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Fetzima

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Fetzima

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the label.

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, placebo-controlled studies. There were 825 patients who continued from short-term studies into a one-year, 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 short-term 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 placebo-controlled 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
aTachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndrome
bPercentage 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.
cerectile dysfunction includes: erectile dysfunction, organic erectile dysfunction and psychogenic erectile dysfunction
dejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature ejaculation
etesticular pain includes: testicular pain, epididymitis, and seminal vesiculitis
fHeart rate increased also includes: orthostatic heart rate response increased
gBlood pressure increased also includes: blood pressure systolic increased, blood pressure diastolic increased and blood pressure orthostatic increased
hRash also includes: rash generalized, rash maculo-papular, rash erythematous and rash macular
i Hypotension also includes: orthostatic hypotension and dizziness postural
jHypertension 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 dose-related 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
aPercentage 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

DRUG INTERACTIONS

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)

[see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]

Serotonergic Drugs

[see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]

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

PK Interactions between Levomilnacipran (LVM) and Other Drugs - Illustration

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.

Alcohol

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

Controlled Substance

FETZIMA is not a controlled substance.

Abuse

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).

Dependence

FETZIMA has not been systematically studied in animals or humans for its potential for dependence.

Last reviewed on RxList: 8/7/2013
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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