Olanzapine and Fluoxetine: Package Insert and Label Information (Page 2 of 13)

5.3 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as 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 after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported [see Warnings and Precautions (5.5)].

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine and fluoxetine capsules if DRESS is suspected.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine’s specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Adults — Healthcare providers should consider the risks and benefits when prescribing olanzapine and fluoxetine capsules to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL). Patients taking olanzapine and fluoxetine capsules should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine and fluoxetine 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.

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 alone, as well as olanzapine taken concomitantly with fluoxetine. 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.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, olanzapine and fluoxetine was associated with a greater mean change in random glucose compared to placebo (+8.65 mg/dL vs -3.86 mg/dL). The difference in mean changes between olanzapine and fluoxetine and placebo was greater in patients with evidence of glucose dysregulation at baseline (including those 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, or a baseline fasting glucose level ≥126 mg/dL). Olanzapine and Fluoxetine-treated patients had a greater mean HbA_1c increase from baseline of 0.15% (median exposure 63 days), compared to a mean HbA_1c decrease of 0.04% in fluoxetine-treated subjects (median exposure 57 days) and a mean HbA_1c increase of 0.12% in olanzapine-treated patients (median exposure 56 days).

In an analysis of 6 controlled clinical studies, a larger proportion of olanzapine and fluoxetine-treated subjects had glycosuria (4.4%) compared to placebo-treated subjects (1.4%).

The mean change in nonfasting glucose in patients exposed at least 48 weeks was +5.9 mg/dL (N=425).

Table 2 shows short-term and long-term changes in random glucose levels from adult olanzapine and fluoxetine studies.

Table 2: Changes in Random Glucose Levels from Adult Olanzapine and Fluoxetine Studies

Table 2: Changes in Random Glucose Levels from Adult Olanzapine and Fluoxetine Studies

			Up to 12 weeks exposure		At least 48 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Random Glucose	Normal to High (<140 mg/dL to ≥200 mg/dL)	Olanzapine and Fluoxetine	609	2.3%	382	3.1%
		Placebo	346	0.3%	NAa	NAa
	Borderline to High (≥140 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine and Fluoxetine	44	34.1%	27	37.0%
		Placebo	28	3.6%	NAa	NAa

^a Not Applicable

In a 47-week olanzapine and fluoxetine study, the mean change from baseline to endpoint in fasting glucose was +4.81 mg/dL (n=130). Table 3 shows the categorical changes in fasting glucose [see Clinical Studies (14.2) ].

Table 3: Changes in Fasting Glucose Levels from a Single Adult Olanzapine and Fluoxetine Study

			Up to 27 Weeks Exposure (Randomized, Double-Blind Phase)		Up to 47 Weeks Exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High	Olanzapine and Fluoxetine	90	4.4%	130	11.5%
		Fluoxetine	96	5.2%	NAa	NAa
	Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	Olanzapine and Fluoxetine	98	18.4%	79	32.9%
		Fluoxetine	97	7.2%	NAa	NAa

^a Not Applicable

Controlled fasting glucose data is limited for olanzapine and fluoxetine; however, in an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (+2.76 mg/dL vs. +0.17 mg/dL).

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

Children and Adolescents — In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for treatment of bipolar I depression in patients 10 to 17 years of age, there were no clinically meaningful differences observed between olanzapine and fluoxetine and placebo for mean change in fasting glucose levels. Table 4 shows categorical changes in fasting blood glucose from the pediatric olanzapine and fluoxetine study.

Table 4: Changes in Fasting Glucose Levels from a Single Pediatric Olanzapine and Fluoxetine Study in Bipolar Depression

			Up to 8 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients
Fasting Glucose	Normal to High (<100 mg/dL to ≥126 mg/dL)	Olanzapine and Fluoxetine	125	4.8%
		Placebo	65	1.5%
	Normal/IGTa to High (<126 mg/dL to ≥126 mg/dL)	Olanzapine and Fluoxetine	156	5.8%
		Placebo	78	1.3%
	Normal/IGT (<126 mg/dL to ≥ 140 mg/dL)	Olanzapine and Fluoxetine	156	1.9%
		Placebo	78	0.0%

^a Impaired Glucose Tolerance.

Olanzapine Monotherapy in Adolescents In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, 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 vs -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 5 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 5: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

			Up to 12 weeks exposure		At least 24 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	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.