6 ADVERSE REACTIONS When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Most common adverse reactions (≥ 5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) Fluoxetine and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax (6) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 have been administered to 10,782 patients with various diagnoses in US clinical trials. 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 US controlled clinical trials and Panic Disorder in US plus non‑US 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 US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non‑US 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 Dis order Placebo-Controlled Clinical Trials1, 2 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System / Adverse Reaction Fluoxetine (N= 1,728) Placebo (N = 975) Fluoxetine (N = 266) Placebo (N = 89) Fluoxetine (N = 450) Placebo (N = 267) Fluoxetine (N = 425) Placebo (N=342) Body as Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- D i g e s t i ve Sy s t em Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 A n o r e x ia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous Sy s t em Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 N e r v o u s n e ss 14 9 14 15 11 5 8 6 S o m n o l e n ce 13 6 17 7 13 5 5 2 T r e m or 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 R e s p i r a t o ry Sy s t em Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital Sy s t em I m p o t e n ce3 2 -- -- -- 7 -- 1 -- Abnormal ejaculation3 -- -- 7 -- 7 -- 2 1 1 Incidence less than 1%. 2 Includes U.S. data for Major Depressive Disorder, OCD, Bulimia andPanic Disorder clinical trials, plus non- U.S. data for Panic Disorder clinical trials. 3 Denominator used was for malesonly (N = 690 fluoxetine Major Depressive Disorder; N = 4 10 p lacebo Major Depressive Disorder; N = 116 fluoxetine OCD; N = 4 3 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 Dis order Placebo-Controlled Clinical Trials1, 2 Percentage of Patients Reporting Event Major Depressive D i s o r d e r , OCD, Bulimia, and Panic D i s o r d er Combined Body Sy s t e m / A dv e r se Reaction F l u o x e t i n e (N= 2869) P l a ce b o (N= 1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu s y n d r o me 5 4 Fever 2 1 C a r d i o va s c u l a r Sy s t em Vasodilatation 2 1 D i g e s t i v e Sy s t em Nausea 22 9 Diarrhea 11 7 A n o r e x ia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional D i s o r d e rs Weight loss 2 1 Nervous Sy s t e m Insomnia 19 10 N e r v o u s n e ss 13 8 Anxiety 12 6 S o m n o l e n ce 12 5 Dizziness 9 6 T r e m or 9 2 Libido decreased 4 1 T h i nk i ng a b n o r m al 2 1 R e s p i r a t o r y Sy s t em Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 1 Incidence less than 1%. 2 Includes U.S. data for Major Depressive Disorder, OCD, Bulimia, andPanic Disorder clinical trials, plus non- U.S. data for Panic Disorder clinical trials. Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo‑controlled clinical 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‑US Panic Disorder clinical trials. Table 5: Most Common Adverse Reactions Associated with Dis continuation in Major Depressive Disorder, OCD, Bulimia, and Panic Dis order Placebo-Controlled Clinical Trials1 Major Depressive D i s o r d e r , OCD, B u li m i a, and P an ic D i s o r d er Combined (N= 1,533) Major Depressive D i s o r d e r (N= 392) OCD (N= 266) Bulimia (N= 450) Panic D i s o r d er (N= 425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- N e r v o u s n e ss (1%) -- -- N e r v o u s n e ss (1%) -- -- Rash (1%) -- -- 1 Includes U.S. Major Depressive Disorder, OCD, Bulimia, andPanic Disorder clinical trials, plus non- U.S. Panic Disorder clinical trials. Other adverse reactions in pediatric patients (children and adolescents) — Treatment‑emergent adverse reactions were collected in 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 US 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, <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. Symptoms of sexual dysfunction occasionally persist after discontinuation of 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1. 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, balance disorder1, bruxism1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. Respiratory System — Rare: larynx edema. Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash. Special Senses — Frequent: taste perversion; Infrequent: mydriasis. Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2 . 1 MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received fluoxetine. 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. 6.3 Post-Marketing 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, galactorrhea, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens‑Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes–type arrhythmias), 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.