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PRISTIQ (desvenlafaxine succinate) Adverse Reactions

Adverse Reactions

Adverse Drug Reaction Overview

The safety of PRISTIQ in major depressive disorder was evaluated in 8,453 patients exposed to at least one dose of PRISTIQ.

The most commonly observed treatment emergent adverse events (all-causality) (incidence of 5% or greater for the PRISTIQ pooled 50- to 400-mg doses, and incidence higher than placebo) in PRISTIQ treated MDD patients in clinical trials were: nausea, headache, dry mouth, dizziness, insomnia, hyperhidrosis, constipation, diarrhea, somnolence, fatigue, decreased appetite, vomiting, and blood pressure increased, and, in men, and erectile dysfunction.

Adverse Events Reported as Reasons for Discontinuation of Treatment in MDD Clinical Trials
In the 8-week placebo-controlled, pre-marketing trials for MDD, 12% of the 1,834 patients who received PRISTIQ (50-400 mg/day) discontinued treatment due to an adverse experience, compared with 3% of the 1,116 placebo-treated patients in those trials.

At the recommended dose of 50 mg, the discontinuation rate due to an adverse experience for PRISTIQ (4.1%) was similar to the rate for placebo (3.8%) and only 1% of patients discontinued due to nausea.

The most common adverse reactions leading to discontinuation (i.e., leading to discontinuation in at least 2% and incidence higher than placebo) of the PRISTIQ-treated patients in short-term trials of up to 8 weeks were: nausea (4%); dizziness, headache and vomiting (2% each).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse Reactions in MDD Clinical Trials

PRISTIQ was evaluated for safety in 8,453 patients diagnosed with major depressive disorder who participated in multiple-dose trials, representing 2,807 patient-years of exposure. Among these 8,453 PRISTIQ-treated patients, 2,495 patients participated in 8-week, placebo-controlled trials at doses ranging from 50 to 400 mg/day. Of the total 8,453 subjects exposed to at least 1 dose of PRISTIQ, 2,140 were exposed to PRISTIQ for greater than 6 months and 521 were exposed for 1 year.

Premarket Clinical Trials

Treatment-Emergent Adverse Events Occurring at an Incidence of ≥ 2% Among PRISTIQ-treated Patients in Short-Term Placebo-controlled Trials

Table 2 lists alphabetically by body system, the treatment-emergent adverse events that occurred with an incidence ≥2% and greater than placebo (pooled 8-week placebo-controlled, premarket clinical trials).

Reported treatment emergent adverse events were classified using a standard MedDRA-based Dictionary terminology.

Table 2:Treatment Emergent Adverse Events (≥2% in Any PRISTIQ Group and More Frequent than Placebo): Percentage of Subjects in Short-Term, Placebo-Controlled MDD Studies

 

Percentage of Patients Reporting Reaction

 

PRISTIQ

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

   Palpitations

2

1

3

2

3

   Tachycardia

1

1

<1

1

2

Ear and labyrinth disorders

   Tinnitus

1

2

1

1

2

   Vertigo

1

2

1

5

3

Eye disorders

   Eye pain

<1

1

2

<1

<1

   Mydriasis

<1

2

2

6

6

   Vision blurred

1

3

4

4

4

Gastrointestinal disorders

   Abdominal pain

2

4

3

1

3

   Constipation

4

9

9

10

14

   Diarrhea

9

11

9

7

5

   Dry mouth

9

11

17

21

25

   Dyspepsia

4

2

3

3

5

   Flatulence

1

2

2

2

2

   Nausea

10

22

26

36

41

   Stomach discomfort

1

2

1

1

1

   Vomiting

3

3

4

6

9

General disorders and administration site conditions

   Chest pain

0

0

1

1

2

   Chills

1

1

<1

3

4

   Fatigue

4

7

7

10

11

   Feeling jittery

1

1

2

3

3

   Irritability

1

2

2

2

2

Infections and infestations

   Gastroenteritis viral

1

0

1

2

<1

   Influenza

1

1

1

2

4

   Sinusitis

1

2

1

2

2

   Urinary tract infection

<1

1

1

1

2

Injury, poisoning and procedural complications

   Accidental overdose

1

0

1

1

2

Investigations

  Blood pressure increased

1

1

1

2

2

  Weight decreased

1

2

1

1

2

Metabolism and nutrition disorders

   Decreased appetite

2

5

8

10

10

   Increased appetite

1

2

1

0

1

Musculoskeletal and connective tissue disorders

   Muscle spasms

1

2

3

2

2

   Muscle tightness

1

1

2

1

<1

Nervous system disorders

   Disturbance in attention

<1

<1

1

2

1

   Dizziness

5

13

10

15

16

   Dysgeusia

1

1

1

1

2

   Headache

23

20

22

29

25

   Migraine

1

1

<1

1

2

   Paresthesia

1

2

2

1

3

   Sedation

1

2

4

3

4

   Somnolence

4

4

9

12

12

   Tremor

2

2

3

9

9

Psychiatric disorders

   Abnormal dreams

1

2

3

2

4

   Agitation

1

0

1

1

3

   Anorgasmia

0

<1

2

2

6

   Anxiety

2

3

5

4

4

   Initial insomnia

1

2

2

0

2

   Insomnia

6

9

12

14

15

   Libido decreased

1

2

3

3

2

   Middle insomnia

1

1

1

3

3

   Nervousness

1

<1

1

2

2

   Orgasm abnormal

<1

1

1

1

2

   Sleep disorder

<1

1

<1

2

1

Renal and urinary disorders

   Dysuria

<1

<1

0

3

2

   Urinary hesitation

0

<1

1

2

2

Reproductive system and breast disorder

   Dysmenorrhea

1

0

1

2

<1

   Ejaculation delayed

<1

<1

2

3

3

   Ejaculation disorder

0

0

1

1

2

   Erectile dysfunction

1

1

2

3

5

Respiratory, thoracic and mediastinal disorders

   Yawning

<1

1

1

4

3

Skin and subcutaneous tissue disorders

   Hyperhidrosis

4

10

11

18

21

   Night sweats

1

2

1

1

1

   Rash

<1

1

1

2

<1

Vascular disorders

   Hot flush

<1

1

1

2

2

   Hypertension

1

1

1

2

1

Sexual Dysfunction Treatment Emergent Adverse Events

Table 3 shows the incidence of sexual dysfunction treatment emergent adverse events that occurred in ≥1% PRISTIQ-treated MDD patients in any fixed dose group (8-week, placebo-controlled, fixed and flexible-dose, pre-marketing clinical trials).

Table 3: Sexual Dysfunction Treatment Emergent Adverse Events (≥ 1% in Men or Women in any PRISTIQ Group) During the On-Therapy Period: Percentage of Subjects in Short-Term, Placebo-Controlled MDD Studies

 

PRISTIQ

 

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

 

PRISTIQ

 

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 Treatment Emergent Adverse Events Observed During Pre-Market and Post-Market Clinical Trials

All MDD Clinical Trials

The following is a list of MedDRA preferred terms that reflect treatment-emergent adverse events that were reported by patients treated with PRISTIQ throughout the dose ranges studied (10 to 400 mg) during both short-term and long-term clinical trials. In general, the adverse events were most frequent in the first week of treatment.

Treatment Emergent Adverse Events are categorized by system organ class and listed in order of decreasing frequency using the following definitions:

Very common: ≥10% of patients
Common: ≥1% and <10% of patients
Uncommon: ≥0.1% and <1% of patients
Rare: ≥0.01% and <0.1% of patients
Very rare: <0.01% of patients

System Organ Class

Treatment Emergent Adverse Events

Immune System Disorders

Uncommon

Hypersensitivity

Metabolism and Nutrition Disorders

Common

Decreased appetite

Rare

Hyponatraemia

Psychiatric Disorders

Very common

Insomnia

Common

Withdrawal syndrome, anxiety, nervousness, abnormal dreams, irritability, libido decreased, anorgasmia

Uncommon

Depersonalisation, orgasm abnormal

Rare

Mania, hypomania, hallucination

Nervous System Disorders

Very common

Headache, dizziness, somnolence

Common

Tremor, paraesthesia, disturbance in attention, dysgeusia

Uncommon

Syncope, dyskinesia

Rare

Convulsion, dystonia

Eye Disorders

Common

Vision blurred, mydriasis

Ear and Labyrinth Disorders

Common

Vertigo, tinnitus

Cardiac Disorders

Common

Palpitations, tachycardia

Vascular Disorders

Common

Blood pressure increased, hot flush

Uncommon

Orthostatic hypotension, peripheral coldness

Respiratory, Thoracic and Mediastinal Disorders

Common

Yawning

Uncommon

Epistaxis

Gastrointestinal Disorders

Very common

Nausea, dry mouth

Common

Constipation, diarrhea, vomiting

Skin and Subcutaneous Tissue Disorders

Very common

Hyperhidrosis

Common

Rash

Uncommon

Alopecia

Rare

Angioedema, photosensitivity reaction

Musculoskeletal, Connective Tissue and Bone Disorders

Common

Musculoskeletal stiffness

Renal and Urinary Disorders

Uncommon

Urinary retention, urinary hesitation, proteinuria

Reproductive System and Breast Disorders

Common

Erectile dysfunction*, ejaculation delayed*

Uncommon

Ejaculation disorder*, ejaculation failure*, sexual dysfunction

General Disorders and Administration Site Conditions

Common

Fatigue, asthenia, chills, feeling jittery

Investigations

Common

Liver function test abnormal, weight increased, weight decreased

Uncommon

Blood cholesterol increased, blood triglycerides increased, blood prolactin increased

* Frequency is calculated based on men only.

ADR = adverse drug reaction; MDD = major depressive disorder.

Ischemic cardiac adverse events

In clinical trials, 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 desvenlafaxine treatment as compared to placebo (see WARNINGS AND PRECAUTIONS/Cardiovascular/Cerebrovascular).

Discontinuation Symptoms

Adverse drug reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD pre-market clinical trials at a rate of ≥5% include: dizziness, nausea, headache, irritability, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS).

Orthostatic Hypotension

Of the 4,158 patients in pre-market clinical trials with PRISTIQ, 6% were 65 years of age or older. No overall differences in safety or efficacy were detected between these subjects and younger subjects. However, there was a higher incidence of orthostatic hypotension in patients ≥ 65 years of age compared to patients <65 years of age treated with desvenlafaxine. Greater sensitivity of some older individuals cannot be ruled out. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see DOSAGE AND ADMINISTRATION, Dosing Considerations, Geriatrics and ACTION AND CLINICAL PHARMACOLOGY, Geriatrics).

ECG Changes

Electrocardiograms were obtained from 1,492 PRISTIQ-treated patients with major depressive disorder and 984 placebo-treated patients in pre-market clinical trials 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 (see ACTION AND CLINICAL PHARMACOLOGY).

A thorough QTc study was designed to assess the potential effect of 200 and 600 mg of PRISTIQ on QT interval prolongation.

Table 4: Estimated and 90% Confidence Interval for QTc Changes from Time-Matched Baseline Relative to Placebo at Hour 8 after Dose with Different Heart Rate Correctionsa
a. Mean (90% confidence intervals)
b. The PRISTIQ doses of 200 and 600 mg were 2 and 6 times the maximum recommended dose, respectively.
TreatmentFridericia’s QT Correction
(ms)
Population QT Correction
(ms)
PRISTIQ 200 mgb1.5
(-0.88, 3.88)
3.18
(0.87, 5.50)
PRISTIQ 600 mgb-2.43
(-4.90, 0.04)
0.98
(-1.42, 3.38)
Moxifloxacin 400 mg
(Active control)
10.80
(8.44, 13.16)
10.92
(8.62, 13.22)

Abnormal Hematologic and Clinical Chemistry Findings

Serum Lipids
Elevations in fasting serum total cholesterol, LDL cholesterol, and triglycerides occurred in the controlled trials. Some of these abnormalities were considered potentially clinically significant (see WARNINGS AND PRECAUTIONS, Serum Cholesterol Elevation and Monitoring and Laboratory Tests, Serum Lipids).

The percentage of subjects who exceeded a predetermined threshold for values of outliers is represented in Table 5.

Table 5: Proportion (%) of Subjects With Lipid Abnormalities of Potential Clinical Significance for All Short-Term, Placebo-Controlled Clinical Trials
a. Includes data from all short-term, placebo-controlled studies including fixed-dose and flexible-dose studies.
  ---------------------- PRISTIQ------------------------
 Placeboa50 mg100 mg200 mg400 mg50-400 mga
Total Cholesterol
Increase ≥1.29 mmol/L and absolute value
≥6.75 mmol/L
2344105
LDL Cholesterol
Increase ≥1.29 mmol/L and absolute value
≥4.91 mmol/L
<110121
Triglycerides
≥3.7 mmol/L
321463

Proteinuria

In pre-market placebo-controlled studies 6.4% of subjects treated with PRISTIQ had treatment-emergent proteinuria. Proteinuria was usually of trace amounts and was not associated with increases in BUN or creatinine or adverse events. The mechanism of the enhanced protein excretion is not clear but may be related to noradrenergic stimulation.

Vital Sign Changes

Tables 6 and 7 summarize the changes that were observed in pre-market placebo-controlled, short-term, premarketing trials with PRISTIQ in patients with MDD.

Table 6: Mean Changes, Vital Signs, at Final On-Therapy for All Short-term, Fixed-dose Controlled Trials
  ----------------------PRISTIQ----------------------
 Placebo50 mg100 mg200 mg400 mg
Blood Pressure
  Supine systolic bp (mm Hg)
-1.41.22.02.52.1
  Supine diastolic bp (mm Hg)-0.60.70.81.82.3
Pulse rate     
  Supine pulse (bpm)-0.31.31.30.94.1
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 trial 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.

Table 7 provides the incidence of patients meeting criteria for sustained hypertension (defined as treatment-emergent supine diastolic blood pressure ≥ 90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits).

Table 7: Incidence (%) of Patients with Sustained Hypertension for All Short-Term Fixed-Dose Clinical Trials
  ----------------------- PRISTIQ--------------------
 Placebo50 mg100 mg200 mg400 mg
Sustained hypertension0.51.30.71.12.3

Adverse Events Identified During Post-Approval Use

The following adverse events have 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:

Nervous System Disorder: serotonin syndrome
Skin and subcutaneous tissue disorders – Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythema multiforme

Gastrointestinal – gastrointestinal bleeding, pancreatitis acute

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