Olanzapine and Fluoxetine: Package Insert and Label Information (Page 10 of 13)

12.4 Specific Populations

Geriatric — Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of olanzapine and fluoxetine may be altered in geriatric patients. Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.

In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly subjects (≥65 years of age) than in non-elderly subjects (<65 years of age).

The disposition of single doses of fluoxetine in healthy elderly subjects (≥65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients.

Renal Impairment — The pharmacokinetics of olanzapine and fluoxetine HCl has not been studied in patients with renal impairment. However, olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. Olanzapine and fluoxetine HCl dosing adjustment based upon renal impairment is not routinely required.

Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on olanzapine metabolite elimination has not been studied.

In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

Hepatic Impairment — Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of olanzapine and fluoxetine HCl may be altered in patients with hepatic impairment. The lowest starting dose should be considered for patients with hepatic impairment [see Dosage and Administration (2.3) and Warnings and Precautions (5.20)].

Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (N=6) with clinically significant cirrhosis (Childs-Pugh Classification A and B) revealed little effect on the pharmacokinetics of olanzapine.

As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects.

Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.

Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely required.

Race — No olanzapine and fluoxetine HCl pharmacokinetic study was conducted to investigate the effects of race. In vivo studies have shown that exposures to olanzapine are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race, therefore, are not routinely required.

Combined Effects — The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance of olanzapine in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Olanzapine and fluoxetine HCl dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of the olanzapine component [see Dosage and Administration (2.3)].

Children and Adolescents (ages10to 17years) — Based on the pediatric olanzapine and fluoxetine study, steady-state olanzapine, fluoxetine, and norfluoxetine plasma concentrations were about 31%, 76%, and 38% higher, respectively, in pediatric patients with lower body weights (less than 50 kg) than in pediatric patients with high body weight (greater than or equal to 50 kg). Exposures in pediatric patients with high body weight were similar to those previously observed in adults. Dose modifications based on bodyweight are not required.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies were conducted with olanzapine and fluoxetine. The following data are based on findings in studies performed with the individual components, and all dose multiples (based on body surface area) reflect the maximum recommended human dose (MRHD) of 12 mg olanzapine, or 50 mg fluoxetine in olanzapine and fluoxetine capsules.

Carcinogenesis

Olanzapine — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, and 30/20 mg/kg/day [equivalent to 1 to 12 times the MRHD based on mg/m² body surface area] and 0.25, 2, and 8 mg/kg/day (equivalent to up to 3 times the oral MRHD based on mg/m² body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5 and 4 mg/kg/day (males) and 0.25, 1, 4 and 8 mg/kg/day (females) (equivalent to up to 3 and 7 times the oral MRHD based on mg/m² body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 3 times the daily oral MRHD based on mg/m² body surface area. These tumors were not increased in another mouse study in females dosed at (up to 12 times the daily oral MRHD based on mg/m² body surface area); 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 (1 and 3 times the oral MRHD based on mg/m² body surface area, respectively). 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 (5.22)].

Fluoxetine — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 2 and 1 times, respectively, the MRHD of 20 mg given to children based on mg/m² body surface area), produced no evidence of carcinogenicity.

Mutagenesis

Olanzapine — No evidence of genotoxic potential for olanzapine was found in following tests: 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.

Fluoxetine — No evidence of genotoxic potential for fluoxetine and norfluoxetine was found in the following tests: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Impairment of Fertility

Olanzapine and Fluoxetine — Fertility studies were not conducted with olanzapine and fluoxetine. However, in a repeat-dose rat toxicology study of 3 months duration, ovary weight was decreased in females treated with the low-dose [2 and 4 mg/kg/day (approximately 2 and 1 times the MRHD of 12 mg (olanzapine) and 50 mg (fluoxetine) based on mg/m² body surface area), respectively] and high-dose [4 and 8 mg/kg/day (3and 2 times the MRHD based on mg/m² body surface area), respectively] combinations of olanzapine and fluoxetine. Decreased ovary weight, and corpora luteal depletion and uterine atrophy were observed to a greater extent in the females receiving the high-dose combination than in females receiving either olanzapine or fluoxetine alone. In a 3-month repeat-dose dog toxicology study, reduced epididymal sperm and reduced testicular and prostate weights were observed with the high-dose combination of olanzapine and fluoxetine [5 and 5 mg/kg/day (14 and 3 times the MRHD based on mg/m² body surface area), respectively] and with olanzapine alone (5 mg/kg/day or 14 times the MRHD based on mg/m² body surface area).

Olanzapine — 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 (18 and 2 times the daily oral MRHD of 12 mg given to adults based on mg/m² body surface area, 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 (4 times the MRHD based on mg/m² body surface area). Diestrous was prolonged and estrous was delayed at 1.1 mg/kg/day (1 times the daily oral MRHD based on mg/m² body surface area); therefore, olanzapine may produce a delay in ovulation.

Fluoxetine —Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 1and 2 times the MRHD of 50 mg given to adolescents based on mg/m² body surface area) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)].

14 CLINICAL STUDIES

Efficacy for olanzapine and fluoxetine capsules was established for the:

• Acute treatment of depressive episodes in Bipolar I Disorder in adults in 2 short-term, placebo-controlled trials (Studies 1, 2, 3) [see Clinical Studies 14.1 ).
• Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials (Studies 4, 5, 6) and 1 randomized withdrawal study with an active control (Study 7)[see Clinical Studies 14.2].

14.1 Depressive Episodes Associated with Bipolar I Disorder

Adults – The efficacy of olanzapine and fluoxetine HCl for the acute treatment of depressive episodes associated with Bipolar I Disorder was established in 2 identically designed, 8-week, randomized, double-blind, controlled studies of patients who met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for Bipolar I Disorder, Depressed utilizing flexible dosing of olanzapine and fluoxetine (6/25 mg, 6/50 mg, or 12/50 mg/day), olanzapine (5 to 20 mg/day), and placebo. These studies included patients (≥18 years of age [n=788]) with or without psychotic symptoms and with or without a rapid cycling course.

The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 to 60. The primary outcome measure of these studies was the change from baseline to endpoint in the MADRS total score. In both studies, olanzapine and fluoxetine was statistically significantly superior to both olanzapine monotherapy and placebo in reduction of the MADRS total score. Refer to Table 18 (Studies 1 and 2).

Children and Adolescents (ages 10 to 17 years) — The efficacy of olanzapine and fluoxetine for the acute treatment of depressive episodes associated with Bipolar I Disorder was established in a single 8-week, randomized, double-blind, placebo-controlled study of patients, 10 to 17 years of age [N=255], who met Diagnostic and Statistical Manual 4th edition-Text Revision (DSM-IV-TR) criteria for Bipolar I Disorder, Depressed. Patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. After Week 2, there was flexible dosing of olanzapine and fluoxetine in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. The average daily dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. The recommended starting dose for children and adolescents is 3/25 mg per day. Flexible dosing is recommended, rather than the forced titration used in the study [see Dosage and Administration (2.1)]. This study included patients with or without psychotic symptoms.

The primary rating instrument used to assess depressive symptoms in these studies was the Children’s Depressive Rating Scale-Revised (CDRS-R), a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary outcome measure of this study was the change from baseline to Week 8 in the CDRS-R total score. In this study, olanzapine and fluoxetine was statistically significantly superior to placebo in reduction of the CDRS-R total score. Refer to Table 18 (Study 3).

Table 18. Summary of the Primary Efficacy Result for Studies in Bipolar Depression^a

Study Number (Primary Efficacy Measure)	Treatment group	Mean baseline score (SD)	LS Mean change from baseline (SE)	Differenceb from Olanzapine and Fluoxetine (95% CI)
Study 1 (MADRS)	Olanzapine and Fluoxetine Olanzapine Placebo	29.9 (5.0) 32.4 (6.3) 31.2 (5.7)	-18.7 (1.8) -14.4 (1.0) -13.3 (1.0)	-4.4 (NA) -5.5 (NA)
Study 2 (MADRS)	Olanzapine and Fluoxetine Olanzapine Placebo	31.7 (6.8) 32.8 (6.1) 31.4 (6.6)	-18.44 (1.7) -15.81 (1.0) -10.68 (1.0)	-2.6 (NA) -7.8 (NA)
Study 3 (CDRS-R)	Olanzapine and Fluoxetine Placebo	54.6 (10.0) 53.7 (8.2)	-28.43 (1.1) -23.40 (1.5)	-5.0 (-8.3, -1.8)
a SD – standard deviation; SE – standard error; LS mean – least-squares mean estimate; CI – unadjusted confidence interval; NA – not available. b Difference (olanzapine and fluoxetine minus active comparator or placebo) in least squares estimates.

14.2 Treatment Resistant Depression

The efficacy of olanzapine and fluoxetine in acute treatment resistant depression was demonstrated with data from 3 clinical studies (n=579) in adults (18 to 85 years). Doses evaluated in these studies ranged from 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine.

An 8-week randomized, double-blind controlled study was conducted to evaluate the efficacy of olanzapine and fluoxetine in patients (n=300) who met DSM-IV criteria for Major Depressive Disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode. Patients who were not responding to an antidepressant in their current episode entered an 8-week open-label fluoxetine lead-in; non-responders were randomized (1:1:1) to receive olanzapine and fluoxetine, olanzapine, or fluoxetine, and were treated for 8 weeks. Olanzapine and fluoxetine was flexibly dosed between 6/50 mg, 12/50 mg, and 18/50 mg. Results from this study yielded statistically significant greater reduction in mean total MADRS scores from baseline to endpoint for olanzapine and fluoxetine versus fluoxetine and olanzapine. See Table 19 (Study 4). A second study with the same treatment-resistant patient population (n=28), when analyzed with change in MADRS as the outcome measure, demonstrated statistically significantly greater reduction in MADRS scores for olanzapine and fluoxetine versus fluoxetine and olanzapine. See Table 19 (Study 5). A third study demonstrated statistically significantly greater reduction in total MADRS scores for olanzapine and fluoxetine versus fluoxetine or olanzapine alone, when analyzed in a subpopulation of depressed patients (n=251) who met the definition of treatment resistance (patients who had not responded to 2 antidepressants of adequate dose and duration in the current episode). See Table 19 (Study 6).

Table 19: Summary of the Primary Efficacy Result for Studies in Treatment-Resistant Depression ^a

Study Number (Primary Efficacy Measure)	Treatment group	Mean baseline score (SD)	LS Mean change from baseline (SE)	Differenceb from Olanzapine and Fluoxetine (95% CI)
Study 4 (MADRS)	Olanzapine and Fluoxetine Olanzapine Fluoxetine	30.6 (6.1) 30.1 (6.3) 30.1 (5.9)	-14.1 (1.0) -7.1 (1.0) -8.3 (1.1)	-6.9 (NA) -5.8 (NA)
Study 5 (HAMD-21)	Olanzapine and Fluoxetine Olanzapine Fluoxetine	26.4 (7.5) 24.5 (5.2) 23.5 (6.0)	-11.7 (3.3) -5.9 (1.9) -3.8 (3.0)	-6.1 (-13.7, 1.5) -6.7 (-14.0, 0.5)
Study 6 (MADRS)	Olanzapine and Fluoxetine Olanzapine Fluoxetine	30.1 (6.6) 31.5 (6.8) 31.1 (5.6)	-13.3 (0.8) -8.8 (1.7) -10.0 (1.4)	NA NA
a SD – standard deviation; SE – standard error; LS mean – least-squares mean estimate; CI – unadjusted confidence interval; NA – not available. b Difference (olanzapine and fluoxetine minus active comparator or placebo) in least squares estimates.

The efficacy of olanzapine and fluoxetine in the maintenance therapy of treatment-resistant depression was demonstrated in a 47-week study (Study 7) in adults (18 to 65 years). Olanzapine and fluoxetine was dosed between 6/25 mg, 12/25 mg, 6/50 mg, 12/50 mg, and 18/50 mg.

Patients (N=892) met DSM-IV criteria for Major Depressive Disorder and for treatment-resistant depression (a lack of response to 2 antidepressants after at least 6 weeks at or above the minimally effective labeled dose in their current episode of major depressive disorder). Patients were initially treated with open-label olanzapine and fluoxetine; those who responded to and were stabilized on treatment over approximately 20 weeks were randomized to continue receiving treatment with olanzapine and fluoxetine (n=221) or to receive treatment with fluoxetine (n=223) for another 27 weeks. Relapse was assessed using 3 criteria: a 50% increase in Montgomery-Åsberg Depression Rating Scale score from randomization with concomitant Clinical Global Impressions–Severity of Depression score increase to 4 or more; hospitalization due to depression or suicidality; or discontinuation due to lack of efficacy/worsening of depression/suicidality. A total of 15.8% of patients on olanzapine and fluoxetine and 31.8% of patients on fluoxetine relapsed; this difference was statistically significant. Patients receiving continued olanzapine and fluoxetine experienced statistically significantly longer time to relapse over the 27 weeks compared with those receiving fluoxetine (Figure 1).