Desvenlafaxine: Package Insert and Label Information (Page 2 of 6)

5.3 Elevated Blood Pressure

Patients receiving desvenlafaxine extended-release tablets should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions ( 6.1)]. Pre-existing hypertension should be controlled before initiating treatment with desvenlafaxine extended-release tablets. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine extended-release tablets. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving desvenlafaxine extended-release tablets, either dose reduction or discontinuation should be considered [see Adverse Reactions ( 6.1)].

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including desvenlafaxine extended-release tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, 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. Inform patients about the risk of bleeding associated with the concomitant use of desvenlafaxine extended-release tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing desvenlafaxine extended-release tablets.

5.5 Angle Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including desvenlafaxine extended-release tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including desvenlafaxine extended-release tablets, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania/Hypomania

During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of patients treated with desvenlafaxine extended-release tablets. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, desvenlafaxine extended-release tablets should be used cautiously in patients with a history or family history of mania or hypomania.

5.7 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration ( 2.5), Adverse Reaction ( 6.1)].

5.8 Seizure

Cases of seizure have been reported in pre-marketing clinical studies with desvenlafaxine extended-release tablets. Desvenlafaxine extended-release tablets have not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from pre-marketing clinical studies. Desvenlafaxine extended-release tablets should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including desvenlafaxine extended-release tablets. In many cases, this 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 [see Use in Specific Populations ( 8.5) and Clinical Pharmacology ( 12.3)] . Discontinuation of desvenlafaxine extended-release tablets should be considered 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.

5.10 Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of desvenlafaxine extended-release tablets) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with desvenlafaxine extended-release tablets who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of desvenlafaxine extended-release tablets should be considered.

6 ADVERSE REACTIONS

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

  • Hypersensitivity [see Contraindications ( 4)]

  • Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [see Warnings and Precautions ( 5.1)]

  • Serotonin Syndrome [see Warnings and Precautions ( 5.2)]

  • Elevated Blood Pressure [see Warnings and Precautions ( 5.3)]

  • Increased Risk of Bleeding [see Warnings and Precautions ( 5.4)]

  • Angle Closure Glaucoma [see Warnings and Precautions ( 5.5)]

  • Activation of Mania/Hypomania [see Warnings and Precautions ( 5.6)]

  • Discontinuation Syndrome [see Warnings and Precautions ( 5.7)]

  • Seizure [see Warnings and Precautions ( 5.8)]

  • Hyponatremia [see Warnings and Precautions ( 5.9)]

  • Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions ( 5.10)]

6.1 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

Desvenlafaxine extended-release tablets were evaluated for safety in 8,394 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 2,784 patient-years of exposure. Of the total 8,394 patients exposed to at least one dose of desvenlafaxine extended-release tablets; 2,116 were exposed to desvenlafaxine extended-release tablets for 6 months, representing 1,658 patient-years of exposure, and 421 were exposed for one year, representing 416 patient-years of exposure.

Adverse reactions reported as reasons for discontinuation of treatment

In the pre-marketing pooled 8-week placebo-controlled studies in patients with MDD, 1,834 patients were exposed to desvenlafaxine extended-release tablets (50 to 400 mg). Of the 1,834 patients, 12% 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 extended-release tablets (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of desvenlafaxine extended-release tablets 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 extended-release tablets treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-term study, up to 9 months, the most common was vomiting (2%).

Common adverse reactions in placebo-controlled MDD studies

The most commonly observed adverse reactions in desvenlafaxine extended-release tablets treated MDD patients in pre-marketing pooled 8-week, placebo-controlled, 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 extended-release tablets treated MDD patients and twice the rate of placebo at any dose in the pre-marketing 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 Pre-marketing Pooled MDD 8-Week Placebo-Controlled Studies
Percentage of Patients Reporting Reaction
Desvenlafaxine Extended-Release Tablets
System Organ Class Preferred Term Placebo (n=636) 50 mg (n=317) 100 mg (n=424) 200 mg (n=307) 400 mg (n=317)
Cardiac disorders
Blood pressure increased 1 1 1 2 2
Gastrointestinal disorders
Nausea 10 22 26 36 41
Dry mouth 9 11 17 21 25
Constipation 4 9 9 10 14
Vomiting 3 3 4 6 9
General disorders and administration site conditions
Fatigue 4 7 7 10 11
Chills 1 1 <1 3 4
Feeling jittery 1 1 2 3 3
Metabolism and nutrition disorders
Decreased appetite 2 5 8 10 10
Nervous system disorders
Dizziness 5 13 10 15 16
Somnolence 4 4 9 12 12
Tremor 2 2 3 9 9
Disturbance in attention <1 <1 1 2 1
Psychiatric disorders
Insomnia 6 9 12 14 15
Anxiety 2 3 5 4 4
Nervousness 1 <1 1 2 2
Abnormal dreams 1 2 3 2 4
Renal and urinary disorders
Urinary hesitation 0 <1 1 2 2
Respiratory, thoracic and mediastinal disorders
Yawning <1 1 1 4 3
Skin and subcutaneous tissue disorders
Hyperhidrosis 4 10 11 18 21
Special Senses
Vision blurred 1 3 4 4 4
Mydriasis <1 2 2 6 6
Vertigo 1 2 1 5 3
Tinnitus 1 2 1 1 2
Dysgeusia 1 1 1 1 2
Vascular 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 extended-release tablets treated MDD patients in any fixed-dose group (pre-marketing pooled 8-week, placebo-controlled, fixed-dose, clinical studies).

Table 3: Sexual Function Adverse Reactions (≥ 2% in Men or Women in any Desvenlafaxine Extended-Release Tablets Group) During the On-Therapy Period
Desvenlafaxine Extended-Release Tablets
Placebo (n=239) 50 mg (n=108) 100 mg (n=157) 200 mg (n=131) 400 mg (n=154)
Men only
Anorgasmia 0 0 3 5 8
Libido decreased 1 4 5 6 3
Orgasm abnormal 0 0 1 2 3
Ejaculation delayed <1 1 5 7 6
Erectile dysfunction 1 3 6 8 11
Ejaculation disorder 0 0 1 2 5
Ejaculation failure 0 1 0 2 2
Sexual dysfunction 0 1 0 0 2
Desvenlafaxine Extended-Release Tablets
Placebo (n=397) 50 mg (n=209) 100 mg (n=267) 200 mg (n=176) 400 mg (n=163)
Women only
Anorgasmia 0 1 1 0 3

Other adverse reactions observed in premarketing and postmarketing clinical studies

Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with desvenlafaxine extended-release tablets 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.

Nervous system disorders – Syncope, convulsion, dystonia.

Psychiatric disorders – Depersonalization, bruxism.

Renal and urinary disorders – Urinary retention.

Skin and subcutaneous tissue disorders – Rash, alopecia, photosensitivity reaction, angioedema.

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 extended-release tablets treatment as compared to placebo.

Laboratory, ECG and vital sign changes observed in MDD clinical studies

The following changes were observed in pre-marketing placebo-controlled, short-term MDD studies with desvenlafaxine extended-release tablets.

Lipids

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*
Desvenlafaxine Extended-Release Tablets
Placebo 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

Proteinuria, greater than or equal to trace, was observed in the pre-marketing 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
Desvenlafaxine Extended-Release Tablets
Placebo 50 mg 100 mg 200 mg 400 mg
Proteinuria 4 6 8 5 7

Vital sign changes

Table 6 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine extended-release tablets 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 Studies
Desvenlafaxine Extended-Release Tablets
Placebo 50 mg 100 mg 200 mg 400 mg
Blood pressure
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
Pulse rate
Supine pulse (bpm) -0.3 1.3 1.3 0.9 4.1
Weight (kg) 0.0 -0.4 -0.6 -0.9 -1.1

Treatment with desvenlafaxine extended-release tablets at all doses from 50 mg per day to 400 mg per 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 extended-release tablets pre-marketing 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 per day.

Table 7: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood Pressure
Treatment Group Proportion of Patients with Sustained Hypertension
Placebo 0.5%
Desvenlafaxine extended-release tablets 50 mg per day 1.3%
Desvenlafaxine extended-release tablets 100 mg per day 0.7%
Desvenlafaxine extended-release tablets 200 mg per day 1.1%
Desvenlafaxine extended-release tablets 400 mg per day 2.3%

Orthostatic hypotension

In the pre-marketing 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 extended-release tablets (8%, 7/87) versus placebo (2.5%, 1/40), compared to patients < 65 years of age receiving desvenlafaxine extended-release tablets (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).

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