"The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.
Major depressive disorder (MDD), commonly referred to as depression, is a mental disorder characterized by mo"...
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]
- Abnormal Bleeding [see WARNINGS AND PRECAUTIONS]
- Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
- Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
- Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS]
- Seizure [see WARNINGS AND PRECAUTIONS]
- Hyponatremia [see WARNINGS AND PRECAUTIONS]
- Interstitial Lung Disease and Eosinophilic Pneumonia [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.
Desvenlafaxine was evaluated for safety in 4,158 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 1,677 patient-years of exposure. Among these 4,158 desvenlafaxine treated patients; 1,834 patients were exposed to desvenlafaxine in 8-week, placebo-controlled studies at doses ranging from 50 to 400 mg/day. Out of the 1,834 patients, 687 desvenlafaxine treated patients continued into a 10-month open-label study. Of the total 4,158 patients exposed to at least one dose of desvenlafaxine; 1,320 were exposed to desvenlafaxine for 6 months, representing 1058 patient-years of exposure, and 274 were exposed for one year, representing 241 patient-years of exposure.
Adverse Reactions Reported As Reasons For Discontinuation Of Treatment
In the pooled 8-week placebo-controlled studies in patients with MDD, 12% of the 1,834 patients who received desvenlafaxine (50 to 400 mg) discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of desvenlafaxine the discontinuation rate due to an adverse reaction was 8.7%.
The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than placebo of the desvenlafaxine treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each); in the longer-term studies, up to 11 months, the most common was vomiting (2%).
Common Adverse Reactions In Placebo-Controlled MDD Studies
The most commonly observed adverse reactions in desvenlafaxine treated MDD patients in short-term fixed-dose studies (incidence ≥ 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders.
Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of desvenlafaxine treated MDD patients and twice the rate of placebo at any dose in the pooled 8-week, placebo-controlled, fixed dose clinical studies
Table 2: Common Adverse Reactions ( ≥ 2% in any
Fixed-Dose Group and Twice the Rate of Placebo) in Pooled MDD 8-Week
|System Organ Class Preferred Term||Placebo
|Percentage of Patients Reporting Reaction|
|Blood pressure increased||1||1||1||2||2|
|General disorders and administration site conditions|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Disturbance in attention||< 1||< 1||1||2||1|
|Renal and urinary disorders|
|Urinary hesitation||0||< 1||1||2||2|
|Respiratory, thoracic and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|Hot flush||< 1||1||1||2||2|
Sexual Function Adverse Reactions
Table 3 shows the incidence of sexual function adverse reactions that occurred in ≥ 2% of desvenlafaxine treated MDD patients in any fixed-dose group (pooled 8-week, placebo-controlled, fixed and flexible-dose, clinical studies).
Table 3: Sexual Function Adverse
Reactions ( ≥ 2% in Men or Women in any Desvenlafaxine Group) During the
|Ejaculation delayed||< 1||1||5||7||6|
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 desvenlafaxine were:
Cardiac disorders – tachycardia.
General disorders and administration site conditions – Asthenia.
Investigations – Weight increased, liver function test abnormal, blood prolactin increased.
Musculoskeletal and connective tissue disorders – Musculoskeletal stiffness.
Psychiatric disorders – Depersonalization, bruxism.
Renal and urinary disorders – Urinary retention.
In clinical studies, there were uncommon reports of ischemic cardiac adverse reactions, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo.
Laboratory, ECG And Vital Sign Changes Observed In MDD Clinical Studies
The following changes were observed in placebo-controlled, short-term MDD studies with desvenlafaxine.
Elevations in fasting serum total cholesterol, LDL (low density lipoproteins) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant.
The percentage of patients who exceeded a predetermined threshold value is shown in Table 4.
Table 4: Incidence (%) of Patients With Lipid
Abnormalities of Potential Clinical Significance*
|50 mg||100 mg||200 mg||400 mg|
|Total Cholesterol *(Increase of ≥ 50 mg/dl and an absolute value of ≥ 261 mg/dl)||2||3||4||4||10|
|LDL Cholesterol *(Increase ≥ 50 mg/dl and an absolute value of ≥ 190 mg/dl)||0||1||0||1||2|
|Triglycerides, fasting *(Fasting: ≥ 327 mg/dl)||3||2||1||4||6|
Proteinuria, greater than or equal to trace, was observed in the fixed-dose controlled studies (see Table 5). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.
Table 5: Incidence (%) of
Patients with Proteinuria in the Fixed-dose Clinical Studies
|50 mg||100 mg||200 mg||400 mg|
Vital sign changes
Table 6 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine in patients with MDD (doses 50 to 400 mg).
Table 6: Mean Changes in
Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled
|50 mg||100 mg||200 mg||400 mg|
|Supine systolic bp (mm Hg)||-1.4||1.2||2.0||2.5||2.1|
|Supine diastolic bp (mm Hg)||-0.6||0.7||0.8||1.8||2.3|
|Supine pulse (bpm)||-0.3||1.3||1.3||0.9||4.1|
Treatment with desvenlafaxine at all doses from 50 mg/day to 400 mg/day in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 7). Analyses of patients in desvenlafaxine short-term controlled studies who met criteria for sustained hypertension revealed a consistent increase in the proportion of patients who developed sustained hypertension. This was seen at all doses with a suggestion of a higher rate at 400 mg/day.
Table 7: Proportion of
Patients with Sustained Elevation of Supine Diastolic Blood Pressure
|Treatment Group||Proportion of Patients with Sustained Hypertension|
|Desvenlafaxine 50 mg/day||1.3%|
|Desvenlafaxine 100 mg/day||0.7%|
|Desvenlafaxine 200 mg/day||1.1%|
|Desvenlafaxine 400 mg/day||2.3%|
In the short-term, placebo-controlled clinical studies with doses of 50 to 400 mg, systolic orthostatic hypotension (decrease ≥ 30 mm Hg from supine to standing position) occurred more frequently in patients ≥ 65 years of age receiving desvenlafaxine (8%, 7/87) versus placebo (2.5%, 1/40), compared to patients < 65 years of age receiving desvenlafaxine (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).
The following adverse reaction has been identified during post-approval use of desvenlafaxine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Skin and subcutaneous tissue disorders –Stevens-Johnson syndrome.
Read the Khedezla (desvenlafaxine extended-release tablets) Side Effects Center for a complete guide to possible side effects
Monoamine Oxidase Inhibitors (MAOIs)
Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties similar to desvenlafaxine (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI. [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
Based on the mechanism of action of KHEDEZLA and the potential for serotonin syndrome, caution is advised when KHEDEZLA is co-administered with other drugs that may affect the serotonergic neurotransmitter systems. [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 that 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 KHEDEZLA is initiated or discontinued [see WARNINGS AND PRECAUTIONS].
Potential For Desvenlafaxine To Affect Other Drugs
Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. Substrates primarily metabolized by CYP2D6 (e.g., desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) should be dosed at the original level when co-administered with KHEDEZLA 100 mg or lower. Reduce the dose of these substrates by one-half if co-administered with 400 mg of KHEDEZLA. The substrate dose should be increased to the original level when 400 mg of KHEDEZLA is discontinued.
Other Drugs Containing Desvenlafaxine Or Venlafaxine
Avoid use of KHEDEZLA with other desvenlafaxine-containing products or venlafaxine products. The concomitant use of KHEDEZLA with other desvenlafaxine-containing products or venlafaxine will increase desvenlafaxine blood levels and increase dose-related adverse reactions [see ADVERSE REACTIONS].
A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking KHEDEZLA.
Drug Abuse And Dependence
KHEDEZLA is not a controlled substance.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/8/2014
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