Free Exhibits - District Court of California - California

Case 3:07-cv-04911-CRB

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DRUGDEX-EV 1728 MICROMEDEX DRUGDEX® Evaluations Database updated February 2007 OLANZAPINE Overview Dosing Information Pharmacokinetics Cautions Clinical Applications References 0.0 Overview 1) Class a) This drug is a member of the following class(es): Antipsychotic Thienobenzodiazepine 2) Dosing Information a) Adult 1) Agitation - Bipolar I disorder - Mania a) initial, 10 mg INTRAMUSCULARLY; lower dose of 5 mg or 7.5 mg may be used if indicated. Usual effective dosage range is 2.5 mg to 10 mg b) subsequent doses may be given INTRAMUSCULARLY in doses up to 10 mg. Maximal dosing, three 10 mg doses given 2 to 4 hours apart (monitor for orthostatic hypotension prior to the administration of repeated doses) 2) Agitation - Schizophrenia a) initial, 10 mg INTRAMUSCULARLY; lower dose of 5 mg or 7.5 mg may be used if indicated. Usual effective dosage range is 2.5 mg to 10 mg b) subsequent doses may be given INTRAMUSCULARLY in doses up to 10 mg. Maximal dosing, three 10 mg doses given 2 to 4 hours apart (monitor for orthostatic hypotension prior to the administration of repeated doses) 3) Bipolar disorder, acute, Mixed or manic with or without psychotic features a) (monotherapy) 10-15 mg ORALLY once a day; may increase/decrease dosage by 5 mg/day at intervals of at least 1 day. Usual effective dosage range is 5-20 mg/day; the safety of doses above 20 mg/day has not been evaluated in clinical trials 4) Bipolar disorder, acute - Bipolar disorder, manic episode a) (in combination with lithium or valproate) 10 mg ORALLY once a day; usual effective dosage range is 5-20 mg/day; the safety of doses above 20 mg/day has not been evaluated in clinical trials 5) Bipolar disorder, Maintenance a) (monotherapy) 5 to 20 mg ORALLY per day (after achieving a responder status for an average duration of two weeks) 6) Schizophrenia a) 5-10 mg ORALLY once a day (target dose of 10 mg/day within several days); may increase/decrease

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dosage by 5 mg/day at intervals of at least 1 week. Usual effective dosage range is 10-15 mg/day; the safety of doses above 20 mg/day has not been evaluated in clinical trials b) Pediatric 1) safety and effectiveness in pediatric patients have not been established 3) Contraindications a) hypersensitivity to olanzapine products 4) Serious Adverse Effects a) Tardive dyskinesia b) Water intoxication syndrome 5) Clinical Applications a) FDA Approved Indications 1) Agitation - Bipolar I disorder - Mania 2) Agitation - Schizophrenia 3) Bipolar disorder, acute, Mixed or manic with or without psychotic features 4) Bipolar disorder, acute - Bipolar disorder, manic episode 5) Bipolar disorder, Maintenance 6) Schizophrenia 1.0 Dosing Information Drug Properties Storage and Stability Adult Dosage Pediatric Dosage 1.1 Drug Properties A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index) B) Synonyms Olanzapine C) Physicochemical Properties 1) Molecular Weight a) 312.44 (Prod Info Zyprexa(R), 2004) 2) Solubility a) Practically insoluble in water (Prod Info Zyprexa(R), 2004) 1.2 Storage and Stability A) Oral route 1) Store at controlled room temperature, 20 to 25 degrees C (68 to 77 degrees F) (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). Protect from light and moisture B) Extemporaneous Formulation - Oral route 1) Olanzapine is practically insoluble in water. A 1-milligram per milliliter (mg/mL) suspension prepared from crushed tablets in a pediatric mixture base (containing syrup, carboxymethylcellulose and parabens) was found to be stable for 14 days when stored in a refrigerator and protected from light (Harvey et al, 2000). Care in preparation and administration is advised as olanzapine may be irritating to the eye and can cause contact dermatitis. When breaking or crushing olanzapine tablets it is recommended to wear gloves and wash hands before and after exposure (Personal Communication, 2001). 1.3 Adult Dosage

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1.3.1 Normal Dosage 1.3.1.A Intramuscular route 1.3.1.A.1 Agitation - Manic bipolar I disorder - Schizophrenia a) The recommended intramuscular dose for the treatment of AGITATION ASSOCIATED WITH SCHIZOPHRENIA OR BIPOLAR MANIA is 10 milligrams (mg). A lower dose of 5 mg or 7.5 mg may be used when clinically indicated. Efficacy of intramuscular olanzapine has been demonstrated in a dosage range of 2.5 mg to 10 mg (Prod Info Zyprexa(R) IntraMuscular, 2004). b) The efficacy of repeated doses of intramuscular olanzapine in agitated patients has not been evaluated in controlled clinical trials. However, if agitation persists after the initial dose and additional intramuscular doses are warranted, subsequent doses up to 10 milligrams (mg) may be given. The safety of total daily doses greater than 30 mg, or 10 mg injections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of intramuscular olanzapine (ie, three 10 mg doses administered 2 to 4 hours apart) may be associated with an increased risk of orthostatic hypotension. It is recommended that patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. Additional doses should not be administered to a patient with a clinically significant postural change in systolic blood pressure. If ongoing olanzapine therapy is necessary, oral olanzapine may be initiated in a range of 5 to 20 mg/day as soon as clinically appropriate (Prod Info Zyprexa(R) IntraMuscular, 2004). c) Intramuscular olanzapine for injection is intended for intramuscular use only; do NOT administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass (Prod Info Zyprexa(R) IntraMuscular, 2004). 1.3.1.B Oral route 1.3.1.B.1 Agitation - Manic bipolar I disorder - Schizophrenia a) In one study, rapid initial dose escalation of oral olanzapine was effective in the treatment of acute agitation in patients with schizophrenia or bipolar disorder. Investigators used a dosing regimen of 20 to 40 milligrams (mg)/day for 2 days, then 20 to 30 mg/day for 2 days, and then 5 to 20 mg/day for 3 days. Also effective was the more conventional dosing regimen of olanzapine 10 mg daily with adjunctive lorazepam as needed for 4 days, and then olanzapine 5 to 20 milligrams for 3 days (Baker et al, 2003). 1.3.1.B.2 Bipolar disorder, Maintenance a) MONOTHERAPY 1) Bipolar patients responding to initial olanzapine therapy for an average period of two weeks have been successfully maintained on olanzapine monotherapy at a dose of 5 to 20 milligrams/day. The long-term usefulness of olanzapine for the individual patient should be periodically re-evaluated if olanzapine is used for extended periods of time (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 1.3.1.B.3 Bipolar disorder, manic episode a) MONOTHERAPY 1) In clinical trials evaluating the short-term (3 to 4 weeks) effects of olanzapine in acute mania, efficacy was observed with doses of 5 milligrams (mg) to 20 mg daily. The recommended initial

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dosage of olanzapine is 10 or 15 milligrams (mg) once daily and doses may be increased, at intervals of not less than 24 hours, by 5 mg daily. Doses above 20 mg/day have not been evaluated for safety in clinical trials (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). b) COMBINATION THERAPY 1) In clinical trials evaluating the short-term (6 weeks) effects of olanzapine in acute mania, efficacy was observed with doses of 5 to 20 milligrams (mg) daily. The recommended initial dosage of olanzapine in combination with lithium or valproate is 10 mg once daily. Doses above 20 mg/day have not been evaluated for safety in clinical trials (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 1.3.1.B.4 Schizophrenia a) Initial dosages are 5 to 10 milligrams administered on a once-a-day schedule without regard to meals. A target dosage of 10 milligrams/day within several days of initiation of therapy is recommended. If dosage adjustments are needed, decrease or increase the dosage by 5 milligrams/day. Dosage adjustments should typically occur at intervals of not less than 1 week (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). b) In clinical trials, antipsychotic efficacy occurred at a dosage range of 10 to 15 milligrams/day. Doses above 10 milligrams/day were not demonstrated to be more efficacious than the 10 milligrams/day dose. The safety of doses above 20 milligrams/day has not been evaluated in clinical trials (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). c) Effective doses of olanzapine in the treatment of schizophrenia have ranged from 7.5 to 40 milligrams daily (Alao, 1999)(Nemeroff, 1997a); (Beasley et al, 1996)(Beasley et al, 1996aa; Anon, 1994b; Anon, 1994aa). Clinical trials have shown that 10 milligrams/day is a therapeutic dose. The 15milligram dose may have greater efficacy in relieving negative symptoms; further studies are needed (Nemeroff, 1997a). 1.3.1.C Parkinson's disease - Psychotic disorder See Drug Consult reference: PATIENTS 1.3.1.D Trichotillomania See Drug Consult reference: TRICHOTILLOMANIA - DRUG THERAPY THERAPY OF PSYCHOTIC DISTURBANCES IN PARKINSONIAN

1.3.1.E) ORAL DISINTEGRATING TABLETS - PATIENT INSTRUCTIONS 1) For administration of oral disintegrating tablets, peel back foil on blister pack to expose tablet; do NOT push the tablet through the foil backing. Use dry hands to remove the tablet from the blister unit and immediately place the entire tablet in the mouth. Tablets disintegrate rapidly in saliva and can be swallowed with or without liquid (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 1.3.1.F) INTRAMUSCULAR SOLUTION PREPARATION 1) For the preparation of solution for intramuscular injection containing approximately 5 milligrams/milliliter (mg/mL) of olanzapine, dissolve the contents of the supplied vial using 2.1 mL of Sterile Water for Injection. The resulting solution should appear clear and yellow. Olanzapine solution should be used immediately (within 1 hour) after reconstitution and any unused portion should be discarded. The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection reconstituted with Sterile Water for Injection (Prod Info Zyprexa(R) IntraMuscular, 2004): Dose (mg)

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Volume of Injection (mL) 10.0 Withdraw total contents of vial 7.5 1.5 5.0 1.0 2.5 0.5 1.3.1.G) SWITCHING TO OLANZAPINE 1) Schizophrenic and schizophreniform patients may be successfully transitioned from clozapine to olanzapine by adding olanzapine 5 milligrams (mg) daily to a stable dose of clozapine (Henderson et al, 1998). Olanzapine is increased by 2.5 to 5 mg weekly to a maximum of 30 mg/day. After the first week, clozapine doses should be gradually decreased by increments of 25 to 50 mg per week. 2) Switching patients to olanzapine from conventional antipsychotic therapy or risperidone was most successful when olanzapine was immediately implemented at the full therapeutic dose and other antipsychotics were gradually discontinued. In a study of 209 clinically stable outpatients diagnosed with schizophrenia or schizoaffective disorder, 4 treatment strategies were used. Patients were randomized to undergo abrupt or gradual discontinuation of their prior antipsychotic drug and immediate or stepwise initiation of olanzapine. Olanzapine was administered in doses of 10 milligrams (mg) daily (QD) for 3 weeks or in a stepwise fashion (1 week of placebo, followed by 1 week of olanzapine 5 mg QD and then 1 week of olanzapine 10 mg). The efficacy of each strategy was assessed using the Clinical Global Impressions (CGI) Improvement scale, Patient's Global Impressions (PGI) improvement scale and Positive and Negative Syndrome Scale (PNSS). These scoring systems showed that immediate initiation of olanzapine with gradual discontinuation of the original drug therapy was the safest and most effective approach. However, all strategies were effective; by week 3, the majority of patients on all regimens had either improved or were clinically unchanged without increased risk of relapse or of drug withdrawal symptoms. Patients who abruptly discontinued antipsychotic medication and gradually implemented olanzapine had a significantly greater incidence of sleep disorders than those using other strategies. Drowsiness occurred significantly more often in when antipsychotic medication was abruptly discontinued with immediate implementation of olanzapine therapy than with other approaches (Kinon et al, 2000). 1.3.2 Dosage in Renal Failure A) Patients with renal impairment DO NOT require a dosage adjustment. The pharmacokinetic parameters were similar between patients with severe renal impairment and normal patients. Only 7% of olanzapine is excreted in the urine as unchanged drug (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). However, a lower initial dose of 5 milligrams daily should be considered (Prod Info Zyprexa(R), 1998). 1.3.3 Dosage in Hepatic Insufficiency A) Olanzapine is extensively metabolized, however, no change in dosage is needed. In patients with significant liver function impairment (Childs Pugh Classification A and B), little effect was seen on the pharmacokinetics of olanzapine (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 1.3.4 Dosage in Geriatric Patients A) Caution should be used when oral olanzapine is administered to the elderly, especially if there are other factors that may influence drug metabolism and/or pharmacodynamic parameters (Prod Info Zyprexa(R),

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Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). B) The recommended intramuscular dose for elderly patients is 5 milligrams per injection (Prod Info Zyprexa(R) IntraMuscular, 2004). 1.3.5 Dosage Adjustment During Dialysis A) HEMODIALYSIS 1) Olanzapine is not removed by dialysis (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). B) PERITONEAL DIALYSIS 1) Olanzapine is not removed by dialysis (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 1.3.6 Dosage in Other Disease States A) SPECIAL POPULATIONS 1) The recommended starting oral dose is 5 milligrams in the following populations: patients who are debilitated, who have a predisposition to hypotensive reactions, who exhibit a combination of factors that may cause a slower metabolism of olanzapine (eg, nonsmoking females 65 or older) or who may be pharmacodynamically sensitive to olanzapine (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 2) The recommended intramuscular dose is 2.5 milligrams per injection for patients who are debilitated, have a predisposition to hypotensive reactions, or may be pharmacodynamically sensitive to olanzapine (Prod Info Zyprexa(R) IntraMuscular, 2004). 3) No dosage modification is needed but the manufacturer reports that the clearance of olanzapine is 30% lower in females (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 4) No dosage modification is needed but the manufacturer reports that the clearance of olanzapine is 40% higher in smokers than in nonsmokers (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). 5) The combined effects of age, smoking, and gender could cause substantial pharmacokinetic differences in populations. For example the clearance in young male smokers may be 3 times higher than that in elderly nonsmoking females (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004b). Age over 65, gender, or smoking status alone does NOT require dosage modification. 1.4 Pediatric Dosage 1.4.1 Normal Dosage 1.4.1.A Anorexia nervosa See Drug Consult reference: ANOREXIA NERVOSA - DRUG THERAPY

2.0 Pharmacokinetics Onset and Duration

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Drug Concentration Levels ADME 2.1 Onset and Duration A) Onset 1) Initial Response a) Schizophrenia: 1 week (Beasley et al, 1996). 2.2 Drug Concentration Levels A) Therapeutic Drug Concentration 1) Schizophrenia, greater than 9 ng/ml (Perry et al, 1997). a) In acutely schizophrenic patients receiving olanzapine (n=79), 45% of patients with a trough level above 9.3 ng/ml responded after 6 weeks of therapy versus only 15% of patients with concentrations less than 9.3 ng/ml responding (Perry et al, 1997). B) Time to Peak Concentration 1) Oral: 6 hours (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). Oral: 6 hours (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). a) In an open-label, inpatient trial involving 8 patients (ages 10 to 18 years) receiving olanzapine 2.5 to 20 milligrams daily for 8 weeks, the mean maximum plasma concentration was 115.6 +/- 26.7 nanograms/milliliter. The mean time to maximum concentration was 4.7 +/- 3.7 hours. The concentrations among these adolescent patients are similar to the concentrations observed in nonsmoking adult patients being treated with olanzapine for schizophrenia, but nearly twice the average concentrations in smokers (Grothe et al, 2000). 2) Intramuscular: 15 to 45 minutes (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). 2.3 ADME 2.3.1 Absorption A) Bioavailability 1) Oral: Well-absorbed (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). a) Extensively eliminated by first-pass metabolism; 40% of dose metabolized before reaching systemic circulation (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004; Bever & Perry, 1998a). B) Effects of Food 1) None (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). 2.3.2 Distribution A) Distribution Sites 1) Protein Binding a) 93% (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). 1) The primary binding sites are albumin and alpha-1- acid glycoprotein (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). B) Distribution Kinetics 1) Volume of Distribution a) 1000 L (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004).

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2.3.3 Metabolism A) Metabolism Sites and Kinetics 1) Liver, extensively metabolized (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004; Anon, 1994). a) The primary metabolic pathways for olanzapine are direct glucuronidation and oxidation mediated by CYP1A2, CYP2D6, and the flavin-containing monooxigenase system. CYP2D6 appears to be a minor pathway (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). b) Forty percent is metabolized via first pass metabolism (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). B) Metabolites 1) 10-N-glucuronide, (inactive) (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). 2) 4'-N-desmethyl olanzapine, (inactive) (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). 2.3.4 Excretion A) Kidney 1) Renal Excretion (%) a) 57% (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004; Anon, 1994). B) Total Body Clearance 1) 26.1 L/hr (Kando, 1997). a) Clearance ranges from 12 to 47 L/hour (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004). b) In 8 pediatric and adolescent patients (ages 10 to 18 years) receiving 2.5 to 20 milligrams olanzapine daily for 8 weeks, the mean plasma clearance was 9.6 +/- 2.4 liters/hour (Grothe et al, 2000). C) Other 1) OTHER EXCRETION a) Feces, 30% (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004; Anon, 1994). 2.3.5 Elimination Half-life A) Parent Compound 1) ELIMINATION HALF-LIFE a) 21 to 54 hours (mean = 30 hours) (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004; Anon, 1994). 1) In 8 pediatric and adolescent patients (ages 10 to 18 years) receiving 2.5 to 20 milligrams olanzapine daily for 8 weeks, the mean elimination half-life was 37.2 +/- 5.1 hours (Grothe et al, 2000). 2) Although the mean elimination half-life of olanzapine is prolonged in the elderly (young patients: 33.8 hours vs. 65 years and older: 51.8 hours) and renal clearance is reduced from 18.2 Liters/hour (L/h) in the young to 17.5 L/h in those 65 years and older, pharmacokinetic variability is not greater than in young patients. Thus, a dose reduction is not necessary in otherwise healthy elderly patients (Prod Info Zyprexa(R), 1998a).

3.0 Cautions

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Contraindications Precautions Adverse Reactions Teratogenicity/Effects in Pregnancy/Breastfeeding Drug Interactions 3.0.A) Black Box WARNING 1) Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 times to 1.7 times that seen 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 (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Olanzapine is not approved for the treatment of patients with dementia-related psychosis (Prod Info ZYPREXA(R), ZYPREXA ZYDIS(R), ZYPREXA IntraMuscular(R), 2005). 3.1 Contraindications A) hypersensitivity to olanzapine products 3.2 Precautions A) diabetes mellitus B) elderly patients with dementia (unapproved use); increased risk of death (1.6 to 1.7 times greater than placebo) reported when atypical antipsychotics were used off-label to treat behavorial disorders associated with dementia; most deaths were attributed to cardiovascular events (eg, heart failure or sudden death) or infections (mostly pneumonia) (Prod Info ZYPREXA(R), ZYPREXA ZYDIS(R), ZYPREXA IntraMuscular(R), 2005) C) elderly patients with dementia-related psychosis; increased risk of cerebrovascular adverse events (ie, stroke, transient ischemic attack) including death D) history of breast cancer E) history of neuroleptic malignant syndrome F) hyperglycemia G) patients at risk for aspiration pneumonia H) patients who experience conditions that may contribute to an elevation in core body temperature I) patients at risk for suicide J) patients with liver disease K) patients with significant prostatic hypertrophy, narrow angle glaucoma, or history of paralytic ileus L) patients with cardiovascular disease, cerebrovascular disease, or conditions that would predispose patients to hypotension M) seizure disorder or conditions that could lower seizure threshold N) signs and symptoms of tardive dyskinesia 3.3 Adverse Reactions 3.3.1 Cardiovascular Effects 3.3.1.A Cardiovascular finding 1) Summary a) The manufacturer reports that POSTURAL HYPOTENSION (3-5%), TACHYCARDIA (3%),

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HYPERTENSION (2%), CHEST PAIN (3%), and PERIPHERAL EDEMA (3%) have occurred with olanzapine therapy (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). Caution is recommended when using olanzapine concurrently with drugs that prolong the QT interval (Prod Info Zyprexa(R), 1998). A case of HYPOTENSION and BRADYCARDIA has been reported (Markowitz et al, 2002). 2) Postural hypotension, tachycardia, hypertension, chest pain, and peripheral edema are reported with olanzapine administration. Caution is recommended when using olanzapine concomitantly with drugs that prolong the QT interval. 3) LITERATURE REPORTS a) A 24-year-old, healthy, non-smoking, woman volunteer experienced hypotension (70/30 mmHg) and bradycardia (pulse 30) one and a half to 2 hours after taking a single oral dose of olanzapine 5 milligrams (mg). Lying down with feet elevated brought both pulse and blood pressure back to her normal values within 20 minutes. The maximum plasma concentration of olanzapine in this subject (13 nanograms/milliliter) was unusually high and occurred earlier (at 3 hours) than the generally reported range for tmax (5 to 6 hours). Her Cmax was in the range expected for a single dose of 10 to 15 mg of olanzapine (Markowitz et al, 2002). b) Unlike other antipsychotic medications, olanzapine does NOT contribute significantly to QTc prolongation that could result in potentially severe ventricular dysrhythmias, due to its mechanism of action (Czekalla et al, 2001; Isbister et al, 2001). c) Although olanzapine has not been associated with sustained QT-interval prolongation, caution is recommended during concomitant treatment with drugs that do prolong the QT-interval, especially in the elderly. In a study of 1685 subjects, only 8 experienced multiple QT-interval prolongations (Prod Info Zyprexa(R), 1998). d) Small reductions in orthostatic blood pressure have been reported in olanzapine-treated patients during clinical trials (Beasley et al, 1996)(Beasley et al, 1996a). e) Tachycardia occurred in greater than 5% of patients in clinical trials, with an overall mean increase in heart rate of 2.4 beats/minute (Prod Info Zyprexa(R), 1996). Chest pain has also been reported in clinical trials. 3.3.1.B Orthostatic hypotension 1) Summary a) ORTHOSTATIC HYPOTENSION has been observed in greater than 5% of patients participating in olanzapine clinical trials . A mean increase in heart rate of 2.4 beats per minute has been reported in clinical trials with TACHYCARDIA occurring in greater than 5% of the patients. It is possible that this effect is associated with orthostatic hypotensive changes (Bronson & Lindenmayer, 2000; Prod Info Zyprexa(R), 1996). Slight reductions in orthostatic blood pressure have been reported in olanzapine-treated patients (Beasley et al, 1996), although this is of doubtful clinical relevance. Heart rate has not been affected (Beasley et al, 1996). 2) Incidence: 2-3% 3.3.2 Dermatologic Effects 3.3.2.A Dermatological finding 1) Summary a) A 36-year-old African-American man developed a PUSTULAR SKIN ERUPTION 2 weeks after beginning olanzapine therapy. Pustular lesions initially began on his face and spread to his hips and buttocks. One day later he developed ERYTHEMATOUS PLAQUES on his neck, hips and buttocks. He had no lymphadenopathy or fever. Olanzapine was discontinued and warm compresses were applied. The eruptions resolved within 1 week (Adams & Mutasim, 1999). 2) Pustular eruptions, sweating and erythematous plaques are reported with olanzapine administration.

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3.3.2.B Sweating symptom 1) Summary a) The manufacturer reports that sweating has been associated with olanzapine therapy (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). 3.3.3 Endocrine/Metabolic Effects 3.3.3.A Body temperature finding 1) Summary a) HYPOTHERMIA developed in a 54-year-old hemodialysis patient with end- stage renal disease following the use of olanzapine. The man initially received a 21-day course of oral olanzapine 2.5 milligrams (mg) daily for the treatment of sudden-onset night delirium with visual hallucinations and abnormal behaviors. The symptoms of delirium resolved, but then reappeared 7 days later. He was given olanzapine again at the same dose for 10 days; however, following the first dose of medication, his body temperature suddenly decreased to less than 34 degrees Celsius. Hypothermia persisted from day 2 of the 10-day olanzapine administration, and did not resolve until 6 days after olanzapine was discontinued (Fukunishi et al, 2003). b) Disruption of the body's ability to reduce core body temperature may occur with antipsychotic agents. ELEVATED BODY TEMPERATURE has been reported following therapeutic doses in clinical trials (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). Patients experiencing conditions that may contribute to an ELEVATED CORE BODY TEMPERATURE (eg exercising strenuously, exposure to extreme heat, or dehydration) should use appropriate care (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). 2) Elevated body temperature, hypothermia, and neuroleptic malignant syndrome (NMS) are reported with olanzapine administration. 3.3.3.B Diabetes mellitus 1) Summary a) New onset diabetes mellitus (DM) and DIABETIC KETOACIDOSIS have been reported with the administration of olanzapine. At least 25 fatalities have been reported in association with olanzapineinduced diabetic ketoacidosis (Torry & Swalwell, 2003)(Goldstein et al, 1999; Lindenmayer & Patel, 1999; Gatta et al, 1999). 2) LITERATURE REPORTS a) A 51-year-old woman with schizoaffective disorder and type 2 diabetes (stabilized on metformin 1 gram twice daily and gliclazide 160 mg twice daily) developed hyperglycemia, without weight gain, when an episode of elevated mood and psychosis was treated with olanzapine. She was initially treated with risperidone for 4 weeks but did not respond. Chlorpromazine also was not effective. Olanzapine, titrated to 30 milligrams at night) brought full remission of psychotic symptoms. Her blood glucose then began to increase, although her diet was controlled by the hospital. Oral hypoglycemic medications were increased to the maximum and she was started on actrapid insulin. Glucose levels remained unstable until olanzapine was tapered and discontinued, at which time her hypoglycemic medications were reduced to previous levels and actrapid insulin was discontinued. Zuclopenthixol was subsequently used to treat her schizoaffective disorder. The patient showed no significant weight gain during treatment with olanzapine, which suggests that olanzapine can have a direct effect on glucose regulation (Ramankutty, 2002). b) A 27-year-old man developed signs of diabetes mellitus (polydipsia, polyphagia, nausea and vomiting, hyperglycemia, ketonuria) 2 years after starting olanzapine for treatment of schizophrenia.

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He was treated with insulin, and his dose of olanzapine was increased from 10 milligrams/day (mg/day) to 15 mg/day to replace valproic acid, which he had taken for 3 years. After 3 months, insulin therapy was replaced by pioglitazone 30 mg/day, resulting in relatively good glycemic control. Olanzapine therapy was not discontinued because of the risk of psychotic worsening (Seaburg et al, 2001). c) A 45-year-old obese man developed elevated fasting glucose 1 year after his treatment for schizophrenia was changed from risperidone to olanzapine (20 to 25 milligrams/day (mg/day)). Six months later, he was treated with glyburide 1.25 mg/day. Over the next 6 months, his glycosylated hemoglobin levels remained stable, but his weight began to increase. Five months later, he complained of diarrhea and weight loss. His glyburide dose was increased to 1.88 mg/day. With further symptoms (polyuria, polydipsia, and diaphoresis), his glyburide dosage was increased to 10 mg twice daily, insulin treatment was started, and olanzapine was replaced by risperidone. Six weeks after discontinuation of olanzapine, the patient's glycosylated hemoglobin had dropped to 6%. Insulin was discontinued, glyburide was reduced to 1.25 mg/day, and his weight stabilized. Five months later, his diabetes was well controlled (Bechara et al, 2001). d) Olanzapine-induced GLUCOSE DYSREGULATION has been reported as an adverse effect, possibly due to drug-induced weight gain. Olanzapine was associated with a severe exacerbation of type 2 diabetes in a 51-year-old woman with a major depressive disorder and substance abuse. Initially, the patient was treated with sertraline and haloperidol decanoate. After 4 weeks, sertraline was replaced by fluoxetine due to continued severe depressive symptoms. At week 18, haloperidol was replaced by olanzapine due to persistent auditory and visual hallucinations. Prior to initiation of olanzapine therapy, the patient's diabetes was well controlled by diet (glycosylated hemoglobin 6.5%, baseline fasting blood glucose 89 to 132 milligrams per deciliter (mg/dL). Twelve days after olanzapine was begun, glucose control diminished and continued to worsen despite treatment with glipizide, metformin, and diet. At week 26, fluoxetine therapy was replaced by venlafaxine due to inadequate antidepressant response. At week 35 (fasting blood glucose 120 to 461 mg/dL, glycosylated hemoglobin 12.5%), insulin therapy (NPH 70/30) was initiated and titrated to 70 units per day. Olanzapine was tapered during weeks 39 and 40 and discontinued. Two weeks after all antipsychotic therapy was stopped, the patient's fasting blood glucose levels had decreased to within 85 and 163 mg/dL. By the time of discharge, the insulin dose had been reduced to 45 units/day NPH 70/30 (Bettinger, 2000). e) Diabetic ketoacidosis following 3 months of olanzapine therapy was reported in a 31-year-old man with no familial or personal history of diabetes. The patient was started on insulin and olanzapine was discontinued. Fifteen days later his insulin requirements decreased and then stopped. Eight months later the patient has remained metabolically stable, free of diabetic symptoms (Gatta et al, 1999). f) Cases of new-onset diabetes mellitus (DM) were reported that developed after initiation of olanzapine treatment. The DM began between 5 weeks and 17 months (mean 26 weeks; median 20 weeks) after olanzapine initiation. Two cases presented with diabetic ketoacidosis. Four patients had a family history of DM and 4 patients experienced weight gain while on olanzapine. Olanzapine was eventually discontinued in all cases but in 4 out of 7 cases, medical treatment for DM was still required (Goldstein et al, 1999). g) A 50-year-old African American man developed diabetic ketoacidosis after receiving 8 months of olanzapine therapy. At the time, he was receiving olanzapine 30 milligrams (mg) daily with divalproex 750 mg twice daily. He began insulin therapy but after the olanzapine was discontinued, his blood sugar returned to normal (Lindenmayer & Patel, 1999). h) A 39-year-old man developed diabetic ketoacidosis after receiving olanzapine 10 milligrams (mg) for a treatment-refractory disorder. He had no family history or previous laboratory evidence of diabetes. His body mass index was high at 40 kilograms/meter(2) (kg/m(2)). He was admitted with asthenia, polyuria, dehydration, severe hyperglycemia [6 millimoles/liter (mmol/L)], and acidosis. His HbA(1c) was 14.7%. He was maintained on insulin 3 times daily. When olanzapine was discontinued, insulin requirements decreased after 15 days. His blood glucose and HbA(1c) became normal (Gatta et al, 1999).

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3.3.3.C Endocrine finding 1) Diabetes mellitus (DM) and elevations in serum prolactin have been reported with olanzapine administration. Pancreatitis has been reported with the administration of olanzapine. 3.3.3.D Hyperglycemia 1) Summary a) A 15-year-old African American boy developed hyperglycemia, along with weight gain and hypertriglyceridemia, while being treated with olanzapine for behavior disorders. At baseline, when the boy had been taking olanzapine for 3 months and valproic acid for over 12 months, all laboratory values were within normal ranges. His body mass index (BMI) was 28.7 kilograms per meter squared (kg/m(2)). Four months later, buspirone was added to his treatment. Within 2 months, his BMI had increased to 34.1 kg/m(2). Three months later, he had experienced weight loss (BMI=27.5 kg/m(2)) and developed polyuria and polydipsia. Fasting blood glucose was 368 milligrams/deciliter. Olanzapine was discontinued. Without hypoglycemic drugs, insulin treatment, or dietary changes, his serum glucose level normalized over the next 8 weeks, as did his serum triglyceride and cholesterol levels. Twenty weeks after the discontinuation of olanzapine, his BMI was 26.5 kg/m(2) (Domon & Webber, 2001). 3.3.3.E Hypoglycemia 1) Summary a) HYPOGLYCEMIC COMA was reported in a frail, 95-year-old woman following olanzapine administration for the treatment of nocturnal psychomotor agitation associated with Alzheimer's dementia. Three days after the initiation of olanzapine at a dose of 2.5 milligrams daily, the woman was pale and sweaty; she appeared sleepy and could not be woken by verbal or tactile stimulation. She was treated with 33% glucose and recovered within approximately 20 minutes, however, hypoglycemia was noted again the following day. Olanzapine was withdrawn and the blood glucose profile stabilized two days later with the ongoing administration of 33% glucose. A direct cause and effect correlation could not be established because the patient had also been receiving enalapril, which has been documented to possibly induce hypoglycemia. While, a drug interaction between enalapril and olanzapine could not be ruled out, the authors did not feel that there was a correlation between enalapril and hypoglycemia because the patient had been receiving enalapril for at least two years previous to this incident (Landi et al, 2003). 3.3.3.F Metabolic finding 1) Summary a) The manufacturer reports that INCREASED APPETITE (3-6%) and WEIGHT GAIN (5-6%) have occurred with olanzapine therapy. (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). 2) Weight gain, increased appetite, increases in serum triglycerides, and hyperglycemia have been reported with olanzapine administration. 3) Olanzapine-induced KETOACIDOSIS has been reported, including one near fatal case in a 44-yearold African American woman. In the near fatal case, the patient had taken olanzapine 25 milligrams/day for approximately one month (Straker et al, 2002). 4) High dose olanzapine was associated with mild extrapyramidal symptoms (EPS), elevated serum prolactin and alanine aminotransferase (ALT) levels, and an average weight gain of 8 kilograms (kg) in 8 men with schizophrenia and schizoaffective disorder. These patients, who were resistant to typical neuroleptics and risperidone or clozapine at adequate doses, were dosed with olanzapine 20 to 40 milligrams (mg) for a mean of 40 weeks (Bronson & Lindenmayer, 2000).

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5) A prospective, multicenter, observational study showed that olanzapine treatment of outpatients (n=2128) with schizophrenia was safer than in a control group of patients (n=821) receiving a variety of other antipsychotic drug therapies. Drugs used in the control group included risperidone, haloperidol, sertindole, zuclopenthixol, fluphenazine, thioridazine, perphenazine, pimozide, clozapine, pipotiazine, sulpiride, chlorpromazine, levomepromazine, clothiapine, and lorazepam. Overall, olanzapine had a significantly lower incidence of adverse events than the control group (48% versus 64%, p less than 0.001). Somnolence and weight gain occurred significantly more frequently in olanzapine-treated patients. Akathisia, dystonia, extrapyramidal syndrome, hypertonia, and tremor were significantly higher in the control group. Abnormal ejaculation and impotence occurred significantly more frequently in men in the control group. Over a 6-month period, fewer olanzapine-treated patients received a concomitant anticholinergic medication in comparison to patients in the control group (36% versus 58%, p less than 0.001) (Gomez et al, 2000). 6) LITERATURE REPORTS a) Adolescent patients taking olanzapine experienced greater weight gain and increased in body mass index (BMI) than patients taking quetiapine in a retrospective study involving 103 patients younger than 18 years of age. Patients received olanzapine (n=50, mean daily dose 13.9 milligrams (mg)) or quetiapine (n=53, mean daily dose 510.9 mg) for at least 2 weeks. Weight and height were measured at baseline and 14 or more days after baseline. Average weight gain from baseline in the olanzapine group was 3.8 kilograms (kg) (p less than 0.001) compared to 0.03 kg in the quetiapine group. Both the olanzapine and quetiapine groups showed slight, but significant, increases in height from baseline (0.006 meters, p=0.042 and 0.006 meters, p less than 0.001, respectively). After controlling for baseline differences, the mean weight change between groups was significant (3.4 kg, p less than 0.001). BMI increased by an average of 1.3 kg per square meter (m(2)) in the olanzapine group (p less than 0.001) compared to a decreased of 0.2 kg/m(2) in the quetiapine group. After controlling for baseline differences, the mean difference in change in BMI was significant (0.9 kg/m(2), p=0.008) (Patel et al, 2004). b) In a continuing day-treatment program 15 out of 16 patients receiving olanzapine gained weight. The mean weight gain was 22 pounds with a mean olanzapine dose of 14 milligrams (mg) and mean treatment duration of 7 months (Gupta et al, 1999). c) Weight gain has been observed in recipients of olanzapine (mean of 3.5 kilograms (kg) with 12.5 to 17.5 milligrams (mg) daily) (Beasley et al, 1996) and is most pronounced in patients on initial doses of 15 mg or above (Prod Info Zyprexa(R), 1998). d) EXCESSIVE APPETITE was seen more commonly with olanzapine therapy than with haloperidol (24% versus 12.4%,p less than 0.05). Olanzapine therapy was also associated with a clinically significant greater increase in weight over haloperidol therapy (p less than 0.001). However, a post hoc analysis revealed that body mass index was the predominant predictor of weight gain. Patients with a low prestudy body mass index were more likely to gain weight during olanzapine treatment. Treatment effect on weight change was consistent between male and female patients (Tollefson et al, 1997a). 3.3.3.G Prolactin level raised 1) Summary a) A case a GALACTORRHEA with elevated serum prolactin levels was reported in a 33-year-old woman after receiving olanzapine (5 to 20 milligrams (mg)/day) for the treatment of schizophreniform disorder. During the fifth week of olanzapine therapy, the patient developed spontaneous whitish discharge from both breasts and reported missing her menstrual period. Her serum prolactin level was 146.55 nanograms/milliliter (ng/mL) (normal range, 1.5 to 19 ng/mL). Olanzapine was discontinued and replaced with quetiapine (25 to 100 mg/day). Symptoms of galactorrhea resolved within 3 weeks of stopping olanzapine, and serum prolactin levels began to decrease. Quetiapine therapy was continued without recurrence of galactorrhea (Mendhekar et al, 2004). b) High dose olanzapine was associated with mild extrapyramidal symptoms (EPS), elevated serum prolactin and alanine aminotransferase (ALT) levels, and an average weight gain of 8 kilograms (kg) in

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8 men with schizophrenia and schizoaffective disorder. These patients, who were resistant to typical neuroleptics and risperidone or clozapine at adequate doses, were dosed with olanzapine 20 to 40 milligrams (mg) for a mean of 40 weeks (Bronson & Lindenmayer, 2000). c) Olanzapine has produced small elevations in serum prolactin [about 0.1 to 0.2 nanomoles/liter(nmol/L)], which have tended to be dose- related. However, significantly greater increases have occurred with haloperidol (Anon, 1994a); (Beasley et al, 1996). Cases of unwanted pregnancies have been reported after switching from conventional neuroleptic medications to olanzapine possibly due to a normalization of prolactin levels and a potential return of FERTILITY (Dickson & Dawson, 1998). 3.3.3.H Serum triglycerides raised 1) Summary a) Increases in serum triglycerides have been reported with olanzapine therapy (Osser et al, 1999); (Sheitman et la, 1999). 2) LITERATURE REPORTS a) Patients (n=25) receiving olanzapine were found to have increases in their weight and serum triglycerides (Osser et al, 1999). In an open study, patients receiving olanzapine [mean dose 13.8 milligrams(mg)] had their weight, cholesterol, and triglycerides measured at baseline and after 12 weeks. Weight increased by a mean of 5.4 kg. Cholesterol levels increased by only 3 milligrams/deciliter (mg/dL) while triglyceride levels increased by 60 mg/dL. The triglyceride change was highly associated with weight change (p less than 0.02). b) After an average of 16 months of olanzapine therapy, 9 patients had marked increases in triglyceride levels (Sheitman et la, 1999). Triglyceride levels increased from a mean of 170 milligrams/deciliter (mg/dL) to a mean of 240 mg/dL. Five patients had at least a 50% increase in levels. Cholesterol levels remained essentially unchanged. The patients had a mean weight gain of 10 kilograms (kg). 3.3.4 Gastrointestinal Effects 3.3.4.A Constipation 1) Summary a) The manufacturer reports that constipation (9-11%) has occurred with olanzapine therapy (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). A relatively common adverse gastrointestinal effect of olanzapine is constipation (secondary to anticholinergic activity), which appears to be dose-related (Anon, 1995); (Beasley et al, 1996). In patients receiving a mean of 12 milligrams (mg) daily and 16 mg daily, respective incidences of constipation were 8% and 15% (Beasley et al, 1996). The incidence of constipation with olanzapine in higher doses (12.5 to 17.5 mg daily) is greater than observed with haloperidol 10 to 20 mg daily (Beasley et al, 1996). Anticholinergic effects, which include constipation, are common adverse effects of olanzapine therapy (Isbister et al, 2001); (Beasley et al, 1996)(Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). 2) Incidence: 5-6% 3.3.4.B Excessive salivation 1) Summary a) Hypersalivation has occurred with olanzapine therapy. A 20-year- old woman experienced morning grogginess and soaking her pillow with saliva during sleep while receiving olanzapine 10 milligrams/day (mg/d). Her symptoms worsened with an increased dose (Perkins & McClure, 1998). Increased salivation has been reported in premarketing clinical trials and in an accidental

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pediatric ingestion (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a; Yip & Graham, 1997). 3.3.4.C Gastrointestinal tract finding 1) Summary a) The manufacturer reports that INCREASED SALIVATION, THIRST and DYSPEPSIA (7-11%) have occurred with olanzapine therapy. ESOPHAGEAL DYSMOBILITY has been associated with antipsychotic therapy. (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). Dyspepsia is not dose-related. (Beasley et al, 1996). ANTICHOLINERGIC EFFECTS, including DECREASED BOWEL SOUNDS, are common adverse effects of olanzapine therapy. These effects are dose-related (Isbister et al, 2001); (Beasley et al, 1996)(Prod Info Zyprexa(R), 1996). There has also been one case report of acute hemorrhagic pancreatitis (Doucette et al, 2000). 2) The manufacturer reports that constipation, increased salivation, vomiting, thirst, dry mouth, dyspepsia, and nausea have occurred with olanzapine therapy. Dry mouth and nausea appear to be doserelated. Esophageal dysmobility has been associated with antipsychotic therapy. 3.3.4.D Nausea and vomiting 1) Summary a) Vomiting (4%) and nausea (greater than or equal to 2%) have occurred with olanzapine therapy. Nausea appears to be dose-related. The incidence of nausea tends to increase with dose (2% with 12 milligrams (mg) daily, 9% with 16 mg daily) and in higher doses (12.5 to 17.5 mg daily) is greater than observed with haloperidol 10 to 20 mg daily (Beasley et al, 1996)(Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). 3.3.4.E Pancreatitis 1) Summary a) ACUTE HEMORRHAGIC PANCREATITIS has been reported as a probable adverse event of olanzapine. Olanzapine was started 6 days prior to the onset of symptoms. Other concomitant drugs were ruled out as contributing to pancreatitis. Death due to secondary unrelenting peritonitis occurred in this case (Doucette et al, 2000). This is a rare adverse effect of olanzapine. b) In one study of reported cases (n=192) of antipsychotic-induced pancreatitis, 33% of the cases were associated with the use of olanzapine at a mean daily dose of 15 milligrams. In most patients, time to onset of pancreatitis was within 6 months after initiation of treatment (Koller et al, 2003c). c) Olanzapine was the probable cause of acute hemorrhagic pancreatitis in a 72-year-old female admitted with abdominal pain and an accidental verapamil overdose. Past medical history included multiple sclerosis, left temporal cerebral infarct (2 weeks prior to admission), depression, chronic pain, and drug abuse. Prior to admission she was taking ketorolac, morphine, and temazepam. Olanzapine (5 milligrams (mg) daily) had been initiated 6 days prior to admission for recent cognitive decline. The patient's chief complaint of abdominal pain began 24 hours before admission for which she inadvertently ingested 10 of her husband's verapamil 240 mg sustained release tablets. Laparotomy revealed hemorrhagic pancreatitis. Despite supportive care, the patient died due to peritonitis related to pancreatitis. Using the Naranjo Probability Scale, olanzapine was considered to be the probable cause of acute pancreatitis in this patient (Doucette, 2000). Other authors have pointed out possible discrepancies in the above case such as the use of multiple medications and chronic alcoholism which they believe could have contributed to the acute pancreatitis (Woodall & DiGregorio, 2001). 3.3.4.F Xerostomia

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1) Summary a) The manufacturer reports that dry mouth (9-22%) has occurred with olanzapine therapy. Dry mouth appears to be dose-related (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). A relatively common adverse gastrointestinal effect of olanzapine is dry mouth (secondary to anticholinergic activity), which appears to be dose-related (Anon, 1995); (Beasley et al, 1996). In patients receiving a mean of 12 milligrams (mg) daily and 16 mg daily, respective incidences of dry mouth were 5% and 13% (Beasley et al, 1996). The incidence of dry mouth with olanzapine in higher doses (12.5 to 17.5 mg daily) is greater than observed with haloperidol 10 to 20 mg daily (Beasley et al, 1996). Anticholinergic effects, which include dry mouth, are common adverse effects of olanzapine therapy (Isbister et al, 2001); (Beasley et al, 1996)(Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). 2) Incidence: 5-15% 3.3.5 Hematologic Effects 3.3.5.A Agranulocytosis 1) Summary a) Fifteen days after starting olanzapine (5 milligrams daily), a 46-year-old male presented to the hospital with fever, chills, and odinophagia. He was also concurrently taking cyanamide. A white blood cell count of 0.5 x 10(9)/liter (L) with a neutrophil count of 0.36 x 10(9)/L was noted. Olanzapine and cyanamide were stopped and antibiotic therapy was initiated. By the sixth hospital day, his white blood cell count had normalized. A temporal relationship between olanzapine therapy and new onset agranulocytosis was noted (Tolosa-Vilella et al, 2002). b) Unlike clozapine, a structurally related drug, olanzapine has not been shown in preclinical trials to cause any significant agranulocytosis (Tollefson et al, 1997a); (Beasley et al, 1996)(Anon, 1994a; Anon, 1995). However, due to the structural similarities of the two drugs, there may be a potential for abnormal hematologic reactions. Subsequently, however, there have been reports of agranulocytosis with olanzapine administration (Oyewumi & Al-Semaan, 2000); (Fachinfo, Zyprexa(R), 1998)(Naumann et al, 1999). There have also been several cases of olanzapine adversely prolonging the recovery time of clozapine-induced granulocytopenia reported (Konakanchi et al, 2000). c) Neutropenia was reported in a 39-year-old African American woman receiving olanzapine for paranoid schizophrenia. Prior to olanzapine, she had received clozapine for 7 years, but this was discontinued due to the development of granulocytopenia. Concurrent medications included divalproex sodium 1000 milligrams (mg) three times daily (TID), nifedipine 60 mg daily, metformin 1000 mg TID, insulin 70/30 (20 units in the morning, 10 units in the evening) and lorazepam 2 mg QD. Her absolute neutrophil count (ANC) was 3,110/millimeter (mm). The patient's absolute ANC was 1410 cells per millimeter (/mm) at the time clozapine was switched to olanzapine (10 mg QD). After 7 days of olanzapine, ANC increased to 1810 cells/mm, but by day 14, it had decreased to 1050 cells/mm. Olanzapine was reintroduced 6 months later without incident. It may be prudent to delay initiating olanzapine therapy in patients with clozapine-induced granulocytopenia until the patient's hematologic status has normalized (Konakanchi et al, 2000). 2) LITERATURE REPORTS a) During clozapine-induced agranulocytosis in 2 patients with schizophrenia, olanzapine [doses greater than 25 milligrams/day (mg/d)] was shown to be a safe and effective treatment. Additionally, olanzapine did not worsen the severe neutropenia or agranulocytosis nor did it prevent recovery (Oyewumi & Al-Semaan, 2000). b) A 27-year-old man who had been previously treated with clozapine therapy and had a normal leukocyte count, developed agranulocytosis with olanzapine. Five months after discontinuing clozapine therapy, olanzapine therapy was begun and rapidly increased to 40 milligrams (mg) daily. After 9 days his white blood cell (WBC) count decreased to 3.4 x 10(9)/Liter (L). Olanzapine therapy was discontinued and 2 days later his WBC count had decreased to 2.3 x 10(9)/L. His neutrophil count also decreased to 0.39 x 10(9)L. He was successfully treated with granulocyte colony-stimulating

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factor 5 micrograms/kilogram (mcg/kg)(Naumann et al, 1999). c) Thirty-two patients with a history of clozapine-induced neutropenia or agranulocytosis did not experience decreased neutrophil counts during olanzapine treatment (Prod Info Zyprexa(R), 1998). However, clinical experience with olanzapine, especially with long-term use, remains limited. 3.3.5.B Hematology finding 1) Significant hematologic abnormalities have not been reported during olanzapine therapy in available studies. However, agranulocytosis, leukopenia and neutropenia have been reported rarely with olanzapine administration. 3.3.5.C Leukopenia 1) Summary a) Unlike clozapine, a structurally related drug, olanzapine has not been shown in preclinical trials to cause any significant leukopenia (Beasley et al, 1996)(Anon, 1994a; Anon, 1995). However, due to the similarities of the two drugs, there may be a potential for abnormal hematologic reactions. Several cases of olanzapine adversely prolonging the recovery time of clozapine-induced granulocytopenia have been reported (Konakanchi et al, 2000). 2) LITERATURE REPORTS a) Two patients treated with olanzapine for levodopa-induced psychosis developed leukopenia. A 56year-old woman experienced decreased leukocytes (2400 microliters) after 4 months of therapy. She was tapered off olanzapine and recovered over 4 weeks. She was then started on clozapine and had a similar reaction. In the other case, a 58-year-old man who had previously had a decline in his white blood cell count (WBC) due to clozapine therapy, had a decline in his WBC (2100 microliters) 13 months after starting olanzapine therapy. After discontinuation of olanzapine, his WBC count returned to normal after 2 weeks (Meissner et al, 1999). 3.3.5.D Neutropenia 1) Summary a) Significant hematologic abnormalities have not been reported during olanzapine therapy in available studies (Tollefson et al, 1997a); (Beasley et al, 1996)(Anon, 1994a; Anon, 1995). However, neutropenia has been reported with olanzapine therapy (Oyewumi & Al-Semaan, 2000; Prod Info Zyprexa(R), 1998; Benedetti et al, 1999). Unlike clozapine, a structurally related drug, olanzapine has not been shown in preclinical trials to cause any significant leukopenia or agranulocytosis. However, due to the similarities of the two drugs, there may be a potential for abnormal hematologic reactions. Several cases of olanzapine adversely prolonging the recovery time of clozapine-induced granulocytopenia have been reported (Konakanchi et al, 2000). 2) LITERATURE REPORTS a) A patient previously treated with clozapine developed neutropenia associated with olanzapine therapy. A 48-year-old African American male with schizoaffective disorder (bipolar type), chronic paranoid schizophrenia, and schizoid personality disorder, had been maintained on clozapine 550 milligrams (mg) daily (QD) for over 1 year. His white blood cell (WBC) count ranged from 4000 to 6000 cells per cubic millimeter (/mm(3)) during that time. Clozapine was discontinued, however, when the absolute neutrophil count (ANC) fell below 1000 cells/mm(3). After 11 days off clozapine, the WBC count increased to 7300 cells/mm(3) (ANC not reported). Olanzapine therapy was initiated at 10 mg QD and titrated to 30 mg QD over a 2-week period. After 1 week (olanzapine dose 15 mg at bedtime), WBC fell to 5500 cells/(mm(3) At 30 mg/day, the WBC count decreased to 4800 cells/mm(3) (ANC 974 cells/ mm(3)). Olanzapine was discontinued and the patient's WBC count slowly began to return to normal, and then remained stable. This case suggests that patients who have previously taken clozapine may have an increased risk for neutropenia with olanzapine (Teter et al,

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2000). b) A 60-year-old African American male with chronic undifferentiated schizophrenia had been treated with clozapine, but this was discontinued during gallbladder surgery. While receiving clozapine, his WBC counts ranged between 4000 and 6000 cells/mm(3). Two years later, he received a 10-month course of olanzapine (30 mg QD), which was discontinued due to hyperglycemia and weight gain. Olanzapine (20 mg/d) was later restarted, and over a 17-month period, the patient's WBC count declined to 3100 cells/mm(3) with an ANC of 1023 cells/mm(3). Olanzapine was again discontinued, and after 5 days, the patient's WBC count had risen to 4500 cells/mm(3) with an ANC of 1986 cells/ mm(3). Olanzapine was restarted at 10 mg/day, with hematologic monitoring performed every other day. Within 1 week, the patient's WBC count again declined to 4100 cells/mm(3) with an ANC of 1860 cells/ mm(3). Olanzapine was continued with intensive monitoring. The patient's WBC ranged between 4000 and 5000 cells/mm(3). This case suggests that patients who have previously taken clozapine may have an increased risk for neutropenia with olanzapine. Teter et al, 2000). c) During clozapine-induced agranulocytosis in 2 patients with schizophrenia, olanzapine [doses greater than 25 milligrams/day (mg/d)] was shown to be a safe and effective treatment. Additionally, olanzapine did not worsen the severe neutropenia or agranulocytosis nor did it prevent recovery (Oyewumi & Al-Semaan, 2000). d) A 31-year-old woman who had previously experienced neutropenia with clozapine, experienced neutropenia secondary to olanzapine (Benedetti et al, 1999). Olanzapine was introduced 5 days after clozapine withdrawal; the neutrophil count had normalized to 2.6 x 10(9)/liter (L). Olanzapine 5 milligrams (mg) was given on the first day and 10 mg daily starting on the second day. After 1 week, her neutrophil count decreased to 0.9 x 10(9)/L. Olanzapine was discontinued and the neutrophil count normalized after 4 weeks. e) Thirty-two patients with a history of clozapine-induced neutropenia or agranulocytosis did not experience decreased neutrophil counts during olanzapine treatment (Prod Info Zyprexa(R), 1998). However, clinical experience with olanzapine, especially with long-term use, remains limited. 3.3.5.E Pancytopenia 1) Summary a) Olanzapine was associated with pancytopenia and exacerbated motor disability in a patient with Parkinson's disease (Onofrj and Thomas, 2001). 2) LITERATURE REPORTS a) Olanzapine was associated with pancytopenia and exacerbated motor disability in a 67-year-old man with Parkinson's disease. Olanzapine 5 milligrams (mg) daily (QD) was added to a regimen of levodopa 1.1 grams (g) and benserazide 275 mg QD to treat psychotic disturbances with hallucinations and paranoid delusions. After 1 week, the dose was increased to 10 mg/d. Complete blood count (CBC) values were within normal limits. After 2 weeks of therapy, visual hallucinations and delusions decreased in frequency, but motor symptoms, neck rigidity, upper and lower limb rigidity, and bradykinesia worsened. Levodopa was increased to 1.3 g/day and benserazide was increased to 325 mg/d. After 4 weeks of olanzapine treatment, the CBC showed a modest reduction in white blood cells (WBC), red blood cells (RBC), and platelets. One week later the hematological parameters continued to decline and olanzapine was discontinued. Subsequently, WBC, RBC, and platelet counts increased. Within 4 weeks of olanzapine withdrawal, counts were within normal limits and remained normal for the following year. This report suggests that olanzapine should be used with caution in patients with Parkinson's disease and that hematologic monitoring may be necessary (Onofrj and Thomas, 2001). 3.3.6 Hepatic Effects 3.3.6.A Increased liver function test 1) Summary

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Case 3:07-cv-04911-CRB

Document 39

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a) Increases in serum alanine aminotransferase (ALT) above 200 International Units/Liter (IU/L) occurred in 2% of patients (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). Elevations of aspartate and alanine aminotransferases and gamma-glutamyl transferase (GGT) have been observed in approximately 10% of patients. These changes appear to be dose-dependent and are reversible upon withdrawal of therapy (Beasley et al, 1996). Close monitoring of liver function is advised, especially with use of higher doses and/or during prolonged olanzapine therapy (Bronson & Lindenmayer, 2000); (Beasley et al, 1996)(Prod Info Zyprexa(R), 1996). 2) LITERATURE REPORTS a) Increases in serum alanine aminotransferase (ALT) above 200 International Units/Liter (IU/L) occurred in 2% of patients. In clinical trials, discontinuation due to transaminase increases occurred in about 1% (Prod Info Zyprexa(R), Zyprexa(R) Zydis(R), Zyprexa(R) IntraMuscular Olanzapine, 2004a). b) High dose olanzapine was asso