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.
|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)|
|Abdominal pain b||6||3||6||7|
|Pain in extremity||6||3||5||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.
|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)|
|Pain in extremity||5||1|
|Liver enzymes increased b||8||1|
|Respiratory tract infection c||3||2|
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)].
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 times ULN at baseline to ≥3 times ULN) 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)] .
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