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Zyprexa Relprevv

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Zyprexa Relprevv

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Post-Injection Delirium/Sedation Syndrome

During premarketing clinical studies of ZYPREXA RELPREVV, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV [see BOXED WARNING and DOSAGE AND ADMINISTRATION]. These events occurred in < 0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These events were correlated with an unintentional rapid increase in serum olanzapine concentrations to supra-therapeutic ranges in some cases. While a rapid and greater than expected increase in serum olanzapine concentration has been observed in some patients with these events, the exact mechanism by which the drug was unintentionally introduced into the blood stream is not known. Clinical signs and symptoms included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced level of consciousness ranging from mild sedation to coma. Time after injection to event ranged from soon after injection to greater than 3 hours after injection. The majority of patients were hospitalized and some required supportive care, including intubation, in several cases. All patients had largely recovered by 72 hours. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections) [see OVERDOSAGE].

Healthcare professionals are advised to discuss this potential risk with patients each time they prescribe and administer ZYPREXA RELPREVV [see PATIENT INFORMATION].

Prescribing and Distribution Program for ZYPREXA RELPREVV

ZYPREXA RELPREVV is available only through a restricted distribution program [see BOXED WARNING, INDICATIONS AND USAGE, and PATIENT INFORMATION]. ZYPREXA RELPREVV must not be dispensed directly to a patient. For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

ZYPREXA RELPREVV must be administered in a registered healthcare facility (such as a hospital, clinic, residential treatment center, or community healthcare center) with ready access to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours and must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation [see OVERDOSAGE]. If parenteral benzodiazepines are required for patient management during an event of post-injection delirium/sedation syndrome, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING, and PATIENT INFORMATION].

In placebo-controlled oral olanzapine clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of oral olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral olanzapine compared to patients treated with placebo. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING and PATIENT INFORMATION].

Suicide

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered and tolerability with oral olanzapine should be established prior to initiating treatment with ZYPREXA RELPREVV [see DOSAGE AND ADMINISTRATION]. The patient should be carefully monitored, since recurrences of NMS have been reported [see PATIENT INFORMATION].

Hyperglycemia

Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see PATIENT INFORMATION].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults

In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥ 200 mg/dL, and/or a baseline fasting glucose level ≥ 126 mg/dL).

Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 12 weeks exposure At least 48 weeks exposure
N Patients N Patients
Fasting Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) Olanzapine 543 2.2% 345 12.8%
Placebo 293 3.4% NAa NAa
Glucose Borderline to High ( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Olanzapine 178 17.4% 127 26.0%
Placebo 96 11.5% NAa NAa
a Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescent patients (13-17 years), including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent oral olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Oral Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 12 weeks exposure At least 24 weeks exposure
N Patients N Patients
Fasting Glucose Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) Olanzapine 124 0% 108 0.9%
Placebo 53 1.9% NAa NAa
Borderline to High ( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Olanzapine 14 14.3% 13 23.1%
Placebo 13 0% NAa NAa
a Not Applicable.

Hyperlipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see PATIENT INFORMATION].

Clinically significant, and sometimes very high ( > 500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults

In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 12 weeks exposure At least 48 weeks exposure
N Patients N Patients
Fasting Triglycerides Increase by ≥ 50 mg/dL Olanzapine 745 39.6% 487 61.4%
Placebo 402 26.1% NAa NAa
Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) Olanzapine 457 9.2% 293 32.4%
Placebo 251 4.4% NAa NAa
Borderline to High ( ≥ 150 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) Olanzapine 135 39.3% 75 70.7%
Placebo 65 20.0% NAa NAa
Fasting Total Cholesterol Increase by ≥ 40 mg/dL Olanzapine 745 21.6% 489 32.9%
Placebo 402 9.5% NAa NAa
Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) Olanzapine 392 2.8% 283 14.8%
Placebo 207 2.4% NAa NAa
Borderline to High ( ≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL) Olanzapine 222 23.0% 125 55.2%
Placebo 112 12.5% NAa NAa
Fasting LDL Cholesterol Increase by > 30 mg/dL Olanzapine 536 23.7% 483 39.8%
Placebo 304 14.1% NAa NAa
Normal to High ( < 100 mg/dL to ≥ 160 mg/dL) Olanzapine 154 0% 123 7.3%
Placebo 82 1.2% NAa NAa
Borderline to High ( ≥ 100 mg/dL and < 160 mg/dL to ≥ 160 mg/dL) Olanzapine 302 10.6% 284 31.0%
Placebo 173 8.1% NAa NAa
a Not Applicable.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescents (13-17 years), including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Oral Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 6 weeks exposure At least 24 weeks exposure
N Patients N Patients
Fasting Triglycerides Increase by ≥ 50 mg/dL Olanzapine 138 37.0% 122 45.9%
Placebo 66 15.2% NAa NAa
Normal to High ( < 90 mg/dL to ≥ 130 mg/dL) Olanzapine 67 26.9% 66 36.4%
Placebo 28 10.7% NAa NAa
Borderline to High ( ≥ 90 mg/dL and ≤ 130 mg/dL to ≥ 130 mg/dL) Olanzapine 37 59.5% 31 64.5%
Placebo 17 35.3% NAa NAa
Fasting Total Cholesterol Increase by ≥ 40 mg/dL Olanzapine 138 14.5% 122 14.8%
Placebo 66 4.5% NAa NAa
Normal to High ( < 170 mg/dL to ≥ 200 mg/dL) Olanzapine 87 6.9% 78 7.7%
Placebo 43 2.3% NAa NAa
Borderline to High ( ≥ 170 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) Olanzapine 36 38.9% 33 57.6%
Placebo 13 7.7% NAa NAa
Fasting LDL Cholesterol Increase by ≥ 30 mg/dL Olanzapine 137 17.5% 121 22.3%
Placebo 63 11.1% NAa NAa
Normal to High ( < 110 mg/dL to ≥ 130 mg/dL) Olanzapine 98 5.1% 92 10.9%
Placebo 44 4.5% NAa NAa
Borderline to High ( ≥ 110 mg/dL and < 130 mg/dL to ≥ 130 mg/dL) Olanzapine 29 48.3% 21 47.6%
Placebo 9 0% NAa NAa
a Not Applicable.

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight [see PATIENT INFORMATION].

Olanzapine Monotherapy in Adults

In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine- treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults

Amount Gained kg (lb) 6 Weeks
(N=7465) (%)
6 Months
(N=4162) (%)
12 Months
(N=1345) (%)
24 Months
(N=474) (%)
36 Months
(N=147) (%)
≤ 0 26.2 24.3 20.8 23.2 17.0
0 to ≤ 5 (0-11 lb) 57.0 36.0 26.0 23.4 25.2
> 5 to ≤ 10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4
> 10 to ≤ 15 (22-33 lb) 1.8 10.9 14.9 11.4 17.0
> 15 to ≤ 20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6
> 20 to ≤ 25 (44-55 lb) 0 0.9 3.3 5.1 4.1
> 25 to ≤ 30 (55-66 lb) 0 0.2 1.4 2.3 4.8
> 30 ( > 66 lb) 0 0.1 0.8 1.2 2

Olanzapine Monotherapy in Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Oral Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

  Olanzapine-treated patients Placebo-treated patients
Mean change in body weight from baseline (median exposure = 3 weeks) 4.6 kg (10.1 lb) 0.3 kg (0.7 lb)
Percentage of patients who gained at least 7% of baseline body weight 40.6% (median exposure to 7% = 4 weeks) 9.8% (median exposure to 7% = 8 weeks)
Percentage of patients who gained at least 15% of baseline body weight 7.1% (median exposure to 15% = 19 weeks) 2.7% (median exposure to 15% = 8 weeks)

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents

Amount Gained kg (lb) 6 Weeks
(N=243) (%)
6 Months
(N=191) (%)
≤ 0 2.9 2.1
0 to ≤ 5 (0-11 lb) 47.3 24.6
> 5 to ≤ 10 (11-22 lb) 42.4 26.7
> 10 to ≤ 15 (22-33 lb) 5.8 22.0
> 15 to ≤ 20 (33-44 lb) 0.8 12.6
> 20 to ≤ 25 (44-55 lb) 0.8 9.4
> 25 to ≤ 30 (55-66 lb) 0 2.1
> 30 to ≤ 35 (66-77 lb) 0 0
> 35 to ≤ 40 (77-88 lb) 0 0
> 40 ( > 88 lb) 0 0.5

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

Orthostatic Hypotension

ZYPREXA RELPREVV may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, probably reflecting its ai-adrenergic antagonistic properties [see PATIENT INFORMATION]. Syncope- related adverse reactions were reported in 0.1% of patients treated with ZYPREXA RELPREVV in clinical studies.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. For patients in this population who have never taken oral olanzapine, tolerability should be established with oral olanzapine prior to initiating treatment with ZYPREXA RELPREVV [see DOSAGE AND ADMINISTRATION].

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see DRUG INTERACTIONS].

Leukopenia, Neutropenia, and Agranulocytosis

Class Effect

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including ZYPREXA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug- induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA RELPREVV should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm³ should discontinue ZYPREXA RELPREVV and have their WBC followed until recovery.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

Seizures

During premarketing testing of ZYPREXA RELPREVV, seizures occurred in 0.15% of patients. During premarketing testing of oral olanzapine, seizures occurred in 0.9% of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Potential for Cognitive and Motor Impairment

Sedation was a commonly reported adverse reaction associated with ZYPREXA RELPREVV treatment, occurring at an incidence of 8% in ZYPREXA RELPREVV patients compared to 2% in placebo patients. Somnolence and sedation adverse reactions led to discontinuation in 0.6% of patients in the premarketing ZYPREXA RELPREVV database.

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely. However, due to the risk of post-injection delirium/sedation syndrome after each injection, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see DOSAGE AND ADMINISTRATION, and PATIENT INFORMATION].

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ZYPREXA RELPREVV for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see PATIENT INFORMATION].

Use in Patients with Concomitant Illness

Experience with ZYPREXA RELPREVV in patients with concomitant systemic illnesses is limited [see CLINICAL PHARMACOLOGY].

Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials with oral olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus or related conditions.

In 5 placebo-controlled studies of oral olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with oral olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING, and PATIENT INFORMATION].

Olanzapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients.

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the oral olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. In premarketing studies with ZYPREXA RELPREVV, statistically significant differences among dose groups have been observed for prolactin levels [see ADVERSE REACTIONS].

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual- related events1 (2% [49/3240] of females), sexual function-related events2 (2% [150/8136] of females and males), and breast-related events3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males), and breast-related events3 (2% [3/168] of females, 2% [7/286] of males) [see Use In Specific Populations].

Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see PATIENT INFORMATION].

REFERENCES

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Patient Counseling Information

See FDA-approved Medication Guide.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA RELPREVV. Patients should be advised to call their doctor if they do not think they are getting better or have concerns about their condition.

Information on Medication Guide

Prescribers or other health professionals should inform patients, their families, and their caregivers about the potential benefits and potential risks associated with treatment with ZYPREXA RELPREVV, and should counsel them in its appropriate use. A patient Medication Guide is available for ZYPREXA RELPREVV. Prescribers or other health professionals should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Post-Injection Delirium/Sedation Syndrome

During premarketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose have been reported in patients following an injection of ZYPREXA RELPREVV. It is mandatory that patients be enrolled in the ZYPREXA RELPREVV Patient Care Program to receive ZYPREXA RELPREVV treatment. Patients should be advised of the risk of post-injection delirium/sedation syndrome each time they receive an injection [see WARNINGS AND PRECAUTIONS]. Patient and caregivers should be advised that after each ZYPREXA RELPREVV injection, patients must be observed at the healthcare facility for at least 3 hours and must be accompanied to their destination upon leaving the facility. The Medication Guide should be distributed each time patients receive an injection.

Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with ZYPREXA had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

ZYPREXA RELPREVV is not approved for elderly patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome (NMS)

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including ZYPREXA. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS].

Hyperglycemia

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions related to ZYPREXA RELPREVV. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking ZYPREXA RELPREVV [see WARNINGS AND PRECAUTIONS].

Hyperlipidemia

Patients should be counseled that hyperlipidemia has occurred during treatment with ZYPREXA RELPREVV. Patients should have their lipid profile monitored regularly [see WARNINGS AND PRECAUTIONS].

Weight Gain

Patients should be counseled that weight gain has occurred during treatment with ZYPREXA RELPREVV. Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS].

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, and in association with the use of concomitant drugs that may potentiate the orthostatic effect of ZYPREXA RELPREVV, e.g., diazepam or alcohol [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.

Potential for Cognitive and Motor Impairment

Because ZYPREXA RELPREVV has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ZYPREXA RELPREVV therapy does not affect them adversely. Additionally, due to the risk of post-injection delirium/sedation syndrome, patients should not drive or operate heavy machinery for the remainder of the day of each injection [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Body Temperature Regulation

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see WARNINGS AND PRECAUTIONS].

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, ZYPREXA or Symbyax® (olanzapine/fluoxetine combination). Patients should also be advised to inform their physicians if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions [see DRUG INTERACTIONS].

Alcohol

Patients should be advised to avoid alcohol while taking ZYPREXA RELPREVV [see DRUG INTERACTIONS].

Use In Specific Populations

Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with ZYPREXA RELPREVV [see Use In Specific Populations].

Nursing Mothers — Patients should be advised not to breast-feed an infant if they are taking ZYPREXA RELPREVV [see Use in Specific Populations].

Pediatric Use — Safety and effectiveness of ZYPREXA RELPREVV in patients under 18 years have not been established. [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the maximum recommended human daily oral dose on a mg/m² basis) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the maximum recommended human daily oral dose on a mg/m² basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice dosed at 8 mg/kg/day (2 times the maximum recommended human daily oral dose on a mg/m² basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2-5 times the maximum recommended human daily oral dose on a mg/m² basis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥ 2 mg/kg/day and in female rats dosed at ≥ 4 mg/kg/day (0.5 and 2 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). Rats were also treated intramuscularly with ZYPREXA RELPREVV once a month for 2 years at doses of 5, 10, 20 mg/kg (males) and 10, 25, 50 mg/kg (females) (equivalent to 0.08-0.8 times the maximum recommended human dose of 300 mg every 2 weeks on a mg/m² basis; dosing was limited due to local reactions at the IM injection site). The incidence of tumors in this study was not altered when compared to solution for ZYPREXA RELPREVV control or pamoic acid treated animals. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis

No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Impairment of Fertility

In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the maximum recommended human daily oral dose on a mg/m² basis). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the maximum recommended human daily oral dose on a mg/m² basis); therefore olanzapine may produce a delay in ovulation.

Use In Specific Populations

Pregnancy

Teratogenic Effects, Pregnancy Category C

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human daily oral dose on a mg/m² basis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m² basis). In an oral rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended human daily oral dose on a mg/m² basis). No evidence of teratogenicity or embryo-fetal toxicity was observed in rats or rabbits with ZYPREXA RELPREVV at intramuscular doses up to 75 mg/kg (1 and 2 times the maximum recommended human dose of 300 mg every 2 weeks, respectively, on a mg/m² basis). Placental transfer of olanzapine occurred in rat pups.

There are no adequate and well-controlled trials with olanzapine in pregnant females. Four pregnancies were observed during clinical trials with ZYPREXA RELPREVV, including 1 resulting in a normal birth and 3 therapeutic abortions. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Neonates exposed to antipsychotic drugs (including olanzapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

ZYPREXA RELPREVV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of olanzapine on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine.

Nursing Mothers

In an oral olanzapine study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady state was estimated to be 1.8% of the maternal olanzapine dose. It is recommended that women receiving ZYPREXA RELPREVV should not breast-feed.

Pediatric Use

Safety and effectiveness of ZYPREXA RELPREVV in children and adolescent patients have not been established [see WARNINGS AND PRECAUTIONS].

Compared to patients from adult clinical trials, adolescents treated with oral ZYPREXA were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.

Geriatric Use

Clinical studies of ZYPREXA RELPREVV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In the premarketing clinical studies with oral olanzapine, there was no indication of any different tolerability of olanzapine in elderly patients compared to younger patients with schizophrenia. Oral olanzapine studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 8/31/2012
This monograph has been modified to include the generic and brand name in many instances.

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