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adverse reactions
6 ADVERSE REACTIONS When using olanzapine and fluoxetine 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: Oral Olanzapine Monotherapy: Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia. (6.1) Schizophrenia (Adolescents) – sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth. ( 6.1 ) Manic or Mixed Episodes, Bipolar I Disorder (Adults) – asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor. (6.1) Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) – sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity. ( 6.1 ) Combination of Olanzapine and Lithium or Valproate: Manic or Mixed Episodes, Bipolar I Disorder (Adults) – dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia. (6.1) Olanzapine and Fluoxetine in Combination: Also refer to the Adverse Reactions section of the package insert for Symbyax. (6) To report SUSPECTED ADVERSE REACTIONS, contact Virtus Pharmaceuticals, LLC at 1-888-848-3593 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Extrapyramidal Symptoms The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Percentage of patients with a Simpson-Angus Scale total score >3. b Percentage of patients with a Barnes Akathisia Scale global score ≥2. Percentage of Patients Reporting Event Placebo Olanzapine 5 ± 2.5 mg/day Olanzapine 10 ± 2.5 mg/day Olanzapine 15 ± 2.5 mg/day Parkinsonism a 15 14 12 14 Akathisia b 23 16 19 27 The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching. Percentage of Patients Reporting Event Placebo (N=68) Olanzapine 5 ± 2.5 mg/day (N=65) Olanzapine 10 ± 2.5 mg/day (N=64) Olanzapine 15 ± 2.5 mg/day (N=69) Dystonic events a 1 3 2 3 Parkinsonism events b 10 8 14 20 Akathisia events c 1 5 11 10 Dyskinetic events d 4 0 2 1 Residual events e 1 2 5 1 Any extrapyramidal event 16 15 25 32 The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day). Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder — Adolescents a Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0. Categories a Percentage of Patients Reporting Event Placebo (N=89) Olanzapine (N=179) Dystonic events 0 1 Parkinsonism events 2 1 Akathisia events 4 6 Dyskinetic events 0 1 Nonspecific events 0 4 Any extrapyramidal event 6 10 Dystonia, Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use. Other Adverse Reactions Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) 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 — Infrequent: chills, face edema, photosensitivity reaction, suicide attempt 1 ; Rare: chills and fever, hangover effect, sudden death 1 . Cardiovascular System — Infrequent: cerebrovascular accident, vasodilatation. Digestive System — Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit. Hemic and Lymphatic System — Infrequent: thrombocytopenia. Metabolic and Nutritional Disorders — Frequent : alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia. Musculoskeletal System — Rare: osteoporosis. Nervous System — Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma. Respiratory System — Infrequent: epistaxis; Rare: lung edema. Skin and Appendages — Infrequent: alopecia. Special Senses — Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis. Urogenital System — Infrequent: amenorrhea 2 , breast pain, decreased menstruation, impotence 2 , increased menstruation 2 , menorrhagia 2 , metrorrhagia 2 , polyuria 2 , urinary frequency, urinary retention, urinary urgency, urination impaired. 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. 2 Adjusted for gender. Clinical Trials in Adolescent Patients (age 13 to 17 years) Commonly Observed Adverse Reactions in Oral Olanzapine Short-Term, Placebo-Controlled Trials Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 21. Table 21: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13 to 17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes) a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. b Patients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper. Adverse Reactions Percentage of Patients Reporting Event 6 Week Trial % Schizophrenia Patients 3 Week Trial % Bipolar Patients Olanzapine (N=72) Placebo (N=35) Olanzapine (N=107) Placebo (N=54) Sedation a 39 9 48 9 Weight increased 31 9 29 4 Headache 17 6 17 17 Increased appetite 17 9 29 4 Dizziness 8 3 7 2 Abdominal pain b 6 3 6 7 Pain in extremity 6 3 5 0 Fatigue 3 3 14 6 Dry mouth 4 0 7 0 Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3 to 6 weeks), Placebo-Controlled Trials Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22. Table 22: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13 to 17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes]) a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. b The terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes. c Patients with the following MedDRA terms were counted in this category: lower respiratory tract infection, respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection. Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=179) Placebo (N=89) Sedation a 44 9 Weight increased 30 6 Increased appetite 24 6 Headache 17 12 Fatigue 9 4 Dizziness 7 2 Dry mouth 6 0 Pain in extremity 5 1 Constipation 4 0 Nasopharyngitis 4 2 Diarrhea 3 0 Restlessness 3 2 Liver enzymes increased b 8 1 Dyspepsia 3 1 Epistaxis 3 0 Respiratory tract infection c 3 2 Sinusitis 3 0 Arthralgia 2 0 Musculoskeletal stiffness 2 0 Vital Signs and Laboratory Studies Vital Sign Changes — Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials [see Warnings and Precautions (5)] . Laboratory Changes Olanzapine Monotherapy in Adults: An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued. In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule. From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients. Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs. Olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions (5.15) ] , with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK. From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients. Olanzapine Monotherapy in Adolescents: In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo: elevated ALT (≥3X ULN in patients with ALT at baseline <3X ULN), (12% vs 2%); elevated AST (28% vs 4%); low total bilirubin (22% vs 7%); elevated GGT (10% vs 1%); and elevated prolactin (47% vs 7%). In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 timesULN at baseline to ≥3timesULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule. ECG Changes — In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapine's potential for inducing orthostatic changes [see Warnings and Precautions (5.7) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of olanzapine. 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. Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash,restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering 1 , and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. 1 Stuttering was studied in oral formulations.