Sentroxatine (Page 3 of 9)

* † ‡ Table 5 6.1 Clinical Trials Experience 6.2 Other Reactions 6.3 Postmarketing Experience

6 ADVERSE REACTIONS

6.1 Clinical Trials 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 trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine had been administered to 10,782 patients with various diagnoses in U.S. clinical trials as of May 8, 1995. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories.

In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in U.S. Major Depressive Disorder, OCD, and bulimia controlled clinical trials and U.S. plus non-U.S. Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3.

Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials * †
Percentage of Patients Reporting Event
Major Depressive DisorderOCDBulimiaPanic Disorder
Body System/Adverse ReactionFlouxetine (N=1728)Placebo (N=975)Flouxetine (N=266)Placebo (N=89)Flouxetine (N=450)Placebo (N=267)Flouxetine (N=425)Placebo (N=342)
Body as a Whole
Asthenia95151121977
Flu Syndrome341078355
Cardiovascular System
Vasodilation325211
Digestive System
Nausea21926132911127
Diarrhea12818138694
Anorexia11217108441
Dry mouth1071239644
Dyspesia7510410662
Nervous System
Insomnia16928223313107
Anxiety12714715962
Nervousness149141511586
Somnolence13617713552
Tremor1039113131
Libido decreased31125112
Abnormal dreams11525311
Respiratory System
Pharyngitis3322910533
Sinusitis14526423
Yawn7111
Skin and Appendages
Sweating8378322
Rash43634422
Urogenital System
Impotence271
Abnormal ejaculation7721
* Incidence less than 1 % † Includes U.S. data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials. ‡ Denominator used was for males only (N = 690 fluoxetine Major Depressive Disorder; N = 410 placebo Major Depressive Disorder; N = 116 fluoxetine OCD; N = 43 placebo OCD; N = 14 fluoxetine bulimia; N = 1 placebo bulimia; N = 162 fluoxetine panic; N = 121 placebo panic).

Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials * †

Percentage of Patients Reporting Event
Major Depressive Disorder, OCD,Bulimia, and Panic Disorder Combined
Body System/Adverse ReactionFluoxetine (N = 2869)Placebo (N = 1673)
Body as a Whole
Headache2119
Asthenia116
Flu syndrome54
Fever21
Cardiovascular System
Vasodilatation21
Digestive System
Nausea229
Diarrhea117
Anorexia103
Dry mouth96
Dyspepsia84
Constipation54
Flatulence32
Vomiting32
Metabolic and NutritionalDisorders
Weight loss21
Nervous System
Insomnia1910
Nervousness138
Anxiety126
Somnolence125
Dizziness96
Tremor92
Libido decreased41
Thinking abnormal21
Respiratory System
Yawn3– –
Skin and Appendages
Sweating73
Rash43
Pruritus32
Special Senses
Abnormal vision21
* Incidence less than 1%. † Includes U.S. data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-U.S. data for PanicDisorder clinical trials.

trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of fluoxetine

treatment (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction

associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-U.S. Panic

Disorder clinical trials.

Table 5: Most Common Adverse Reactions Associated With Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials *
Major Depressive Disorder, OCD, Bulimia,and Panic DisorderCombined (N = 1533)Major DepressiveDisorder(N = 392)OCD(N = 266)Bulimia(N = 450)Panic Disorder(N = 425
Anxiety (1%)– –Anxiety (1%)– –Anxiety (2%)
– –– –– –Insomnia (2%)– –
– –Nervousness (1%)– –– –Nervousness (1%)
– –– –Rash (1%)– –– –
* Includes U.S. data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-U.S. Panic Disorderclinical trials.

322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to

that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the

body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an

incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary

frequency, and menorrhagia.

The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in

3 pediatric placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8%

for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was

collected.

Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction

often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular,

some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity

of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because

patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and

performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in U.S. Major Depressive

Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least

2% of patients taking fluoxetine (4% fluoxetine, less than 1% placebo). There have been spontaneous reports in women taking fluoxetine of

orgasmic dysfunction, including anorgasmia.

There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely

inquire about such possible side effects.

6.2 Other Reactions

Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is

not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote,

(3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which

occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least

1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer

than 1/1000 patients.

Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.

Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia.

Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer,

esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage.

Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura.

Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, buccoglossal syndrome, euphoria, hypertonia, libido

increased, myoclonus, paranoid reaction; Rare: delusions.

Respiratory System — Rare: larynx edema.

Skin and Appendages — Rare: purpuric rash.

Special Senses — Frequent: taste perversion; Infrequent: mydriasis.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported

voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to

drug exposure.

Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and

that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular

accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary

tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over

the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema

nodosum, exfoliative dermatitis, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immunerelated

hemolytic anemia, kidney failure, movement disorders developing in patients with risk factors including drugs associated with

such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism,

pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular

tachycardia (including torsade de pointes–type arrhythmias), and vaginal bleeding, and violent behaviors1.

1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions.

They are included here because of their seriousness.

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