
Levomilnacipran Hydrochloride · Capsule, Extended Release · Oral
Uses
1 INDICATIONS AND USAGE 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 a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of Major Depressive Disorder (MDD) in adults ( 1 ). 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 ( 1 ).
Dosage and administration
Recommended dosage: 40 mg to 120 mg once daily with or without food ( 2.1 ). Initial dosage is 20 mg once daily for 2 days and then increase to 40 mg once daily ( 2.1 ). Based on clinical response and tolerability, increase dose in increments of 40 mg at intervals of 2 or more days ( 2.1 ). The maximum recommended dosage is 120 mg once daily ( 2.1 ). Take capsules whole; do not open, chew or crush ( 2.1 ) Renal impairment ( 2.3 ) : ○ Severe renal impairment: Maximum recommended dosage is 40 mg once daily. ○ Moderate renal impairment: Maximum recommended dosage is 80 mg once daily. Discontinuation : Reduce dose gradually whenever possible ( 2.4 ) 2.1 Recommended Dosage The recommended dosage range for FETZIMA is 40 mg to 120 mg once daily, with or without food. FETZIMA should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on clinical response and tolerability, FETZIMA may be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dosage is 120 mg once daily. Take FETZIMA at approximately the same time each day. Swallow FETZIMA whole; do not open, chew, or crush the capsule. 2.2 Screen for Bipolar Disorder Prior to Starting FETZIMA Prior to initiating treatment with FETZIMA or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.8 ) ] . 2. 3 Dosage Recommendations for Patients with Renal Impairment End stage renal disease (ESRD): FETZIMA is not recommended; Severe renal impairment (creatinine clearance of 15 to 29 mL/min), the dosage should not exceed 40 mg once daily; Moderate renal impairment (creatinine clearance of 30 to 59 mL/min), the dosage should not exceed 80 mg once daily; Mild renal impairment (creatinine clearance of 60 to 89 mL/min): no dosage adjustment recommended [see Use in Specific Populations ( 8.7 )]. 2.4 Discontinuing Treatment with FETZIMA Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as FETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing FETZIMA. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate [see Warnings and Precautions ( 5.10 )] . 2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days must elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with FETZIMA. Conversely, at least 7 days should be allowed after stopping FETZIMA before starting an MAOI antidepressant [see Contraindications ( 4 )] . 2.6 Dosage Recommendations for Use with Strong CYP3A4 Inhibitors The maximum recommended dosage of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [ s ee Drug Interactions ( 7.1 )] .
Dosage forms and strengths
(levomilnacipran) is available as 20 mg, 40 mg, 80 mg, and 120 mg extended-release capsules. Capsule Strength Capsule Color/Shape Capsule Markings 20 mg yellow cap white body black "FL" on cap black "20" on body 40 mg yellow cap yellow body black "FL" on cap black "40" on body 80 mg pink cap white body black "FL" on cap black "80" on body 120 mg pink cap pink body black "FL" on cap black "120" on body Extended-release capsules: 20 mg, 40 mg, 80 mg, and 120 mg ( 3 ).
Contraindications
4 CONTRAINDICATIONS 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 [see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.2 )] . Hypersensitivity to levomilnacipran, milnacipran HCl, or any excipient in the FETZIMA formulation ( 4 ). Do not use MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA. Do not use FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start FETZIMA in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ).
Warnings and precautions
Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue FETZIMA and serotonergic agents and initiate supportive treatment ( 5.2 ). Elevated Blood Pressure and Heart Rate : Control hypertension before initiating therapy with FETZIMA. Monitor blood pressure regularly during treatment ( 5.3 , 5.4 ). Increased Risk of Bleeding : Concomitant use of NSAIDs, aspirin, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.5 ). A ngle C losure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.6 ). Urinary Hesitation or Retention : Can occur. If such symptoms occur, discontinue FETZIMA or consider other appropriate medical intervention ( 5.7 ). Activation of Mania/Hypomania : Screen patients for bipolar disorder. Caution patients about risk of activation of mania/hypomania ( 5.8 ). Seizures: Can occur. Use with caution in patients with a seizure disorder ( 5.9 ). Discontinuation Syndrome : Taper dose when possible and monitor for discontinuation symptoms ( 5.10 ). Hyponatremia : Can occur in association with SIADH ( 5.11 ). Sexual Dysfunction: FETZIMA may cause symptoms of sexual dysfunction ( 5.12 ) . 5.1 Suicidal Thoug hts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥65 years old 6 fewer patients *Fetzima is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing FETZIMA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including FETZIMA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ), Drug Interactions ( 7.1 )]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of FETZIMA with MAOIs is contraindicated. In addition, do not initiate FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking FETZIMA, discontinue FETZIMA before initiating treatment with the MAOI [see Dosage and Administration ( 2.5 , 2.6 ) and Contraindications ( 4 ), Drug Interactions ( 7.1 )]. Monitor all patients taking FETZIMA for the emergence of serotonin syndrome. Discontinue treatment with FETZIMA and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of FETZIMA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure SNRIs, including FETZIMA, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout FETZIMA treatment.
Side effects
The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity [see Contraindications ( 4 )] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Elevated Blood Pressure [see Warnings and Precautions ( 5.3 )] Elevated Heart Rate [see Warnings and Precautions ( 5.4 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.5 )] Angle Closure Glaucoma [see Warnings and Precautions ( 5.6 )] Urinary Hesitation or Retention [see Warnings and Precautions ( 5.7 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8 )] Seizure [see Warnings and Precautions ( 5.9 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.10 )] Hyponatremia [see Warnings and Precautions ( 5.11 )] Sexual Dysfunction [see Warnings and Precautions ( 5.12 )] The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) are: nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 studies of another drug and may not reflect the rates observed in clinical practice. Patient e xposure The safety of FETZIMA was evaluated in 3,317 patients (18 to 78 years of age) diagnosed with MDD who participated in clinical studies, representing 1,186 patient-years of exposure. Among the 3,317 FETZIMA-treated patients, 1,583 were exposed to FETZIMA in short-term, placebo-controlled studies. There were 825 patients who continued from short-term studies into a one-year, open-label extension study. Of the 3,317 patients exposed to at least one dose of FETZIMA, 895 patients were exposed to FETZIMA for at least 6 months and 367 were exposed for one year. In these studies, FETZIMA was given at doses ranging from 40 mg to 120 mg once daily and was given without regard to food. Adverse r eacti ons r eported as r easons for discontinuation of t reatment In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received FETZIMA (40 mg to 120 mg) discontinued treatment due to an adverse reaction, compared with 3% of the 1,040 placebo-treated patients in those studies. The most common adverse reaction leading to discontinuation in at least 1% of the FETZIMA-treated patients in the short-term placebo-controlled studies was nausea (1.5%). Common a dverse r eactions in p lacebo- c ontrolled MDD s tudies The most commonly observed adverse reactions in FETZIMA-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations. Table 3 shows the incidence of adverse reactions that occurred in ≥ 2% of FETZIMA-treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies. Table 3 Adverse Reactions Occurring in ≥ 2% of FETZIMA-treated Patients and at Least Twice the rate of Placebo-treated Patients in Pooled MDD Studies System Organ Class Preferred Term Placebo (N =1040) % FETZIMA 40 mg to 120 mg per day (N = 1583) % Gastrointestinal disorders Nausea 6 17 Constipation 3 9 Vomiting 1 5 Cardiac disorders Tachycardia a 2 6 Palpitations 1 5 Reproductive system and breast disorders b Erectile dysfunction c 1 6 Testicular pain d <1 4 Ejaculation disorder e <1 5 Investigations Heart rate increased f 1 6 Blood pressure increased g 1 3 Renal and urinary disorders Urinary hesitation 0 4 Skin and s ubcutaneous t issue d isorders Hyperhidrosis 2 9 Rash h 0 2 Vascular disorders Hot flush 1 3 Hypotension i 1 3 Hypertension j 1 3 Metabolism and nutrition disorders Decreased appetite 1 3 a Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndrome b Percentage is relative to the number of patients in the associated demographic sex category. Fewer than 2% of FETZIMA-treated MDD female patients in placebo-controlled clinical studies reported adverse events related to sexual function. c Erectile dysfunction includes: erectile dysfunction, organic erectile dysfunction, and psychogenic erectile dysfunction d Testicular pain includes: testicular pain, epididymitis, and seminal vesiculitis e Ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature ejaculation f Heart rate increased also includes: orthostatic heart rate response increased g Blood pressure increased also includes: blood pressure systolic increased, blood pressure diastolic increased, and blood pressure orthostatic increased h Rash also includes: rash generalized, rash maculo-papular, rash erythematous, and rash macular i Hypotension also includes: orthostatic hypotension and dizziness postural j Hypertension also includes: labile hypertension N = number of patients in the Safety Population Dose- r elated a dverse r eactions In pooled data from the short-term placebo-controlled fixed-dose studies, there were no dose-related adverse reactions (greater than 2% overall incidence) in patients treated with FETZIMA across the dose range 40 mg to 120 mg once daily, with the exception of erectile dysfunction and urinary hesitation (see Table 4). Table 4 Dose-Related Adverse Reactions System Organ Class Preferred Term Placebo (N = 362) % FETZIMA 40 mg per day (N = 366) % 80 mg per day (N = 367) % 120 mg per day (N = 180) % Urinary hesitation 0 4 5 6 Erectile dysfunction a 2 6 8 10 a Percentage is relative to the number of male patients.
Drug interactions
Strong CYP3A4 inhibitors : Maximum recommended dosage is 80 mg once daily ( 7 ). 7.1 Drugs Having Clinically Important Interactions with FETZIMA Table 5 includes clinically important drug interactions with FETZIMA. Table 5: Clinically Important Drug Interactions with FETZIMA Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs and SNRIs including FETZIMA with MAOIs increases the risk of serotonin syndrome. Intervention: Concomitant use of FETZIMA is contraindicated: With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with FETZIMA. Within 14 days of stopping an MAOI intended to treat psychiatric disorders In a patient who is being treated with linezolid or intravenous methylene blue [see Dosage and Administration ( 2.5 , 2.6 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] . Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact: Concomitant use of FETZIMA with other serotonergic drugs increases the risk of serotonin syndrome. Intervention: Monitor for symptoms of serotonin syndrome when FETZIMA is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, immediately discontinue FETZIMA and/or concomitant serotonergic drugs [ see Dosage and Administration ( 2.5 , 2.6 ) , Contraindications ( 4 ) , and Warnings and Precautions ( 5.2 ) ] . Examples: other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort Drugs that Interfere with Hemostasis Clinical Impact: Concomitant use of FETZIMA with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of FETZIMA on the release of serotonin by platelets. Intervention: Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when FETZIMA is initiated or discontinued [see Warnings and Precautions ( 5.5 )] . Examples: NSAIDs, aspirin, and warfarin Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of FETZIMA with strong CYP3A4 inhibitors increases levomilnacipran exposure [see Pharmacokinetics ( 12.3 )] . Intervention: The dose of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [see Dosage and Administration ( 2.6 ). Examples: Ketoconazole, itraconazole, clarithromycin Alcohol Clinical Impact: Concomitant use of FETZIMA and alcohol may result in accelerated release of levomilnacipran. Intervention: Avoid concomitant use of FETZIMA and alcohol [see Clinical Pharmacology ( 12.3 )] .
Use in specific populations
Pregnancy : Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate. ( 8.1 ) 8.1 Pregnancy 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 advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/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 FETZIMA 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 FETZIMA, 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/m 2 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 FETZIMA 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 FETZIMA, 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/m 2 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/m 2 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 postnatal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the MRHD on a mg/m 2 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/m 2 basis. 8.2 Lactation 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 FETZIMA and any potential adverse effects on the breastfed child from FETZIMA or from the underlying maternal conditions. Clinical Considerations Infants exposed to FETZIMA 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.
Pregnancy
8.1 Pregnancy 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 advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/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 FETZIMA 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 FETZIMA, 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/m 2 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 FETZIMA 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 FETZIMA, 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/m 2 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/m 2 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 postnatal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the MRHD on a mg/m 2 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/m 2 basis.
Pediatric use
8. 4 Pediatric Use The safety and effectiveness of FETZIMA have not been established in pediatric patients for the treatment of major depressive disorder (MDD). The safety and efficacy of FETZIMA 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. FETZIMA 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 FETZIMA were similar to those observed in adults [see Adverse Reactions ( 6.1 )]. FETZIMA 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 FETZIMA 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.
Geriatric use
8. 5 Geriatric Use 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 FETZIMA, 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 FETZIMA, 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 )].
Overdosage
10.1 Human Experience There is limited clinical experience with FETZIMA overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal. 10.2 Management of Overdose No specific antidotes for FETZIMA are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations.
Description
11 DESCRIPTION FETZIMA contains levomilnacipran, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in the form of hydrochloride salt with the chemical name of levomilnacipran hydrochloride is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride. Its empirical formula is C 15 H 2 2 N 2 O∙HCl and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure of levomilnacipran hydrochloride is: FETZIMA extended-release capsules are intended for oral administration. Each FETZIMA capsule contains 23.0, 45.9, 91.8, or 137.8 mg of levomilnacipran hydrochloride equivalent to 20, 40, 80, or 120 mg of levomilnacipran, respectively. Inactive ingredients include ethylcellulose, hypromellose, povidone, sugar spheres, talc, titanium dioxide, and triethyl citrate. Inactive ingredients also include black iron oxide, red iron oxide (80 mg and 120 mg capsules only), shellac glaze, and yellow iron oxide (20 mg and 40 mg capsules only). The chemical structure of FETZIMA is levomilnacipran, which is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of levomilnacipran is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride; its empirical formula is C15H23ClN2O and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran.
Mechanism of action
12.1 Mechanism of Action The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of reuptake at serotonin and norepinephrine transporters. Non-clinical studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING FETZIMA extended-release capsules are supplied in the following configurations: Capsule Strength Capsule Color/Shape Capsule Markings Package Configuration NDC Code 20 mg yellow cap white body black "FL" on cap black "20" on body Bottle / 30 count 0456-2220-30 Hospital Unit Dose (Blister) / 10 x 10 0456-2220-63 40 mg yellow cap yellow body black "FL" on cap black "40" on body Bottle / 30 count 0456-2240-30 Bottle / 90 count 0456-2240-90 Hospital Unit Dose (Blister) / 10 x 10 0456-2240-63 80 mg pink cap white body black "FL" on cap black "80" on body Bottle / 30 count 0456-2280-30 Bottle / 90 count 0456-2280-90 Hospital Unit Dose (Blister) /10 x 10 0456-2280-63 120 mg pink cap pink body black "FL" on cap black "120" on body Bottle / 30 count 0456-2212-30 Bottle / 90 count 0456-2212-90 Hospital Unit Dose (Blister) / 10 x 10 0456-2212-63 FETZIMA Titration Pack is supplied in the following configuration: Capsule Strength Capsule Color/Shape Capsule Markings Package Configuration NDC Code 20 mg yellow cap white body black "FL" on cap black "20" on body Titration Pack (Blister) containing two 20 mg capsules and twenty-six 40 mg capsules 0456-2202-28 40 mg yellow cap yellow body black "FL" on cap black "40" on body Storage and Handling All package configurations: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature] .
Patient information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Suicide Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] . Dosing and Administration Advise patients that FETZIMA should be swallowed whole and should not be chewed, crushed, or opened. Advise patients that FETZIMA can be taken with or without food. Instruct patients if they miss a dose, to take the missed dose as soon as they remember. If it is almost time for the next dose, instruct them to skip the missed dose and take their next dose at the regular time. Advise them not to take two doses of FETZIMA at the same time. Concomitant Medication Instruct patients not to take FETZIMA with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping FETZIMA before starting an MAOI [ see Contraindications ( 4 ) ] . Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [ see Drug Interactions ( 7.1 ) ] . Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [ see Contraindications ( 4 ) ] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA with other serotonergic agents (including triptans, tricyclic antidepressants, opioids, lithium, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements) [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.1 )] . Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome. E levated Blood Pressure and Heart Rate Advise patients that they should have regular monitoring of blood pressure and heart rate when taking FETZIMA [ see Warnings and Precautions ( 5.3 , 5.4 ) ] . Increased Risk of Bleeding Caution patients about the concomitant use of FETZIMA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation because combined use has been associated with an increased risk of bleeding. Advise patients to inform their healthcare provider if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions ( 5.5 )] . Angle Closure Glaucoma Patients should be advised that taking FETZIMA can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma [see Warnings and Precautions ( 5.6 )] . Urinary Hesitation or Retention Caution patients about the risk of urinary hesitation and retention while taking FETZIMA, particularly in patients prone to obstructive urinary disorders. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [ see Warnings and Precautions ( 5.7 ) ] . Activation of Mania/Hypomania Advise patients and their caregivers to look for signs of activation of mania/hypomania [ see Warnings and Precautions ( 5.8 ) ] . Seizures Caution patients about using FETZIMA if they have a history of a seizure disorder [see Warnings and Precautions ( 5.9 )] . Discontinuation Syndrome Advise patients not to abruptly stop taking FETZIMA without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping FETZIMA and they should monitor for discontinuation symptoms [ see Warnings and Precautions ( 5.10 ) ] . Hyponatremia Advise patients that hyponatremia has been reported as a result of treatment with FETZIMA. Advise patients of the signs and symptoms of hyponatremia [ see Warnings and Precautions ( 5.11 ) ] . Sexual Dysfunction Advise patients that use of FETZIMA may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [ see Warnings and Precautions ( 5.12 )] . Alcohol Advise patients to avoid consumption of alcohol while taking FETZIMA [see Drug Interactions ( 7.1 ) , Clinical Pharmacology ( 12.3 ) ] . Pregnancy Advise pregnant females to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with FETZIMA. Advise patients that FETZIMA may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding. Advise patient that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FETZIMA during pregnancy [see Use in Specific Populations ( 8.1 )] Lactation Advise breastfeeding patients using FETZIMA to monitor infants for sedation, agitation, irritability, poor feeding, and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )]. Interference with Cognitive and Motor Performance Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that FETZIMA therapy does not adversely affect their ability to engage in such activities. Distributed by: AbbVie, Inc. 1 N Waukegan Rd. North Chicago, IL 60064 ©2024 AbbVie. All rights reserved. FETZIMA and its design are trademarks of Pierre Fabre Medicament. Licensed from Pierre Fabre Medicament. 20085454
Label text from the FDA structured product label by Allergan, Inc. (revised Apr 30, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Levomilnacipran Hydrochloride in 4 products
Fetzima NDC products (6)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0456-2200 | Kit | Allergan, Inc. | NDA |
| 0456-2202 | Kit | Allergan, Inc. | NDA |
| 0456-2212 | Levomilnacipran Hydrochloride 120 mg/1 Capsule, Extended Release | Allergan, Inc. | NDA |
| 0456-2220 | Levomilnacipran Hydrochloride 20 mg/1 Capsule, Extended Release | Allergan, Inc. | NDA |
| 0456-2240 | Levomilnacipran Hydrochloride 40 mg/1 Capsule, Extended Release | Allergan, Inc. | NDA |
| 0456-2280 | Levomilnacipran Hydrochloride 80 mg/1 Capsule, Extended Release | Allergan, Inc. | NDA |
Frequently asked questions
What is Fetzima used for?
1 INDICATIONS AND USAGE 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 a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for…
What are the side effects of Fetzima?
The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity [see Contraindications ( 4 )] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Elevated Blood Pressure [see Warnings and Precautions ( 5.3 )] Elevated Heart Rate [see… See the full label for the complete list.
Who makes Fetzima?
Fetzima is listed by 1 labeler in the FDA NDC directory, including Allergan, Inc..