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Clinical Trials Experience
The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for ZYPREXA RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral olanzapine studies was reported using the COSTART and MedDRA dictionaries.
The stated frequencies of adverse reactions 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. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA RELPREVV.
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 adverse reaction incidence in the population studied.
Adverse Reactions Associated with Discontinuation of Treatment in a Short-Term, Placebo-Controlled Trial
Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.
Commonly Observed Adverse Reactions in a Short-Term, Placebo-Controlled Trial
In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.
Adverse Reactions Occurring at an Incidence of 2% or More among ZYPREXA RELPREVV-Treated Patients in a Short- Term, Placebo-Controlled Trial
Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.
Table 9: Treatment-Emergent Adverse Reactions: Incidence
in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV
|Percentage of Patients Reporting Adverse Event|
|ZYPREXA RELPREVV 405 mg/4 wks
|ZYPREXA RELPREVV 210 mg/2 wks
|ZYPREXA RELPREVV 300 mg/2 wks
|Ear and Labyrinth Disorders|
|General Disorders and Administration Site Conditions|
|Injection site pain||0||2||3||2|
|Infections and Infestations|
|Upper respiratory tract infection||2||3||1||4|
|Injury, Poisoning and Procedural Complications|
|Electrocardiogram QT-corrected interval prolonged||1||0||0||2|
|Hepatic enzyme increasedc||1||4||1||3|
|Metabolism and Nutrition Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|Nervous System Disorders|
|Reproductive System and Breast Disorders|
|Respiratory, Thoracic and Mediastinal Disorders|
|Skin and Subcutaneous Tissue Disorders|
|a The term abdominal pain upper was combined
under abdominal pain.
b The term tooth abscess was combined under tooth infection.
c The terms alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased were combined under hepatic enzyme increased.
d The term tension headache was combined under headache.
e The term somnolence was combined under sedation.
f The term sinus congestion was combined under nasal congestion.
Dose Dependency of Adverse Reactions
A dose group difference for oral olanzapine has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see WARNINGS AND PRECAUTIONS].
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 10: 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
|Percentage of Patients Reporting Event|
|Placebo||Olanzapine 5 ± 2.5 mg/day||Olanzapine 10 ±2.5 mg/day||Olanzapine 15 ±2.5 mg/day|
|a Percentage of patients with a Simpson-Angus
Scale total score > 3.
b Percentage of patients with a Barnes Akathisia Scale global score ≥ 2.
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 11: Treatment-Emergent Extrapyramidal Symptoms
Assessed by Adverse Reactions Incidence in a Fixed Dosage Range,
Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute
|Percentage of Patients Reporting Event|
|Olanzapine 5 ± 2.5 mg/day
|Olanzapine 10 ±2.5 mg/day
|Olanzapine 15 ±2.5 mg/day
|Any extrapyramidal event||16||15||25||32|
|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.
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
Local Injection Site Reactions
Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients experienced treatmentemergent injection-related adverse reactions (injection site pain, buttock pain, injection site mass, induration, injection site induration) in the placebo-controlled database. The most frequently occurring treatment-emergent adverse reaction was injection site pain (2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated).
Other Adverse Reactions Observed During the Clinical Trial Evaluation of Olanzapine for Extended-Release Injectable Suspension
Injection site abscess has been reported in clinical trials with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.
Commonly Observed Adverse Reactions During the Clinical Trial Evaluation of Oral Olanzapine
In clinical trials of oral olanzapine monotherapy for the treatment of schizophrenia in adult patients, treatmentemergent adverse reactions with an incidence of 5% or greater in the olanzapine treatment arm and at least twice that of placebo were: postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia.
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 adverse reactions are those occurring in fewer than 1/1000 patients.
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.
Respiratory System — Infrequent: epistaxis; Rare: lung edema.
Skin and Appendages — Infrequent: alopecia.
Urogenital System — Infrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, 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.
Vital Signs and Laboratory Studies
ZYPREXA RELPREVV in Adults: Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from placebo, were observed for the following: eosinophils, monocytes, cholesterol, low-density lipoprotein (LDL), triglycerides, and direct bilirubin. There were no statistically significant differences between ZYPREXA RELPREVV and placebo in the incidence of potentially clinically significant changes in any of the laboratory values studied.
Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from oral olanzapine (in a 24-week double-blind study), were observed for the following: gammaglutamyltransferase (GGT) and sodium.
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.
Statistically significant differences were observed between ZYPREXA RELPREVV and oral olanzapine for the incidence of treatment-emergent low platelet count (0% ZYPREXA RELPREVV vs 1% oral olanzapine); and low total bilirubin (2.8% ZYPREXA RELPREVV vs 0.7% for oral olanzapine). There was a statistically significant difference between ZYPREXA RELPREVV and oral olanzapine in potentially clinically significant changes for high leukocyte count (0% ZYPREXA RELPREVV vs 1% oral olanzapine).
Changes in aminotransferases observed with ZYPREXA RELPREVV treatment were similar to those reported with ZYPREXA treatment. In placebo-controlled ZYPREXA RELPREVV studies, clinically significant ALT elevations ( ≥ 3 times the upper limit of the normal range) were observed in 2.7% (8/291) of patients exposed to olanzapine compared to 3.2% (3/94) of the placebo patients. None of these patients experienced jaundice. In 3 of these patients, liver enzymes reverted to the normal range despite continued treatment, and in 5 cases enzymes values decreased, but were still above the normal range at the end of therapy.
Within the larger premarketing ZYPREXA RELPREVV database of 1886 patients with baseline ALT ≤ 90 IU/L, the incidence of ALT elevation to > 200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while ZYPREXA RELPREVV treatment was continued.
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 Adults: An assessment of the premarketing experience for oral 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 oral 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.
Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.
Oral olanzapine administration was also associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.
Comparison of ZYPREXA RELPREVV and oral olanzapine, in a 24 week study, revealed no significant differences on ECG changes. Between-group comparisons for pooled placebo-controlled trials revealed no significant oral olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Oral olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to olanzapine's potential for inducing orthostatic changes [see WARNINGS AND PRECAUTIONS].
Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA 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), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, rhabdomyolysis, 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. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.
Read the Zyprexa Relprevv (olanzapine extended release injectable suspension) Side Effects Center for a complete guide to possible side effects
Potential For Other Drugs To Affect Olanzapine
The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Potential for Olanzapine to Affect Other Drugs].
Inducers of CYP1A2
Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.
Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The coadministration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Potential for Olanzapine to Affect Other Drugs].
Inhibitors of CYP1A2
Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.
Inhibitors of CYP2D6
Fluoxetine caused a small decrease in olanzapine clearance leading to a minimal change in olanzapine steady-state concentrations and, therefore dose modification is not routinely recommended.
Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Potential for Olanzapine to Affect Other Drugs].
Inducers of CYP1A2 or Glucuronyl Transferase Enzymes
Omeprazole and rifampin may cause an increase in olanzapine clearance.
Potential For Olanzapine To Affect Other Drugs
CNS Acting Drugs
Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.
Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.
Levodopa and Dopamine Agonists
Olanzapine may antagonize the effects of levodopa and dopamine agonists.
Co-administration of lorazepam does not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of lorazepam with olanzapine potentiated the somnolence observed with either drug alone.
Olanzapine (10 mg daily for 2 weeks) did not affect the steady-state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.
Effect of Olanzapine on Drug Metabolizing Enzymes
In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.
Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.
Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Potential For Other Drugs To Affect Olanzapine].
Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite Ndesmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Potential For Other Drugs To Affect Olanzapine].
Multiple doses of olanzapine did not influence the kinetics of ethanol [see Potential For Other Drugs To Affect Olanzapine].
Multiple doses of olanzapine did not influence the kinetics of biperiden.
Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.
Drug Abuse And Dependence
In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the maximum recommended human daily oral dose (20 mg) and rhesus monkeys administered oral doses up to 8 times the maximum recommended human daily oral dose on a mg/m² basis.
Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Because ZYPREXA RELPREVV is to be administered by healthcare professionals, the potential for misuse or abuse by patients is low.
Read the Zyprexa Relprevv Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/9/2015
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