ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label;
- Hypersensitivity [see Contraindications (
4.1
)]
- Effects on blood pressure [see Warnings and Precautions (
5.3
)]
- Abnormal bleeding [see Warnings and Precautions (
5.4
)]
- Mydriasis [see Warnings and Precautions (
5.5
)]
- Hypomania and mania [see Warnings and Precautions (
5.6
)]
- Serum cholesterol and triglyceride elevation [see Warnings and Precautions (
5.8
)]
- Seizure [see Warnings and Precautions (
5.11
)]
Clinical Studies Experience
The most commonly observed adverse reactions in PRISTIQ 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.
Adverse reactions reported as reasons for discontinuation of treatment
Combined across 8-week placebo-controlled pre-marketing studies for major depressive disorder, 12% of the 1,834 patients who received PRISTIQ (50-400 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,116 placebo-treated patients in those studies. At the recommended dose of 50 mg, the discontinuation rate due to an adverse event for PRISTIQ (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of PRISTIQ the discontinuation rate due to an adverse event was 8.7%.
The most common adverse reactions leading to discontinuation in at least 2% of the PRISTIQ treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each); in the long-term study, up to 9 months, the most common was vomiting (2%).
Patient exposure
PRISTIQ was evaluated for safety in 3,292 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 1,289 patient-years of exposure. Among these 3,292 PRISTIQ treated patients, 1,834 patients were exposed to PRISTIQ in 8-week, placebo-controlled studies at doses ranging from 50 to 400 mg/day. Out of the 1,834 patients, 687 PRISTIQ treated patients continued into a 10-month open-label study. Of the total 3,292 patients exposed to at least one dose of PRISTIQ, 1,070 were exposed to PRISTIQ for 6 months, representing 842 patient-years of exposure, and 274 were exposed for one year, representing 241 patient-years of exposure.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Common adverse reactions in placebo-controlled MDD studies
Table 3 shows the incidence of common adverse reactions that occurred in ≥ 2% of PRISTIQ treated MDD patients at any dose in the 8-week, placebo-controlled, fixed dose, pre-marketing clinical studies. In general, the adverse reactions were most frequent in the first week of treatment.
Table 3: Common Adverse Reactions: Percentage of Patients (≥ 2% in any Fixed-Dose Group) in MDD 8‑Week Placebo-Controlled Studiesa
|
Percentage of Patients Reporting Reaction
|
|
|
PRISTIQ
|
System Organ Class
Preferred Term
|
Placebo
|
50 mg
|
100 mg
|
200 mg
|
400 mg
|
Cardiac disorders
|
Palpitations |
2 |
1 |
3 |
2 |
3 |
Tachycardia |
1 |
1 |
<1 |
1 |
2 |
Blood pressure increased |
1 |
1 |
1 |
2 |
2 |
Gastrointestinal disorders
|
Nausea |
10 |
22 |
26 |
36 |
41 |
Dry mouth |
9 |
11 |
17 |
21 |
25 |
Diarrhea |
9 |
11 |
9 |
7 |
5 |
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 |
Asthenia |
1 |
1 |
2 |
1 |
1 |
Metabolism and nutrition disorders
|
Decreased appetite |
2 |
5 |
8 |
10 |
10 |
Weight decreased |
1 |
2 |
1 |
1 |
2 |
Nervous system disorders
|
Dizziness |
5 |
13 |
10 |
15 |
16 |
Somnolence |
4 |
4 |
9 |
12 |
12 |
Headache |
23 |
20 |
22 |
29 |
25 |
Tremor |
2 |
2 |
3 |
9 |
9 |
Paraesthesia |
1 |
2 |
2 |
1 |
3 |
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 |
Irritability |
1 |
2 |
2 |
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 |
Rash |
<1 |
1 |
1 |
2 |
<1 |
Special Senses
|
Vision blurred |
1 |
3 |
4 |
4 |
4 |
Mydriasis |
<1 |
2 |
2 |
6 |
6 |
Tinnitus |
1 |
2 |
1 |
1 |
2 |
Dysgeusia |
1 |
1 |
1 |
1 |
2 |
Vascular disorders
|
Hot flush |
<1 |
1 |
1 |
2 |
2 |
a: Percentage based on the number of patients (placebo, n = 636; PRISTIQ 50 mg, n = 317; PRISTIQ 100 mg, n = 424; PRISTIQ 200 mg, n = 307; PRISTIQ 400 mg, n = 317). |
Sexual function adverse reactions
Table 4 shows the incidence of sexual function adverse reactions that occurred in ≥ 2% of PRISTIQ treated MDD patients in any fixed-dose group (8-week, placebo-controlled, fixed and flexible-dose, pre-marketing clinical studies).
Table 4: Sexual Function Disorders: Adverse Reactions (≥ 2% in Mena or Womenb in any PRISTIQ Group) During the On-Therapy Period
|
|
PRISTIQ
|
System Organ Class
Preferred Term
|
Placebo
|
50 mg
|
100 mg
|
200 mg
|
400 mg
|
a: Percentage based on the number of men (placebo, n = 239; PRISTIQ 50 mg, n = 108; PRISTIQ 100 mg, n = 157; PRISTIQ 200 mg, n = 131; PRISTIQ 400 mg, n = 154).
b: Percentage based on the number of women (placebo, n = 397; PRISTIQ 50 mg, n = 209; PRISTIQ 100 mg, n = 267; PRISTIQ 200 mg, n = 176; PRISTIQ 400 mg, n = 163).
|
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 |
Women only
|
Anorgasmia |
0 |
1 |
1 |
0 |
3 |
Other adverse reactions observed in pre-marketing clinical studies
Other infrequent adverse reactions, not described elsewhere in section 6.1, occurring at an incidence of < 2% in MDD patients treated with PRISTIQ were:
Immune system disorders –
Hypersensitivity.
Investigations –
Weight increased, liver function test abnormal, blood prolactin increased.
Nervous system disorders –
Convulsion, syncope, extrapyramidal disorder.
Musculoskeletal and connective tissue disorders –
Musculoskeletal stiffness.
Psychiatric disorders –
Depersonalization, hypomania.
Respiratory, thoracic and mediastinal disorders –
Epistaxis.
Vascular disorders –
Orthostatic hypotension.
In clinical studies, there were uncommon reports of ischemic cardiac adverse events, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during PRISTIQ treatment as compared to placebo [see Warnings and Precautions (
5.7
)].
Discontinuation events
Adverse events reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical studies at a rate of ≥ 5% include: dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy [see Dosage and Administration (
2.4) and Warnings and Precautions (
5.9
)].
Laboratory, ECG and vital sign changes observed in MDD clinical studies
The following changes were observed in placebo-controlled, short-term, pre-marketing MDD studies with PRISTIQ.
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 [see Warnings and Precautions (
5.8
)].
The percentage of patients who exceeded a predetermined threshold value is shown in Table 5.
Table 5: Incidence (%) of Patients With Lipid Abnormalities of Potential Clinical Significance*
|
|
PRISTIQ
|
|
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 fixed-dose controlled studies (see Table 6). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.
Table 6: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical Studies
|
|
PRISTIQ
|
|
Placebo
|
50 mg
|
100 mg
|
200 mg
|
400 mg
|
Proteinuria |
4 |
6 |
8 |
5 |
7 |
ECG changes
Electrocardiograms were obtained from 1,492 PRISTIQ treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between PRISTIQ treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval.
Vital sign changes
Table 7 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with PRISTIQ in patients with MDD (doses 50 to 400 mg).
Table 7: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled Studies
|
|
PRISTIQ
|
|
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 |
At the final on-therapy assessment in the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to PRISTIQ during the initial 12-week, open-label phase, there was no statistical difference in mean weight change between PRISTIQ and placebo-treated patients.
Orthostatic hypotension
In the short-term, placebo-controlled clinical studies with doses of 50-400 mg, systolic orthostatic hypotension (decrease ≥ 30 mm Hg from supine to standing position) occurred more frequently in patients ≥ 65 years of age receiving PRISTIQ (8.0%, 7/87) versus placebo (2.5%, 1/40), compared to patients < 65 years of age receiving PRISTIQ (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).
Adverse Reactions Identified During Post-Approval Use
The following adverse reaction has been identified during post-approval use of PRISTIQ. Because post-approval 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
– Angioedema.
Adverse Reactions Reported With Other SNRIs
Although the following are not considered adverse reactions for PRISTIQ, they are adverse reactions for other SNRIs and may also occur with PRISTIQ: gastrointestinal bleeding, hallucinations, photosensitivity reactions and severe cutaneous reactions (such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and/or erythema multiforme).
|