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ZOLOFT (sertraline hydrochloride) Adverse Reactions

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Adverse Reactions

Depression:

In clinical development programs, ZOLOFT (sertraline hydrochloride) has been evaluated in 1902 subjects with depression. The most commonly observed adverse events associated with the use of ZOLOFT were: gastrointestinal complaints; including nausea, diarrhea/loose stools and dyspepsia; male sexual dysfunction (primarily ejaculatory delay) (see PRECAUTIONS); insomnia and somnolence; tremor; increased sweating and dry mouth; and dizziness. In the fixed dose placebo controlled study, the overall incidence of side effects was dose related with a majority occurring in the patients treated with 200 mg dose.

The discontinuation rate due to adverse events was 15% in 2710 subjects who received ZOLOFT in premarketing multiple dose clinical trials. The more common events (reported by at least 1% of subjects) associated with discontinuation included agitation, insomnia, male sexual dysfunction (primarily ejaculatory delay), somnolence, dizziness, headache, tremor, anorexia, diarrhea/loose stools, nausea and fatigue.Table 1 enumerates adverse events that occurred at a frequency of 1% or more among ZOLOFT patients who participated in controlled trials comparing titrated ZOLOFT with placebo for depression in adults.

TABLE 1
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS FOR DEPRESSION IN ADULTS*
*
Events reported by at least 1% of patients treated with ZOLOFT are included.
(1)
%based on male patients only: 271 ZOLOFT and 271 placebo patients. Male sexual dysfunction can be broken down into the categories of decreased libido, impotence and ejaculatory delay. In this data set, the percentages of males in the ZOLOFT group with these complaints are 4.8%, 4.8% and 8.9%, respectively. It should be noted that since some ZOLOFT patients reported more than one category of male sexual dysfunction, the incidence of each category of male sexual dysfunction combined is larger than the incidence for the general category of male sexual dysfunction, in which each patient is counted only once.
(2)

% based on female patient only: 590 ZOLOFT and 582 placebo patients.

 

Percent of Patients Reporting

ADVERSE EVENTS

ZOLOFT

(N=861)

PLACEBO

(N=853)

Autonomic Nervous System Disorders

Mouth Dry

Sweating Increased

16.3

8.4

9.3

2.9

Cardiovascular

Palpitations

Chest Pain

3.5

1.0

1.6

1.6

Centr. & Periph. Nerv. System Disorders

Headache

Dizziness

Tremor

Paresthesia

Hypoesthesia

Twitching

Hypertonia

20.3

11.7

10.7

2.0

1.7

1.4

1.3

19.0

6.7

2.7

1.8

0.6

0.1

0.4

Disorders of Skin and Appendages

Rash

2.1

1.5

Gastro-Intestinal Disorders

Nausea

Diarrhea/Loose Stools

Constipation

Dyspepsia

Vomiting

Flatulence

Anorexia

Abdominal Pain

Appetite Increased

26.1

17.7

8.4

6.0

3.8

3.3

2.8

2.4

1.3

11.8

9.3

6.3

2.8

1.8

2.5

1.6

2.2

0.9

General

Fatigue

Hot Flushes

Fever

Back Pain

10.6

2.2

1.6

1.5

8.1

0.5

0.6

0.9

Metabolic and Nutritional Disorders

Thirst

1.4

0.9

Musculo-Skeletal System Disorders

Myalgia

1.7

1.5

Psychiatric Disorders

Insomnia

Sexual Dysfunction - Male (1)

Somnolence

Agitation

Nervousness

Anxiety

Yawning

Sexual Dysfunction - Female (2)

Concentration Impaired

16.4

15.5

13.4

5.6

3.4

2.6

1.9

1.7

1.3

8.8

2.2

5.9

4.0

1.9

1.3

0.2

0.2

0.5

Reproduction

Menstrual Disorder (2)

1.0

0.5

Respiratory System Disorders

Rhinitis

Pharyngitis

2.0

1.2

1.5

0.9

Special Senses

Vision Abnormal

Tinnitus

Taste Perversion

4.2

1.4

1.2

2.1

1.1

0.7

Urinary System Disorders

Micturition Frequency

Micturition Disorder

2.0

1.4

1.2

0.5

Panic Disorder:

In placebo-controlled clinical trials, 430 patients with panic disorder were treated with ZOLOFT in doses of 25 - 200 mg/day. During treatment, most patients received doses of 50 - 200 mg/day. Adverse events observed at an incidence of at least 5% for ZOLOFT and at an incidence that was twice or more the incidence among placebo-treated patients included: diarrhea, ejaculation failure (primarily ejaculatory delay), anorexia, constipation, libido decreased, agitation, and tremor.

In the total safety data base for panic disorder, 14% of patients discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.6%), insomnia (2.3%), somnolence (2.3%), and agitation (2.1%).

Obsessive-Compulsive Disorder:

In placebo-controlled clinical trials for OCD, adverse events observed at an incidence of at least 5% for ZOLOFT and at an incidence that was twice or more the incidence among placebo-treated patients included: nausea, insomnia, diarrhea, decreased libido, anorexia, dyspepsia, ejaculation failure (primarily ejaculatory delay), tremor, and increased sweating.

In placebo-controlled clinical trials for OCD, 10% of patients treated with ZOLOFT discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.8%), insomnia (2.6%), and diarrhea (2.1%).

Incidence in Controlled Clinical Trials for Panic and Obsessive compulsive disorder in adults:

Table 2 enumerates adverse events that occurred at a frequency of 2% or more among patients on ZOLOFT who participated in controlled trials comparing ZOLOFT with placebo in the treatment of panic disorder and obsessive-compulsive disorder. Only those adverse events which occurred at higher rate during ZOLOFT treatment than during placebo treatment are included.

TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED - CLINICAL TRIALS FOR PANIC AND OBSESSIVE-COMPULSIVE DISORDER IN ADULTS*
*
Events reported by at least 2% of patients treated with ZOLOFT are included, except for the following events which had an incidence on placebo greater than or equal to ZOLOFT [Panic Disorder]: headache, dizziness, malaise, abdominal pain, respiratory disorder, pharyngitis, flatulence, vision abnormal, pain, upper respiratory tract infection, and paroniria. [OCD]: abdominal pain, respiratory disorder, depression, and amnesia.
(1)
Primarily ejaculatory delay; % based on male patients only: Panic Disorder: 216 ZOLOFT and 134 placebo patients, OCD: 296 ZOLOFT and 219 placebo patients.
(2)
% based on male patients only: Panic Disorder: 216 ZOLOFT and 134 placebo patients, OCD: 296 ZOLOFT and 219 placebo patients.
 
 

(Percent of Patients Reporting)

ADVERSE EVENTS

PANIC DISORDER

OBSESSIVE COMPULSIVE DISORDER

 

ZOLOFT

(N=430)

Placebo

(N=275)

ZOLOFT

(N=533)

Placebo

(N=373)

Autonomic Nervous System Disorders        
Mouth Dry 15 10 14 9
Sweating Increased 5 1 6 1
Cardiovascular        
Palpitations - - 3 2
Chest Pain - - 3 2
Centr. & Periph. Nerv. System Disorders        
Tremor 5 1 8 1
Paresthesia 4 3 3 1
Headache - - 30 24
Dizziness - - 17 9
Hypertonia - - 2 1
Disorders of Skin and Appendages        
Rash 4 3 2 1
Gastrointestinal Disorders        
Nausea 29 18 30 11
Diarrhea 20 9 24 10
Dyspepsia 10 8 10 4
Constipation 7 3 6 4
Anorexia 7 2 11 2
Vomiting 6 3 3 1
Flatulence - - 4 1
Appetite Increased - - 3 1
General        
Fatigue 11 6 14 10
Hot Flushes 3 1 2 1
Pain - - 3 1
Back Pain - - 2 1
Metabolic and Nutritional Disorders        
Weight Increase - - 3 0
Musculoskeletal System Disorders        
Arthralgia 2 1 - -
Psychiatric Disorders        
Insomnia 25 18 28 12
Somnolence 15 9 15 8
Nervousness 9 5 7 6
Libido Decreased 7 1 11 2
Agitation 6 2 6 3
Anxiety 4 3 8 6
Concentration Impaired 3 0 - -
Depersonalization 2 1 3 1
Paroniria - - 2 1
Respiratory System Disorders        
Pharyngitis - - 4 2
Special Senses        
Tinnitus 4 3 - -
Vision Abnormal - - 4 2
Taste Perversion - - 3 1
Urogenital        
Ejaculation Failure (1) 19 1 17 2
Impotence (2) 2 1 5 1

Suicidality-related adverse events from clinical trials in major depressive disorder in the pediatric population

In the safety analysis from controlled clinical trials in children and adolescents with major depressive disorder aged 6 to 17 years, both the number and percentage of patients for whom suicide attempts were reported was the same for the sertraline arm (2/189, 1.1%) as for the placebo arm (2/184, 1.1%), while the corresponding event rates of suicide attempts were 1.1% (2 attempts in 2/189 patients) in sertraline-treated patients versus 1.6% in placebo-treated patients (3 attempts in 2/184 patients). For the additional category of “other events possibly related to self-harm”, which includes suicidal ideation and self-injurious behaviors such as cutting, event rates were 2.1% (4 events in 189 patients) in sertraline-treated patients and 0% in placebo-treated patients.

Overall, the total reported event rates for both suicide attempts and other events possibly related to self-harm are as follows: 3.2% or 6 /189 for sertraline versus 1.6% or 3/184 for placebo - see WARNINGS, POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Cardiac Electrophysiology

In a randomised, three-way crossover, double-blind, placebo- and positive-controlled ECG assessment study, healthy subjects (N=50) were upward titrated over 6 days to a target 200 mg BID dose of sertraline that was administered from days 7-13, with a single 200 mg dose on day 14. Serial ECG data collected over 24 h on day 14 showed QTcF (QTcF=QT/RR0.33) prolongation averaging approximately 6-10 ms, with a maximum difference from placebo in the mean change from baseline QTcF of 9.7 ms (90% CI 7.6, 11.7) at the 4 h time point. Exposure-response analysis demonstrated a statistically significant positive relationship between the change from baseline QTcF and sertraline plasma concentrations. The observed mean Cmax (234 ng/mL) at the supratherapeutic 200 mg BID dose in this study is slightly higher than the mean Cmax of 190 ng/mL reported for the maximum recommended therapeutic dose of 200 mg following once-daily doses.

Other events observed during the premarketing evaluation of ZOLOFT (sertraline hydrochloride):

During its premarketing assessment, multiple doses of ZOLOFT were administered to 2710 subjects. The conditions and duration of exposure to ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for indications other than depression. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

All events are included except those already listed in the previous table or in the PRECAUTIONS - section, and those reported in terms so general as to be uninformative.

It is important to emphasize that although the events reported occurred during treatment with ZOLOFT, they were not necessarily caused by it.

Autonomic Nervous System Disorders - Infrequent: flushing, mydriasis, increased saliva, cold clammy skin; Rare: pallor.

Cardiovascular - Infrequent: postural dizziness, hypertension, hypotension, postural hypotension, edema, dependent edema, periorbital edema, peripheral edema, peripheral ischemia, syncope, tachycardia; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, varicose veins.

Central and Peripheral Nervous System Disorders - Frequent: confusion; Infrequent: ataxia, abnormal coordination, abnormal gait, hyperesthesia, hyperkinesia, hypokinesia, migraine, nystagmus, vertigo; Rare: local anesthesia, coma, convulsions, dyskinesia, dysphonia, hyporeflexia, hypotonia, ptosis.

Disorders of Skin and Appendages - Infrequent: acne, alopecia, pruritus, erythematous rash, maculopapular rash, dry skin; Rare: bullous eruption, dermatitis, erythema multiforme, abnormal hair texture, hypertrichosis, photosensitivity reaction, follicular rash, skin discoloration, abnormal skin odor, urticaria.

Endocrine Disorders - Rare: exophthalmos, gynecomastia.

Gastro-Intestinal Disorders -Infrequent: dysphagia, eructation; Rare: diverticulitis, fecal incontinence, gastritis, gastroenteritis, glossitis, gum hyperplasia, hemorrhoids, hiccup, gastrointestinal bleeding, melena, hemorrhagic peptic ulcer, proctitis, stomatitis, ulcerative stomatitis, tenesmus, tongue edema, tongue ulceration.

General - Frequent: allergic reaction, allergy, asthenia; Infrequent: malaise, generalized edema, rigors, weight decrease, weight increase; Rare: enlarged abdomen, halitosis, otitis media, aphthous stomatitis.

Hematopoietic and Lymphatic - Infrequent: lymphadenopathy, purpura; Rare: anemia, anterior chamber eye hemorrhage.

Metabolic and Nutritional Disorders - Rare: dehydration, hypercholesterolemia, hypoglycemia.

Musculo-Skeletal System Disorders - Infrequent: arthralgia, arthrosis, dystonia, muscle cramps, muscle weakness; Rare: hernia.

Psychiatric Disorders - Infrequent: abnormal dreams, aggressive reaction, amnesia, apathy, delusion, depersonalization, depression, aggravated depression, emotional lability, euphoria, hallucination, neurosis, paranoid reaction, suicide attempt (including suicidal ideation), teeth-grinding, abnormal thinking; Rare: hysteria, somnambulism, withdrawal reactions.

Reproductive - Infrequent: dysmenorrhea (2), intermenstrual bleeding (2); Rare: amenorrhea (2), balanoposthitis (1), breast enlargement (2), female breast pain (2), leukorrhea (2), menorrhagia (2), atrophic vaginitis (2).

(1) - % based on male subjects only: 1005

(2) - % based on female subjects only: 1705

Respiratory System Disorders - Infrequent: bronchospasm, coughing, dyspnea, epistaxis; Rare: bradypnea, hyperventilation, sinusitis, stridor.

Special Senses - Infrequent: abnormal accommodation, conjunctivitis, diplopia, earache, eye pain, xerophthalmia; Rare: abnormal lacrimation, photophobia, visual field defect.

Urinary System Disorders - Infrequent: dysuria, face edema, nocturia, polyuria, urinary incontinence; Rare: enuresis, oliguria, renal pain, urinary retention.

Laboratory Tests - In man, asymptomatic elevations in serum hepatic transaminases (SGOT [or AST] and SGPT [or ALT]) to a value ≥ 3 times the upper limit of normal have been reported infrequently (approximately 0.6% and 1.1%, respectively) in association with ZOLOFT administration. The proportion of patients having these elevations was greater in the ZOLOFT group than in the placebo group. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

ZOLOFT therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%).

Uricosuric Effect - ZOLOFT is associated with a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.

Other Events Observed During the Postmarketing Evaluation of ZOLOFT

Adverse events not listed above which have been reported in temporal association with ZOLOFT since market introduction include:

Blood and Lymphatic Disorders: agranulocytosis, aplastic anemia, pancytopenia, leukopenia, thrombocytopenia

Cardiovascular Disorders: bradycardia, AV block, atrial arrhythmias, ventricular tachycardia (including torsade de pointes-type arrhythmias)

Endocrine Disorders: hypothyroidism, syndrome of inappropriate ADH secretion, hyperprolactinemia

Eye Disorders: blindness, cataract, oculogyric crisis

Gastrointestinal Disorders: pancreatitis

Hepatobilary Disorders: liver events

Immune System Disorders: anaphylactoid reaction, serum sickness

Investigations: increased coagulation times, QT interval prolongation

Metabolism and Nutrition Disorders: diabetes mellitus, hyperglycemia, hypoglycemia

Musculoskeletal System Disorders: Muscle contractions involuntary, Lupus-like syndrome, trismus, bone fractures, rhabdomyolysis

Nervous System Disorders: cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and call-fleming syndrome), optic neuritis, neuroleptic malignant syndrome, extrapyramidal symptoms, serotonin syndrome

Psychiatric Disorders: psychosis

Reproductive System Disorders: priapism, galactorrhea

Respiratory Disorders: pulmonary hypertension

Skin Disorders: angioedema, severe skin reactions such as Stevens-Johnson syndrome, epidermal necrosis, photosensitivity, other severe cutaneous disorders

Urinary System Disorders: acute renal failure, hematuria

Vascular Disorders: vasculitis

The causal relationship between ZOLOFT treatment and the emergence of these events has not been established. The clinical features of hepatic events (which in the majority of cases appeared to be reversible with discontinuation of ZOLOFT) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death. There have been spontaneous reports of symptoms such as dizziness, paresthesia, nausea, headache, anxiety, fatigue, and agitation following the discontinuation of ZOLOFT treatment.

Adverse Reactions following Discontinuation of Treatment (or Dose Reduction):

There have been reports of adverse reactions upon the discontinuation of ZOLOFT (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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