"The U.S. Food and Drug Administration today approved the first generic versions of Cymbalta (duloxetine delayed-release capsules), a prescription medicine used to treat depression and other conditions.
Aurobindo Pharma Ltd., Dr. Reddy's La"...
The following adverse reactions are discussed in greater detail in other sections of the label.
- Hypersensitivity [see CONTRAINDICATIONS]
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
- Elevated Blood Pressure [see WARNINGS AND PRECAUTIONS]
- Elevated Heart Rate [see WARNINGS AND PRECAUTIONS]
- Abnormal Bleeding [see WARNINGS AND PRECAUTIONS]
- Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
- Urinary Hesitation or Retention [see WARNINGS AND PRECAUTIONS]
- Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
- Seizure [see WARNINGS AND PRECAUTIONS]
- Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS]
- Hyponatremia [see WARNINGS AND PRECAUTIONS]
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.
The safety of FETZIMA was evaluated in 2,673 patients (18-78 years of age) diagnosed with MDD who participated in clinical studies, representing 942 patient-years of exposure. Among the 2,673 FETZIMA-treated patients, 1,583 were exposed to FETZIMA in short-term, placebocontrolled studies. There were 825 patients who continued from short-term studies into a oneyear, open-label extension study.
Of the 2,673 patients exposed to at least one dose of FETZIMA, 737 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 40-120 mg once daily and was given without regard to food.
Adverse Reactions Reported As Reasons For Discontinuation Of Treatment
In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received FETZIMA (40-120 mg) discontinued treatment due to an adverse event, 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 shortterm placebo-controlled studies was nausea (1.5%).
Common Adverse Reactions In Placebo-Controlled MDD Studies
The most commonly observed adverse events in FETZIMA-treated MDD patients in placebocontrolled studies (incidence ≥ 5% and at least twice the rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, 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
|System Organ Class
(N =1040) %
|FETZIMA 40-120 mg/d
(N = 1583) %
|Reproductive system and breast disordersb|
|Testicular paind||< 1||4|
|Ejaculation disordere||< 1||5|
|Heart rate increasedf||1||6|
|Blood pressure increasedg||1||3|
|Renal and urinary disorders|
|Skin and subcutaneous tissue disorders|
|Metabolism and nutrition disorders|
|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-related Adverse Reactions
In pooled data from the short-term placebo-controlled fixed-dose studies, there were no doserelated adverse reactions (greater than 2% overall incidence) in patients treated with FETZIMA across the dose range 40-120 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) %
(N = 366) %
(N = 367) %
(N = 180) %
|a Percentage is relative to the number of male
N = number of patients in the Safety Population
Other Adverse Reactions Observed In Clinical Studies
Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with FETZIMA were:
General disorders: Chest pain; Thirst
Gastrointestinal disorders: Abdominal pain; Flatulence
Investigations disorders: Blood cholesterol increased; Liver function test abnormal
Respiratory, thoracic and mediastinal disorders: Yawning
Read the Fetzima (levomilnacipran) extended-release capsules) Side Effects Center for a complete guide to possible side effects
Other than CYP3A4 drug interactions, FETZIMA is predicted, based on in vitro studies, to have a low potential to be involved in clinically significant pharmacokinetic drug interactions.
Monoamine Oxidase Inhibitors (MAOIs)
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when FETZIMA is initiated or discontinued [see WARNINGS AND PRECAUTIONS].
Potential For Other Drugs To Affect FETZIMA
Dose adjustment is recommended when FETZIMA is co-administered with strong inhibitors of CYP3A4 (e.g. ketoconazole) [see DOSAGE AND ADMINISTRATION]. An in vivo study showed a clinically meaningful increase in levomilnacipran exposure when FETZIMA was coadministered with the CYP3A4 inhibitor ketoconazole (see Figure 1). No dose adjustment of FETZIMA is needed when co-administered with a CYP3A4 inducer or substrate. In vivo studies showed no clinically meaningful change in levomilnacipran exposure when co-administered with the CYP3A4 inducer carbamazepine or the CYP3A4 substrate alprazolam (see Figure 1).
No dose adjustment of FETZIMA is needed when co-administered with inhibitors of CYP2C8 , CYP2C19, CYP2D6, CYP2J2, P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is a weak substrate of P-gp.
Figure 1 : PK Interactions between Levomilnacipran
(LVM) and Other Drugs
Potential For FETZIMA To Affect Other Drugs
No dose adjustment of the concomitant medication is recommended when FETZIMA is administered with a substrate of CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies have shown that levomilnacipran is not an inhibitor of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Concomitant use of FETZIMA with alprazolam or carbamazepine, substrates of CYP3A4, had no significant effect on alprazolam or carbamazepine plasma concentrations (see Figure 1).
Central Nervous System (CNS)-Active Agents
The risk of using FETZIMA in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when FETZIMA is prescribed in combination with other CNS-active drugs, including those with a similar mechanism of action.
In an in vitro study, alcohol interacted with the extended-release properties of FETZIMA. If FETZIMA is taken with alcohol, a pronounced accelerated drug release may occur. It is recommended that FETZIMA extended-release capsules not be taken with alcohol.
Drug Abuse And Dependence
FETZIMA is not a controlled substance.
FETZIMA 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 FETZIMA (e.g., development of tolerance or drug-seeking behavior).
FETZIMA has not been systematically studied in animals or humans for its potential for dependence.
Last reviewed on RxList: 11/24/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Fetzima Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get tips on therapy and treatment.