Olanzapine and Fluoxetine: Package Insert and Label Information (Page 4 of 13)

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine and fluoxetine capsules. Patients receiving olanzapine and fluoxetine should receive regular monitoring of weight.

Adults — In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, the mean weight increase for olanzapine and fluoxetine-treated patients was greater than placebo-treated patients [4 kg (8.8 lb) vs -0.3 kg (-0.7 lb)]. Twenty-two percent of olanzapine and fluoxetine-treated patients gained at least 7% of their baseline weight, with a median exposure to event of 6 weeks. This was greater than in placebo-treated patients (1.8%). Approximately 3% of olanzapine and fluoxetine-treated patients gained at least 15% of their baseline weight, with a median exposure to event of 8 weeks. This was greater than in placebo-treated patients (0%). Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 2.5% of olanzapine and fluoxetine-treated patients and 0% of placebo-treated patients.

In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), the mean weight gain was 6.7 kg (14.7 lb) (median exposure of 448 days, N=431). The percentages of patients who gained at least 7%, 15% or 25% of their baseline body weight with long-term exposure were 66%, 33%, and 10%, respectively. Discontinuation due to weight gain occurred in 1.2% of patients treated with olanzapine and fluoxetine in combination following at least 48 weeks of exposure.

Table 11 presents the distribution of weight gain in a single long-term relapse prevention study of patients treated for up to 47 weeks with olanzapine and fluoxetine [see Clinical Studies (14.2)].

Table 11: Weight Gain with Olanzapine and Fluoxetine Use in a Single Relapse Prevention Study in Adults

Amount Gained kg (lb)	Up to 8 Weeks (N=881) (%)	Up to 20 Weeks (N=651) (%)	Up to 47 Weeks (N=220) (%)
≤0	19.8	14.9	19.1
0 to ≤5 (0 to 11 lb)	64.1	47.2	37.7
>5 to ≤10 (11 to 22 lb)	15.1	30.3	27.7
>10 to ≤15 (22 to 33 lb)	0.9	5.8	10.0
>15 to ≤20 (33 to 44 lb)	0.1	1.2	3.2
>20 to ≤25 (44 to 55 lb)	0.0	0.6	1.4
>25 to ≤30 (55 to 66 lb)	0.0	0.0	0.5
>30 (>66 lb)	0.0	0.0	0.5

In long-term olanzapine 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 12 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 12: 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 to 11 lb)	57.0	36.0	26.0	23.4	25.2
>5 to ≤10 (11 to 22 lb)	14.9	24.6	24.2	24.1	18.4
>10 to ≤15 (22 to 33 lb)	1.8	10.9	14.9	11.4	17.0
>15 to ≤20 (33 to 44 lb)	0.1	3.1	8.6	9.3	11.6
>20 to ≤25 (44 to 55 lb)	0	0.9	3.3	5.1	4.1
>25 to ≤30 (55 to 66 lb)	0	0.2	1.4	2.3	4.8
>30 (>66 lb)	0	0.1	0.8	1.2	2

Dose group differences with respect to weight gain have been observed. 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, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Children and Adolescents — In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar I depression in patients 10 to 17 years of age, olanzapine and fluoxetine was associated with greater mean change in weight compared to placebo (+4.4 kg vs +0.5 kg, respectively). The percentages of children and adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with 8-week exposure were 52%, 14%, and 1%, respectively. The proportion of patients who had clinically significant weight gain was greater in children and adolescent patients compared to short-term data in adults. Discontinuation due to weight gain occurred in 2.9% of olanzapine and fluoxetine-treated patients and 0% of placebo-treated patients. Table 13 depicts weight gain observed in the pediatric olanzapine and fluoxetine study.

Table 13: Weight Gain with Olanzapine and Fluoxetine Use Seen in a Single Pediatric Study in Bipolar Depression

Amount Gained kg (lb)	Up to 8 Weeks (N=170) (%)
≤0	7.1
0 to ≤5(0 to 11 lb)	54.7
>5 to ≤10 (11 to 22 lb)	31.2
>10 to ≤15 (22 to 33 lb)	7.1
>15 to ≤20 (33 to 44 lb)	0
>20 to ≤25 (44 to 55 lb)	0
>25 to ≤30 (55 to 66 lb)	0
>30 (>66 lb )	0

Olanzapine Monotherapy in Adolescents —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 14: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

Mean change in body weight from baseline (median exposure = 3 weeks)	Olanzapine-treated patients	Placebo-treated patients
	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 olanzapine 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 15 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 15: 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 to 11 lb)	47.3	24.6
>5 to ≤10 (11 to 22 lb)	42.4	26.7
>10 to ≤15 (22 to 33 lb)	5.8	22.0
>15 to ≤20 (33 to 44 lb)	0.8	12.6
>20 to ≤25 (44 to 55 lb)	0.8	9.4
>25 to ≤30 (55 to 66 lb)	0	2.1
>30 to ≤35 (66 to 77 lb)	0	0
>35 to ≤40 (77 to 88 lb)	0	0
>40 (>88 lb)	0	0.5

5.6 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including olanzapine and fluoxetine, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants ), fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of olanzapine and fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Olanzapine and fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking olanzapine and fluoxetine. Olanzapine and fluoxetine should be discontinued before initiating treatment with the MAOI [see Dosage and Administration (2.4, 2.5) and Contraindications (4.1)].

If concomitant use of olanzapine and fluoxetine with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with olanzapine and fluoxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.