Included as part of the "PRECAUTIONS" Section
Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phase of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
||Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
||Increases Compared to Placebo
||14 additional cases
||5 additional cases
||Decreases Compared to Placebo
||1 fewer case
||6 fewer cases
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see DOSAGE AND ADMINISTRATION and Discontinuation Syndrome for a description of the risks of discontinuation of FETZIMA].
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for FETZIMA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients For Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that FETZIMA is not approved for use in treating bipolar depression.
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
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). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of FETZIMA with MAOIs intended to treat psychiatric disorders is contraindicated. FETZIMA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking FETZIMA. FETZIMA should be discontinued before initiating treatment with the MAOI [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].
If concomitant use of FETZIMA with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with FETZIMA and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
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. Pre-existing hypertension should be controlled before initiating treatment with FETZIMA. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience a sustained increase in blood pressure while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.
Table 2 shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in FETZIMA-treated patients in the short-term placebo-controlled studies.
Table 2 Blood Pressure Mean Changes, Sustained Hypertension, and Upward Shifts in Hypertensive Status
|Mean change from baseline to end of treatment, mm Hg
| Systolic blood pressure (SBP)
| Diastolic blood pressure (DBP)
|Sustained Hypertension, % of patients
| Broad Criteria:
SBP ≥ 140 mm Hg and an increase >15 mm Hg OR
DBP ≥ 90 mm Hg and an increase > 10 mm Hg for at least 3 consecutive visits
SBP ≥ 140 mm Hg and an increase >15 mm Hg AND
DBP ≥ 90 mm Hg and an increase > 10 mm Hg for at least 3 consecutive visits
|Upward Shifts in Hypertensive Statusa, % of patients
| Normal/ Pre-hypertensive → Stage I/ Stage II
a Normal Blood Pressure: SBP < 120 mm Hg and DBP < 80 mm Hg
Pre-hypertension: SBP ≥ 120 mm Hg and ≤ 139 mmHg or DBP ≥ 80 mm Hg and ≤ 89 mm Hg
Stage I hypertension: SBP ≥ 140 mm Hg and ≤ 159 mmHg or DBP ≥ 90 mm Hg and ≤ 99 mm Hg
Stage II hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg
In the short-term, placebo-controlled MDD studies, the mean increase from initiation of treatment in systolic BP was 3 mm Hg and diastolic BP was 3.2 mm Hg, as compared to no change in the placebo group. There were no dose-related changes in systolic and diastolic blood pressure observed.
In patients exposed to one-year, open-label treatment of FETZIMA (doses range from 40-120 mg once daily), the mean change from initiation of treatment in systolic BP was 3.9 mm Hg and diastolic BP was 3.1 mm Hg.
In the short-term, placebo-controlled studies, 11.6 % of patients met orthostatic hypotension criteria (SBP or DBP) in the FETZIMA group compared to 9.7% in the placebo group. Orthostatic reductions of blood pressure ≥ 10 mm Hg in DBP occurred in 5.8%, 6.1% and 9.8% of FETZIMA-treated patients with doses of 40, 80 and 120 mg/day respectively, compared to 6.2% of placebo-treated patients.
Concomitant use of FETZIMA with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. Effects of FETZIMA on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. FETZIMA should be used with caution in these patients.
Elevated Heart Rate
SNRIs including FETZIMA have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Preexisting
tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.
In short-term clinical studies, FETZIMA treatment was associated with a mean increase in heart rate of 7.4 beats per minute (bpm) compared to a mean decrease of 0.3 bpm in placebo-treated patients. Heart rate increase in FETZIMA-treated patients receiving doses of 40 mg, 80 mg and 120 mg was 7.2, 7.2, and 9.1 bpm.
FETZIMA has not been systematically evaluated in patients with a cardiac rhythm disorder.
SSRIs and SNRIs, including FETZIMA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
Angle Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including FETZIMA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Urinary Hesitation Or Retention
The noradrenergic effect of SNRIs including FETZIMA, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of FETZIMA-treated patients receiving doses of 40, 80 and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of FETZIMA in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with FETZIMA, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered.
Activation Of Mania/Hypomania
Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. As with all antidepressants, use FETZIMA cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
FETZIMA has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. FETZIMA should be prescribed with caution in patients with a seizure disorder. One case of seizure has been reported in premarketing
clinical studies with FETZIMA.
There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Monitor patients for these symptoms when discontinuing FETZIMA. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see DOSAGE AND ADMINISTRATION].
Although no adverse events of hyponatremia were reported for FETZIMA-treated patients in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. FETZIMA should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION)
Information For Patients
Advise patients, their families, and their caregivers about the benefits and risks associated with treatment with FETZIMA and counsel them on its appropriate use. Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down [see BOX WARNING and WARNINGS AND PRECAUTIONS].
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. FETZIMA should be initiated with a dose of 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on efficacy and tolerability, FETZIMA may then be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dose is 120 mg once daily.
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.
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].
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA and triptans, tramadol, amphetamines, tryptophan supplements, other serotonergic agents, or antipsychotic drugs [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Effect On 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].
Caution patients about the concomitant use of FETZIMA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [see WARNINGS AND PRECAUTIONS].
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. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
Activation Of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].
Caution patients about using FETZIMA if they have a history of a seizure disorder [see WARNINGS AND PRECAUTIONS]. Patients with a history of seizures were excluded from clinical studies.
Advise patients not to stop taking FETZIMA without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping FETZIMA [see WARNINGS AND PRECAUTIONS].
Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking FETZIMA [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid consumption of alcohol while taking FETZIMA [see DRUG INTERACTIONS].
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with FETZIMA [see Use In Specific Populations].
Advise patients to notify their healthcare provider if they are breastfeeding an infant and would like to continue or start FETZIMA [see Use In Specific Populations].
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Levomilnacipran administered by oral gavage to rats for 2 years and Tg.rasH2 mice for 6 months did not increase the incidence of tumors in either study.
Rats received levomilnacipran at doses up to 90/70 mg/kg/day (the dose was lowered in males after 45 weeks of dosing). The 90 mg/kg/day dose is 7 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis.
Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day. This dose is 6 times the MRHD.
Levomilnacipran was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vivo micronucleus assay in rats. Additionally, levomilnacipran was not genotoxic in the in vitro mouse lymphoma (L5178Y TK+/-) cell forward mutation assay.
Impairment Of Fertility
When levomilnacipran was administered orally to male and female rats before mating, through mating and up to Day 7 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is 8 times the MRHD.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of FETZIMA in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as FETZIMA), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Levomilnacipran was not teratogenic 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. FETZIMA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Neonates exposed to SSRIs or SNRIs, 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 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 [see WARNINGS AND PRECAUTIONS].
A prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
No teratogenic effects 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.
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. 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.
It is not known if FETZIMA is present in human milk. Studies have shown that levomilnacipran is present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FETZIMA, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
Clinical studies on the use of FETZIMA in pediatric patients have not been conducted; therefore, the safety and effectiveness of FETZIMA in the pediatric population have not been established. FETZIMA is not approved for use in pediatric patients [see BOX WARNING and WARNINGS AND PRECAUTIONS].
No dose adjustment is recommended on the basis of age (see Figure 2). In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years).
Of the total number of subjects in clinical studies of FETZIMA, 2.8% of patients were age 65 or older.
Because levomilnacipran is predominately excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose [see DOSAGE AND ADMINISTRATION].
SSRIs and SNRIs, including FETZIMA, 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].
Hepatic elimination of levomilnacipran is low. Dose adjustment is not recommended in subjects with mild (Child-Pugh score of 1-6), moderate (Child-Pugh score of 7-9), or severe (Child-Pugh score of 10-13) hepatic impairment (see Figure 2).
Renal excretion plays a predominant role in the elimination of levomilnacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60-89 ml/min) renal impairment. Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30-59 ml/min) or severe (creatinine clearance of 15-29 ml/min) renal impairment (see Figure 2). FETZIMA is not recommended for patients with end stage renal disease [see DOSAGE AND ADMINISTRATION].
Dose adjustment based on gender is not recommended (see Figure 2).
Figure 2: Effect of Intrinsic Factors on Levomilnacipran PK