ZYPREXA (Olanzapine) Tablets

1 PV 6241 AMP ZYPREXA® Olanzapine Tablets ZYPREXA® ZYDIS® Olanzapine Orally Disintegrating Tablets ZYPREXA® IntraMuscular Olanzapine for Injection WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ZYPREXA (olanzapine) is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION ZYPREXA (olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44. The chemical structure is: Olanzapine is a yellow crystalline solid, which is practically insoluble in water. ZYPREXA tablets are intended for oral administration only. Each tablet contains olanzapine equivalent to 2.5 mg (8 µmol), 5 mg (16 µmol), 7.5 mg (24 µmol), 10 mg (32 µmol), 15 mg (48 µmol), or 20 mg (64 µmol). Inactive ingredients are carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium 2 stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum Lake (15 mg), or Synthetic Red Iron Oxide (20 mg). The 2.5, 5, 7.5, and 10 mg tablets are imprinted with edible ink which contains FD&C Blue No. 2 Aluminum Lake. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is intended for oral administration only. Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 µmol), 10 mg (32 µmol), 15 mg (48 µmol) or 20 mg (64 µmol). It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) also contains the following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl paraben and sodium propyl paraben. ZYPREXA IntraMuscular (olanzapine for injection) is intended for intramuscular use only. Each vial provides for the administration of 10 mg (32 µmol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH. CLINICAL PHARMACOLOGY Pharmacodynamics Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT2A/2C, 5HT6, (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β adrenergic receptors (Ki>10 µM). The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug’s efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is unknown. Antagonism at receptors other than dopamine and 5HT2 may explain some of the other therapeutic and side effects of olanzapine. Olanzapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic-like effects. Olanzapine’s antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine’s antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. Pharmacokinetics Oral Administration 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 ZYPREXA tablets and ZYPREXA ZYDIS (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). 3 Administration of olanzapine once daily leads to steady-state concentrations in about one 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 (see Special Populations). 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 α1-acid glycoprotein. Metabolism and Elimination — Following a single oral dose of 14C 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 ZYPREXA IntraMuscular 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. Special 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 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 (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine. Age — In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (>65 years) than in non-elderly subjects (≤65 years). Caution should be used in dosing the elderly, especially if there are other factors that might 4 additively influence drug metabolism and/or pharmacodynamic sensitivity (see DOSAGE AND ADMINISTRATION). 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 recommended. Race — In vivo studies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended. Combined Effects — The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine (see DOSAGE AND ADMINISTRATION). For specific information about the pharmacology of lithium or valproate, refer to the CLINICAL PHARMACOLOGY section of the package inserts for these other products. CLINICAL EFFICACY DATA Schizophrenia The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in one of the two trials, but this trial did not compare these two drugs on the full range of clinically relevant doses for both. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, two more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow: (1) In a 6-week, placebo-controlled trial (n=149) involving two fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity. (2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the two highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the 5 highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high dose group over the medium dose group. Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings. In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open label treatment for at least 8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months. Bipolar Disorder Monotherapy — The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow: (1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome. (2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. (3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar disorder who had responded during an initial open-label treatment phase for about two weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse. 6 Combination Therapy — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of acute manic episodes was established in two controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow: (1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 µg/mL to 125 µg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score. (2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 µg/mL to 125 µg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score. Agitation 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 inpatients from two 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 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 five 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 one individual item score ≥4 using a 1-7 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 Compo