WARNING
SUICIDAL THOUGHTS AND BEHAVIORS
ANTIDEPRESSANTS INCREASED THE RISK OF SUICIDAL THOUGHTS AND BEHAVIOR IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS IN SHORT-TERM STUDIES. THESE STUDIES DID NOT SHOW AN INCREASE IN THE RISK OF SUICIDAL THOUGHTS AND BEHAVIOR WITH ANTIDEPRESSANT USE IN PATIENTS OVER AGE 24; THERE WAS A REDUCTION IN RISK WITH ANTIDEPRESSANT USE IN PATIENTS AGED 65 AND OLDER [SEE WARNINGS AND PRECAUTIONS].
IN PATIENTS OF ALL AGES WHO ARE STARTED ON ANTIDEPRESSANT THERAPY, MONITOR CLOSELY FOR WORSENING, AND FOR EMERGENCE OF SUICIDAL THOUGHTS AND BEHAVIORS. ADVISE FAMILIES AND CAREGIVERS OF THE NEED FOR CLOSE OBSERVATION AND COMMUNICATION WITH THE PRESCRIBER [SEE WARNINGS AND PRECAUTIONS].
FETZIMA IS NOT APPROVED FOR USE IN PEDIATRIC PATIENTS [SEE USE IN SPECIFIC POPULATIONS].
INDICATIONS
FETZIMA, A SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITOR (SNRI) IS INDICATED FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD). THE EFFICACY OF FETZIMA WAS ESTABLISHED IN THREE 8-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES IN ADULT PATIENTS WITH A DIAGNOSIS OF MDD [SEE CLINICAL STUDIES].
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.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
FETZIMA (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 βFLβ ON CAP BLACK β20β ON BODY
40 MG
YELLOW CAP YELLOW BODY
BLACK βFLβ ON CAP BLACK β40β ON BODY
80 MG
PINK CAP WHITE BODY
BLACK βFLβ ON CAP BLACK β80β ON BODY
120 MG
PINK CAP PINK BODY
BLACK βFLβ ON CAP BLACK β120β ON BODY
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 βFLβ ON CAP BLACK β20β 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 βFLβ ON CAP BLACK β40β 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 βFLβ ON CAP BLACK β80β 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 βFLβ ON CAP BLACK β120β 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 βFLβ ON CAP BLACK β20β 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 βFLβ ON CAP BLACK β40β ON BODY
STORAGE AND HANDLING
ALL PACKAGE CONFIGURATIONS: STORE AT 25Β°C (77Β°F); EXCURSIONS PERMITTED BETWEEN 15Β°C AND 30Β°C (59Β°F AND 86Β°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
DISTRIBUTED BY: FOREST PHARMACEUTICALS, INC., SUBSIDIARY OF FOREST LABORATORIES, INC., ST. LOUIS, MO 63045 USA. REVISED: JULY 2014
DOSAGE AND ADMINISTRATION
GENERAL INSTRUCTION FOR USE
THE RECOMMENDED DOSE 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 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.
FETZIMA SHOULD BE TAKEN AT APPROXIMATELY THE SAME TIME EACH DAY. FETZIMA SHOULD BE SWALLOWED WHOLE. DO NOT OPEN, CHEW OR CRUSH THE CAPSULE.
MAINTENANCE/CONTINUATION/EXTENDED TREATMENT
IT IS GENERALLY AGREED THAT ACUTE EPISODES OF MAJOR DEPRESSIVE DISORDER REQUIRE SEVERAL MONTHS OR LONGER OF SUSTAINED PHARMACOLOGIC THERAPY. PATIENTS SHOULD BE REASSESSED PERIODICALLY TO DETERMINE THE NEED FOR MAINTENANCE TREATMENT AND THE APPROPRIATE DOSE FOR TREATMENT. THE EFFICACY OF FETZIMA HAS NOT BEEN ESTABLISHED BEYOND 8 WEEKS.
SPECIAL POPULATIONS
RENAL IMPAIRMENT
DOSE ADJUSTMENT IS NOT RECOMMENDED IN PATIENTS WITH MILD RENAL IMPAIRMENT (CREATININE CLEARANCE OF 60-89 ML/MIN). FOR PATIENTS WITH MODERATE RENAL IMPAIRMENT (CREATININE CLEARANCE OF 30-59 ML/MIN), THE MAINTENANCE DOSE SHOULD NOT EXCEED 80 MG ONCE DAILY. FOR PATIENTS WITH SEVERE RENAL IMPAIRMENT (CREATININE CLEARANCE OF 15-29 ML/MIN), THE MAINTENANCE DOSE SHOULD NOT EXCEED 40 MG ONCE DAILY. FETZIMA IS NOT RECOMMENDED FOR PATIENTS WITH END STAGE RENAL DISEASE [SEE USE IN SPECIFIC POPULATIONS].
DISCONTINUING TREATMENT
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].
SWITCHING A PATIENT TO OR FROM A MONOAMINE OXIDASE INHIBITOR (MAOI) INTENDED TO TREAT PSYCHIATRIC DISORDERS
AT LEAST 14 DAYS SHOULD 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].
USE OF FETZIMA WITH OTHER MAOIS SUCH AS LINEZOLID OR METHYLENE BLUE
DO NOT START FETZIMA IN A PATIENT WHO IS BEING TREATED WITH LINEZOLID OR INTRAVENOUS METHYLENE BLUE BECAUSE THERE IS AN INCREASED RISK OF SEROTONIN SYNDROME. IN A PATIENT WHO REQUIRES MORE URGENT TREATMENT OF A PSYCHIATRIC CONDITION, OTHER INTERVENTIONS, INCLUDING HOSPITALIZATION, SHOULD BE CONSIDERED [SEE CONTRAINDICATIONS].
IN SOME CASES, A PATIENT ALREADY RECEIVING FETZIMA THERAPY MAY REQUIRE URGENT TREATMENT WITH LINEZOLID OR INTRAVENOUS METHYLENE BLUE. IF ACCEPTABLE ALTERNATIVES TO LINEZOLID OR INTRAVENOUS METHYLENE BLUE TREATMENT ARE NOT AVAILABLE AND THE POTENTIAL BENEFITS OF LINEZOLID OR INTRAVENOUS METHYLENE BLUE TREATMENT ARE JUDGED TO OUTWEIGH THE RISKS OF SEROTONIN SYNDROME IN A PARTICULAR PATIENT, FETZIMA SHOULD BE STOPPED PROMPTLY, AND LINEZOLID OR INTRAVENOUS METHYLENE BLUE CAN BE ADMINISTERED. THE PATIENT SHOULD BE MONITORED FOR SYMPTOMS OF SEROTONIN SYNDROME FOR 2 WEEKS OR UNTIL 24 HOURS AFTER THE LAST DOSE OF LINEZOLID OR INTRAVENOUS METHYLENE BLUE, WHICHEVER COMES FIRST. THERAPY WITH FETZIMA MAY BE RESUMED 24 HOURS AFTER THE LAST DOSE OF LINEZOLID OR INTRAVENOUS METHYLENE BLUE [SEE WARNINGS AND PRECAUTIONS].
THE RISK OF ADMINISTERING METHYLENE BLUE BY NON-INTRAVENOUS ROUTES (SUCH AS ORAL TABLETS OR BY LOCAL INJECTION) OR IN INTRAVENOUS DOSES MUCH LOWER THAN 1 MG/KG WITH FETZIMA IS UNCLEAR. THE CLINICIAN SHOULD, NEVERTHELESS, BE AWARE OF THE POSSIBILITY OF EMERGENT SYMPTOMS OF SEROTONIN SYNDROME WITH SUCH USE [SEE WARNINGS AND PRECAUTIONS].
USE OF FETZIMA WITH STRONG INHIBITORS OF CYTOCHROME P450 (CYP3A4) ENZYME
THE DOSE OF FETZIMA SHOULD NOT EXCEED 80 MG ONCE DAILY WHEN USED WITH STRONG CYP3A4 INHIBITORS (E.G. KETOCONAZOLE, CLARITHROMYCIN, RITONAVIR) [SEE DRUG INTERACTIONS]
SIDE EFFECTS
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.
PATIENT EXPOSURE
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 PATIENTS
SYSTEM ORGAN CLASS
PREFERRED TERM
PLACEBO
(N =1040) %
FETZIMA 40-120 MG/D
(N = 1583) %
GASTROINTESTINAL DISORDERS
NAUSEA
6
17
CONSTIPATION
3
9
VOMITING
1
5
CARDIAC DISORDERS
TACHYCARDIAA
2
6
PALPITATIONS
1
5
REPRODUCTIVE SYSTEM AND BREAST DISORDERSB
ERECTILE DYSFUNCTIONC
1
6
TESTICULAR PAIND
< 1
4
EJACULATION DISORDERE
< 1
5
INVESTIGATIONS
HEART RATE INCREASEDF
1
6
BLOOD PRESSURE INCREASEDG
1
3
RENAL AND URINARY DISORDERS
URINARY HESITATION
0
4
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
HYPERHIDROSIS
2
9
RASHH
0
2
VASCULAR DISORDERS
HOT FLUSH
1
3
HYPOTENSIONI
1
3
HYPERTENSIONJ
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-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) %
FETZIMA
40 MG/D
(N = 366) %
80 MG/D
(N = 367) %
120 MG/D
(N = 180) %
URINARY HESITATION
0
4
5
6
ERECTILE DYSFUNCTIONA
2
6
8
10
A PERCENTAGE IS RELATIVE TO THE NUMBER OF MALE PATIENTS.
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:
CARDIAC DISORDERS: ANGINA PECTORIS; SUPRAVENTRICULAR AND VENTRICULAR EXTRASYSTOLES
EYE DISORDERS: DRY EYE; VISION BLURRED; CONJUNCTIVAL HEMORRHAGE
GENERAL DISORDERS: CHEST PAIN; THIRST
GASTROINTESTINAL DISORDERS: ABDOMINAL PAIN; FLATULENCE
INVESTIGATIONS DISORDERS: BLOOD CHOLESTEROL INCREASED; LIVER FUNCTION TEST ABNORMAL
NERVOUS SYSTEM DISORDERS: MIGRAINE; PARAESTHESIA; SYNCOPE; EXTRAPYRAMIDAL DISORDER
PSYCHIATRIC DISORDERS: AGITATION; ANGER; BRUXISM; PANIC ATTACK; TENSION; AGGRESSION
RENAL AND URINARY DISORDER: POLLAKIURIA; HEMATURIA; PROTEINURIA
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: YAWNING
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: DRY SKIN; PRURITUS; URTICARIA
READ THE FETZIMA (LEVOMILNACIPRAN) EXTENDED-RELEASE CAPSULES) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
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.
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.
CLINICAL PHARMACOLOGY
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).
PHARMACODYNAMICS
LEVOMILNACIPRAN BINDS WITH HIGH AFFINITY TO THE HUMAN SEROTONIN (5-HT) AND NOREPINEPHRINE (NE) TRANSPORTERS (KI = 11 AND 91 NM, RESPECTIVELY) AND POTENTLY INHIBITS 5-HT AND NE REUPTAKE (IC50 = 16-19 AND 11 NM, RESPECTIVELY). LEVOMILNACIPRAN LACKS SIGNIFICANT AFFINITY FOR ANY OTHER RECEPTORS, ION CHANNELS OR TRANSPORTERS TESTED IN VITRO, INCLUDING SEROTONERGIC (5HT1-7), ?- AND ?- ADRENERGIC, MUSCARINIC, OR HISTAMINERGIC RECEPTORS AND CA2+, NA+, K+ OR CL- CHANNELS. LEVOMILNACIPRAN DID NOT INHIBIT MONOAMINE OXIDASE (MAO).
CARDIOVASCULAR ELECTROPHYSIOLOGY
AT A DOSE 2.5 TIMES THE MAXIMUM RECOMMENDED DOSE, LEVOMILNACIPRAN DOES NOT PROLONG QTC TO ANY CLINICALLY RELEVANT EXTENT.
PHARMACOKINETICS
THE CONCENTRATION OF LEVOMILNACIPRAN AT STEADY STATE IS PROPORTIONAL TO DOSE WHEN ADMINISTERED FROM 25 TO 300 MG ONCE DAILY. FOLLOWING AN ORAL ADMINISTRATION, THE MEAN APPARENT TOTAL CLEARANCE OF LEVOMILNACIPRAN IS 21-29 L/H. STEADY-STATE CONCENTRATIONS OF LEVOMILNACIPRAN ARE PREDICTABLE FROM SINGLE-DOSE DATA. THE APPARENT TERMINAL ELIMINATION HALF-LIFE OF LEVOMILNACIPRAN IS APPROXIMATELY 12 HOURS. AFTER DAILY DOSING OF FETZIMA 120 MG, THE MEAN CMAX VALUE IS 341 NG/ML, AND THE MEAN STEADY-STATE AUC VALUE IS 5196 NGΒ·H/ML. INTERCONVERSION BETWEEN LEVOMILNACIPRAN AND ITS STEREOISOMER DOES NOT OCCUR IN HUMANS.
ABSORPTION
THE RELATIVE BIOAVAILABILITY OF LEVOMILNACIPRAN AFTER ADMINISTRATION OF FETZIMA ER WAS 92% WHEN COMPARED TO ORAL SOLUTION. LEVOMILNACIPRAN CONCENTRATION WAS NOT SIGNIFICANTLY AFFECTED WHEN FETZIMA WAS ADMINISTERED WITH FOOD.
THE MEDIAN TIME TO PEAK CONCENTRATION (TMAX) OF LEVOMILNACIPRAN IS 6-8 HOURS AFTER ORAL ADMINISTRATION.
DISTRIBUTION
LEVOMILNACIPRAN IS WIDELY DISTRIBUTED WITH AN APPARENT VOLUME OF DISTRIBUTION OF 387-473 L; PLASMA PROTEIN BINDING IS 22% OVER CONCENTRATION RANGE OF 10 TO 1000 NG/ML.
METABOLISM
LEVOMILNACIPRAN UNDERGOES DESETHYLATION TO FORM DESETHYL LEVOMILNACIPRAN AND HYDROXYLATION TO FORM P-HYDROXY-LEVOMILNACIPRAN. BOTH OXIDATIVE METABOLITES UNDERGO FURTHER CONJUGATION WITH GLUCURONIDE TO FORM CONJUGATES. THE DESETHYLATION IS CATALYZED PRIMARILY BY CYP3A4 WITH MINOR CONTRIBUTION BY CYP2C8, 2C19, 2D6, AND 2J2 [SEE DRUG INTERACTIONS].
ELIMINATION/EXCRETION
LEVOMILNACIPRAN AND ITS METABOLITES ARE ELIMINATED PRIMARILY BY RENAL EXCRETION. FOLLOWING ORAL ADMINISTRATION OF 14C-LEVOMILNACIPRAN SOLUTION, APPROXIMATELY 58% OF THE DOSE IS EXCRETED IN URINE AS UNCHANGED LEVOMILNACIPRAN. N-DESETHYL LEVOMILNACIPRAN IS THE MAJOR METABOLITE EXCRETED IN THE URINE AND ACCOUNTED FOR APPROXIMATELY 18% OF THE DOSE. OTHER IDENTIFIABLE METABOLITES EXCRETED IN THE URINE ARE LEVOMILNACIPRAN GLUCURONIDE (4%), DESETHYL LEVOMILNACIPRAN GLUCURONIDE (3%), P-HYDROXY LEVOMILNACIPRAN GLUCURONIDE (1%), AND P-HYDROXY LEVOMILNACIPRAN (1%). THE METABOLITES ARE INACTIVE [SEE DOSAGE AND ADMINISTRATION].
CLINICAL STUDIES
TREATMENT OF MAJOR DEPRESSIVE DISORDER
THE EFFICACY OF FETZIMA FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD) WAS ESTABLISHED IN THREE 8-WEEK RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES (AT DOSES 40- 120 MG ONCE DAILY) IN ADULT (18 - 78 YEARS OF AGE) OUTPATIENTS WHO MET THE DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS (DSM-IV-TR) CRITERIA FOR MDD. TWO OF THE STUDIES WERE FIXED DOSE (STUDY 1 AND STUDY 2) AND ONE STUDY WAS FLEXIBLE DOSE (STUDY 3).
IN STUDY 1, PATIENTS RECEIVED 40 MG (N = 178), 80 MG (N = 179), OR 120 MG (N = 180) OF FETZIMA ONCE DAILY, OR PLACEBO (N = 176). IN STUDY 2, PATIENTS RECEIVED EITHER 40 MG (N = 188) OR 80 MG (N = 188) OF FETZIMA ONCE DAILY, OR PLACEBO (N = 186). IN THE FLEXIBLE-DOSE STUDY (STUDY 3), PATIENTS RECEIVED 40 TO 120 MG (N = 217) OF FETZIMA ONCE DAILY, OR PLACEBO (N = 217) WITH 21%, 34%, AND 44% OF FETZIMA PATIENTS ON 40 MG, 80 MG, AND 120 MG, RESPECTIVELY AT THE END OF THEIR TREATMENT.
IN ALL THREE STUDIES, FETZIMA DEMONSTRATED SUPERIORITY OVER PLACEBO IN THE IMPROVEMENT OF DEPRESSIVE SYMPTOMS AS MEASURED BY THE MONTGOMERY-ASBERG DEPRESSION RATING SCALE (MADRS) TOTAL SCORE (SEE TABLE 5). FETZIMA ALSO DEMONSTRATED SUPERIORITY OVER PLACEBO AS MEASURED BY IMPROVEMENT IN THE SHEEHAN DISABILITY SCALE (SDS) FUNCTIONAL IMPAIRMENT TOTAL SCORE.
TABLE 5: SUMMARY OF RESULTS FOR THE PRIMARY EFFICACY ENDPOINT MADRS
POST-HOC ANALYSES OF THE RELATIONSHIPS BETWEEN TREATMENT OUTCOME AND AGE, GENDER, AND RACE DID NOT SUGGEST ANY DIFFERENTIAL RESPONSIVENESS ON THE BASIS OF THESE PATIENT CHARACTERISTICS.