Olanzapine 10 mg/2mL Injection, Powder, For Solution — NDC 31722-308-01 (Billing 31722-0308-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism.

12.2Pharmacodynamics Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C , 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11-31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA A , BZD, and β-adrenergic receptors (K i >10 μM).

12.3Pharmacokinetics Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption.

Pharmacokinetic studies showed that olanzapine tablets and olanzapine orally disintegrating tablets dosage forms of olanzapine are bioequivalent. Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).

Administration of olanzapine once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age. Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L.

It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α 1 -acid glycoprotein. Metabolism and Elimination — Following a single oral dose of 14 C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively.

In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4´-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo , because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Intramuscular Administration — olanzapine for injection results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose.

The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism.

12.3Pharmacokinetics Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption.

Pharmacokinetic studies showed that olanzapine tablets and olanzapine orally disintegrating tablets dosage forms of olanzapine are bioequivalent. Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).

Administration of olanzapine once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age. Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L.

It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α 1 -acid glycoprotein. Metabolism and Elimination — Following a single oral dose of 14 C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively.

In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4´-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo , because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Intramuscular Administration — olanzapine for injection results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose.

The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.

Specific Populations Renal Impairment — 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 metabolite elimination has not been studied. Hepatic Impairment — Although the prese… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C , 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11-31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA A , BZD, and β-adrenergic receptors (K i >10 μM).

14 CLINICAL STUDIES

14.3Agitation Associated with Schizophrenia and Bipolar I Mania The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients from 2 diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar I mania study).

Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with at least 1 individual item score ≥4 using a 1 to 7 scoring system (1=absent, 4=moderate, 7=extreme).

In the studies, the mean baseline PANSS Excited Component score was 18.4, with scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to 3 injections during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed.

The results of the trials follow: (1) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=270), 4 fixed intramuscular olanzapine for injection doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. However, the effect was larger and more consistent for the 3 highest doses.

There were no significant pairwise differences for the 7.5 and 10 mg doses over the 5 mg dose. (2) In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=311), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

(3) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (and currently displaying an acute manic or mixed episode with or without psychotic features) (n=201), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 to 5 times the daily oral MRHD based on mg/m 2 body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06 to 2 times the daily oral MRHD based on mg/m 2 body surface area). 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 to 2 and 0.13 to 4 times the daily oral MRHD based on mg/m 2 body surface area, respectively).

The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 2 times the daily oral MRHD based on mg/m 2 body surface area. These tumors were not increased in another mouse study in females dosed up to 2 to 5 times the daily oral MRHD based on mg/m 2 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 (0.5 and 2 times the daily oral MRHD based on mg/m 2 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 ( 5.15 )]. 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 daily oral MRHD based on mg/m 2 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 (2.5 times the daily oral MRHD based on mg/m 2 body surface area).

Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m 2 body surface area); therefore olanzapine may produce a delay in ovulation.

13.2Animal Toxicology and/or Pharmacology In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m 2 body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m 2 body surface area) in studies of 3 months’ duration.

Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the da… [Excerpted — this section continues on DailyMed.]