7
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`ZYPREXA
`Tablets
`(Olanzapine)
`
`PV 333+2 AMP
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`ZYPREXA 7 ZYDIS 7
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`
`(Olanzapine} Orally Disintegrating Tablets
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`DESCRIPTION
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`ZYPREXA (olanzapine) is a psychotropic
`agent that belongs to the thienobenzodiazepine class. The
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`chemical design ation is 2-methyl-4-(4-methyl-1-piper
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`azinyl)-l 0H-thieno[2,3-b] [1,S]benzodiazepine.
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`The molecular formula is CI7lhoN4S, which corresponds to a molecular weight of 312.44. The chemical
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`structure is:
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`�
`' .··c::�
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`.0
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`Olanzapine is a yellow crystalline solid, which is practically insoluble in water.
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`ZYPREXA tablets are intended for oral administration only.
`Each tablet contains olanz.apine equivalent to 2.5 mg (8 Fmol), 5 mg (16 µmol), 7.5 mg (24 µmol),
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`wax, crospovidone, are carnauba Inactive ingredients 10 mg (32 µmo!), or 15 mg (48 µmol).
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`hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline
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`cellulose, and other inactive ingredients. The color coating contains Titanium Dioxide (all strengths) and
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`FD&C Blue No. 2 Aluminum Lake (15 mg). The 2 5, 5.0, 7.5, and 10 mg tablets are imprinted with
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`edible ink which contains FD&C Blue No. 2 Aluminum Lake.
`ZYPREXA ZYDIS ( olanzapine orally disintegrating tablets) is
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`intended for oral administration only.
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`Each orally disintegrating tablet contains olanzapine equivalent
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`to 5 mg (16 µmol), 10 mg (32 µmol), 15 mg (48 µmol) or 20 mg
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`(64 µmol). It begins disintegrating in the mouth within seconds,
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`allowing its contents to be subsequently swallowed with or
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`without liquid. ZYPREXA ZYDIS ( olanzapine orally
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`disintegrating tablets) also contains the following inactive
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`ingredients: gelatin, mannitol, aspartame, sodium methyl paraben
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`and sodium propyl paraben.
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`8E\i Lilly and Company, 1997, 2000 PY 333l-2AMP
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`LATUDA03187583
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`1
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`Exhibit 2002
`Slayback v. Sumitomo
`IPR2020-01053
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`CLINICAL PHARMACOLOGY
`
`Pharmacodynamics:
`Olanzapineis a selective monoaminergic antagonist with high affinity binding to the following receptors:
`serotonin SHT>,2c (Ki=4 and 11 nM,respectively), dopamine D,_4 (Ki=1 1-31 nM), muscarinic Mj_5
`(Ki=1.9-25 nM), histamine H; (Ki=7 nM), and adrenergic «| receptors (Ki=19 nM). Olanzapine
`binds weakly to GABA,, BZD, and 8 adrenergic receptors (Ki > 10 M).
`The mechanism of action ofolanzapine, 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 (SHT>) antagonism. The mechanism ofaction of
`olanzapinein the treatment of acute manic episodes associated with Bipolar I Disorder is unknown.
`Antagonism at receptors other than dopamine and 5HT> with similar receptoraffinities may explain
`someofthe other therapeutic and side effects of olanzapine. Olanzapineantagonism of muscarinic Mi.
`5 receptors may explain its anticholinergic effects. Olanzapine’s antagonism of histamine Hi receptors
`may explain the somnolence observed with this drug. Olanzapine*s antagonism of adrenergic a1
`receptors may explain the orthostatic hypotension observed with this drug.
`Pharmacokinetics:
`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 overthe clinical dosing range. Its half-life ranges from 21 to 54
`hours (Sth 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 one week that
`are approximately twice the concentrationsafter 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).
`Olanzapineis extensively distributed throughoutthe body, with a volumeof distribution of
`approximately 1000 L. It is 93% bound to plasmaproteins over the concentration range of 7 to 1100
`ng/mL, binding primarily to albumin and o1-acid glycoprotein.
`Metabolism and Elimination--Followinga single oral dose of '“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 AUCfortotal 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
`pathwaysfor olanzapine. In vitro studies suggest that CYPs [A2 and 2D6,and the flavin-containing
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to
`be a minor metabolic pathway in vivo, because the clearance of olanzapineis not reduced in subjects
`whoare deficient in this enzyme.
`Special Populations--
`Renal Impairment--Because olanzapine is highly metabolized before excretion and only 7°of the
`drug is excreted unchanged, renal dysfunction aloneis 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 bydialysis.
`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 additively influence drug
`metabolism and/or pharmacodynamicsensitivity (see DOSAGE AND ADMINISTRATION).
`Gender--Clearance of olanzapine is approximately 30%o lower in women than in men. There were,
`however, no apparent differences between men and womenin 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--No specific pharmacokinetic study was conducted to investigate the effects of race. A cross-
`study comparison between data obtained in Japan and data obtained in the US suggests that exposure
`to olanzapine may be about 2-fold greater in the Japanese when equivalent doses are administered.
`Clinical trial safety and efficacy data, however, did not suggestclinically significant differences among
`Caucasian patients, patients of African descent, and a third pooled category including Asian and
`Hispanic patients. Dosage modificationsfor 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
`whoexhibit a combination of factors that may result in slower metabolism of olanzapine (see DOSAGE
`AND ADMINISTRATION).
`Clinical Efficacy Data:
`Schizophrenia
`The efficacy of olanzapine in the management ofthe manifestations of psychotic disorders 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 treatmentin one ofthe twotrials,
`but this trial did not compare these two drugsonthefull range ofclinically relevant doses for both.
`Several instruments were used for assessing psychiatric signs and symptomsin 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 psychosis. The BPRS psychosis cluster
`(conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second
`traditional assessment, the Clinical Global Impression (CGD),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 but less well evaluated scales were employed; these
`included the 30-item Positive and Negative Symptoms Scale (PANSS), in which is embedded the 18
`items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries
`belowfocus on the following outcomes: PANSStotal and/or BPRStotal; BPRS psychosis cluster;
`PANSSnegative subscale or SANS; and CGI Severity. Theresults 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 PANSStotal score (also on the extracted BPRStotal), on the BPRS psychosiscluster, 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
`(5.0+2.5 mg/day, 10.0+2.5 mg/day, and 15.0+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 BPRStotal score, BPRS psychosis cluster, and CGI severity score; the 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.
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`Bipolar Mania
`Theefficacy of olanzapine in the treatment of acute manic episodes wasestablished 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. Thesetrials included patients with or without
`psychotic features and with or without a rapid-cycling course.
`The primary rating instrument used for assessing manic symptomsin these trials was the Young Mania Rating
`Scale (Y-MRS), an 1 l-item clinician-rated scale traditionally used to assess the degree of manic
`symptomatology in a range from O (no manic features) to 60 (maximum score). The primary outcomein these
`trials was change from baseline in the Y-MRStotal score. The results ofthe 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-MRStotal score.
`In an identically designed trial conducted simultaneously with thefirst 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 placeboin the reduction of Y-MRStotal score.
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`INDICATIONS AND USAGE
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`Schizophrenia
`ZYPREXA isindicated for the management ofthe manifestations of psychotic disorders,
`The efficacy of ZYPREXAwasestablished in short-term (6-week) controlled trials of schizophrenic
`inpatients (see CLINICAL PHARMACOLOGY).
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`LATUDA03187586
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`The effectiveness of ZYPREXAin long-term use, that is, for more than 6 weeks, has not been
`systematically evaluated in controlled trials. Therefore, the physician whoelects to use ZYPREXA for
`extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
`patient (see DOSAGE AND ADMINISTRATION).
`Bipolar Mania
`ZYPREXAisindicated for the short-term treatment of acute manic episodes associated with Bipolar I
`Disorder.
`Theefficacy of ZYPREXA wasestablished in two placebo-controlled trials (one 3-week and one 4-week)
`with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed
`episode with or without psychotic features (see CLINICAL PHARMACOLOGY).
`The effectiveness of ZYPREXA for longer-term use, that is, for more than 4 weeks treatmentof an acute
`episode, and for prophylactic use in mania, has not been systematically evaluated in controlled clinical trials.
`Therefore, physicians whoelect to use ZYPREXAfor extended periods should periodically re-evaluate the
`long-term risks and benefits of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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`CONTRAINDICATIONS
`ZYPREXAis contraindicated in patients with a known hypersensitivity to the product.
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`WARNINGS
`Neuroleptic Malignant Syndrome (NMS)--A potentially fatal symptom complex sometimesreferred
`to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of
`antipsychotic drugs. Clinical manifestations ofNMSare hyperpyrexia, muscle rigidity, altered mental
`status and evidence of autonomicinstability (irregular pulse or blood pressure, tachycardia, diaphoresis
`and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase,
`myoglobinuria (rhabdomyolysis), and acute renal failure.
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is
`important to exclude cases where the clinical presentation includes both serious medical illness (e.g.,
`pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and
`symptoms (EPS), Other important considerations in the differential diagnosis include central
`anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
`The management of NMSshould include: 1) immediate discontinuation of antipsychotic drugs and
`other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical
`monitoring; and 3) treatment of any concomitant serious medical problems for whichspecific treatments
`are available. There is no general agreement about specific pharmacological treatment regimensfor
`NMS.
`If a patient requires antipsychotic drug treatmentafter recovery from NMS,the potential
`reintroduction of drug therapy should be carefully considered. The patient should be carefully
`monitored, since recurrences of NMS havebeen reported.
`Tardive Dyskinesia--A syndromeof potentially irreversible, involuntary, dyskinetic movements may
`develop in patients treated with antipsychotic drugs. Although the prevalence ofthe syndrome appears
`to be highest amongtheelderly, especially elderly women,it is impossible to rely upon prevalence
`estimates to predict, at the inception of antipsychotic treatment, whichpatients are likely to develop the
`syndrome. Whether antipsychotic drug productsdiffer in their potential to cause tardive dyskinesia is
`unknown,
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
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`Therisk of developing tardive dyskinesia and the likelihood that it will becomeirreversible are
`believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs
`administered to the patient increase. However, the syndrome can develop, although much less
`commonly,after relatively brief treatment periods at low doses.
`There is no known treatment for established cases of tardive dyskinesia, although the syndrome may
`remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself,
`however, may suppress(orpartially suppress) the signs and symptoms of the syndrome and thereby
`may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-
`term course of the syndrome is unknown.
`Given these considerations, olanzapine should be prescribed in a mannerthat is most likely to minimize
`the occurrence oftardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for
`patients (1) whosuffer from a chronic illness that is known to respondto antipsychotic drugs, and (2)
`for whom alternative, equally effective, but potentially less harmful treatments are not available or
`appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of
`treatment producing a satisfactory clinical response should be sought. The need for continued treatment
`should be reassessed periodically.
`If signs and symptoms oftardive dyskinesia appear in a patient on olanzapine, drug discontinuation
`should be considered. However, some patients may require treatment with olanzapine despite the
`presence of the syndrome.
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`PRECAUTIONS
`
`General
`Orthostatic Hypotension--Olanzapine may induce orthostatic hypotension associated with dizziness,
`tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably
`reflecting its q1-adrenergic antagonistic properties. Syncope was reported in 0.6% (15/2500) of
`olanzapine-treated patients in phase 2-3 studies. The risk of orthostatic hypotension and syncope may
`be minimized by initiating therapy with 5 mg QD (see DOSAGE AND ADMINISTRATION). A more
`gradualtitration to the target dose should be considered if hypotension occurs. Olanzapine should be
`used with particular caution in patients with known cardiovascular disease (history of myocardial
`infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
`conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment
`with antihypertensive medications).
`Seizures--During premarketingtesting, seizures occurred in 0.9% (22/2500) of olanzapine-treated
`patients. There were confounding factors that may have contributed to the occurrence of seizures in
`many ofthese cases. Olanzapine should be used cautiously in patients with a history of seizures or with
`conditions that potentially lowerthe seizure threshold, e.g., Alzheimer dementia. Conditions that lower
`the seizure threshold may be more prevalent in a population of 65 years or older.
`Hyperprolactinemia--As with other drugs that antagonize dopamine D» receptors, olanzapine elevates
`prolactin levels, and a modest elevation persists during chronic administration. Tissue culture
`experiments indicate that approximately one-third of humanbreast cancers are prolactin dependentin
`vitro, a factor of potential importanceif the prescription of these drugs is contemplated in a patient with
`previously detected breast cancer ofthis type. Although disturbances such as galactorrhea, amenorrhea,
`gynecomastia, and impotence have been reported with prolactin-elevating compounds,theclinical
`significance of elevated serum prolactin levels is unknown for most patients. As is common with
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in
`the olanzapine carcinogenicity studies conducted in mice and rats (see Carcinogenesis). However,
`neither clinical studies nor epidemiologic studies have shown an association between chronic
`administration of this class of drugs and tumorigenesis in humans;the available evidence is considered
`too limited to be conclusive.
`Transaminase Elevations--In placebo-controlled studies, clinically significant ALT (SGPT)elevations
`($3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to
`olanzapine compared to none (0/115) of the placebo patients. None of these patients experienced
`jaundice. In two ofthese patients, liver enzymes decreased toward normal despite continued treatment
`and in two others, enzymes decreased upon discontinuation of olanzapine. In the remaining twopatients,
`one, seropositive for hepatitis C, had persistent enzymeelevation for four monthsafter discontinuation,
`and the other hadinsufficient follow-up to determine if enzymes normalized.
`Within the larger premarketing database of about 2400 patients with baseline SGPT #90 IU/L,the
`incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients
`experienced jaundice or other symptoms attributable to liver impairment and most had transient changes
`that tended to normalize while olanzapine treatment was continued.
`Amongall 2500 patients in clinical trials, about 1% (23/2500) discontinued treatment due to
`transaminaseincreases.
`Caution should be exercised in patients with signs and symptomsof hepatic impairment, in patients
`with pre-existing conditions associated with limited hepatic functional reserve, and in patients whoare
`being treated with potentially hepatotoxic drugs. Periodic assessment of transaminases is recommended
`in patients with significant hepatic disease (see Laboratory Tests).
`
`Potential for Cognitive and Motor Impairment--Somnolence was a commonly reported adverse event
`associated with olanzapinetreatment, occurring at an incidence of 26%in olanzapine patients compared
`to 15%in placebo patients. This adverse event wasalso dose related. Somnolence led to
`discontinuation in 0.4% (9/2500)ofpatients in the premarketing database.
`Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be
`cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain
`that olanzapine therapy does not affect them adversely.
`Body Temperature Regulation--Disruption of the body's ability to reduce core body temperature has
`been attributed to antipsychotic agents. Appropriate care is advised when prescribing olanzapine for
`patients whowill be experiencing conditions which may contribute to an elevation in core body
`temperature, ¢.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication
`with anticholinergicactivity, or being subject to dehydration.
`Dysphagia--Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
`Two olanzapine-treated patients (2/407) in two studies in patients with Alzheimer’s disease died from
`aspiration pneumonia during or within 30 days of the termination of the double-blind portion of their
`respective studies; there were no deathsin the placebo-treated_patients. One of these patients had
`experienced dysphagia prior to the development ofaspiration pneumonia. Aspiration pneumoniais a
`common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine
`and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
`Suicide--The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder, and
`close supervision ofhigh-risk patients should accompany drug therapy. Prescriptions for olanzapine
`should be written for the smallest quantity of tablets consistent with good patient management, in order
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`to reduce the risk of overdose.
`Use in Patients with Concomitant Ilness--Clinical experience with olanzapinein patients with certain
`concomitant systemic illnesses (see Renal Impairment and Hepatic Impairment wader CLINICAL
`PHARMACOLOGY,Special Populations)is limited.
`Olanzapine exhibits in vitro muscarinic receptor affinity, In premarketing clinical trials with olanzapine,
`olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse events possibly
`related to cholinergic antagonism. Such adverse events were not often the basis for discontinuations
`from olanzapine, but olanzapine should be used with caution in patients with clinically significant prostatic
`hypertrophy, narrow angle glaucoma, ora history ofparalytic ileus.
`In a fixed-dose study of olanzapine (olanzapine at doses of 5, 10, and 15 mg/day) and placebo in
`nursing homepatients (mean age: 83 years, range: 61-97; median Mini-Mental State Examination
`(MMSE): 5, range: 0-22) having various psychiatric symptomsin association with Alzheimer’s disease,
`the following treatment-emergent adverse events were reported in all (each and every) olanzapine-
`treated groups at an incidenceofeither (1) two-fold or more in excess of the placebo-treated group,
`where at least 1 placebo-treated patient was reported to have experienced the event, or (2) at least 2
`cases if no placebo-treated patient was reported to have experienced the event: somnolence, abnormal
`gait, fever, dehydration, and back pain. The rate of discontinuation in this study for olanzapine was 12%
`vs 4% with placebo. Discontinuations due to abnormal gait (1% for olanzapine vs 0%for placebo),
`accidental injury (1% for olanzapine vs 0%for placebo), and somnolence (3%for olanzapine vs 0% for
`placebo) were considered to be drug related. As with other CNS-active drugs, olanzapine should be
`used with caution in elderly patients with dementia (see PRECAUTIONS).
`Olanzapine has not been evaluated or used to any appreciable extentin patients with a recent history
`of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from
`premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution
`should be observed in cardiac patients (see Orthostatic Hypotension).
`Informationfor Patients--Physiciansare advised to discuss the following issues with patients for
`whom they prescribe olanzapine:
`Orthostatic Hypotension--Patients should be advised ofthe risk of orthostatic hypotension, especially
`during the period ofinitial dosetitration and in association with the use of concomitant drugs that may
`potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol (see Drug Interactions).
`Interference with Cognitive and Motor Performance--Because olanzapine has the potential to impair
`judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery,
`including automobiles, until they are reasonablycertain that olanzapine therapy does not affect them
`adversely,
`Pregnancy--Patients should be advised to notify their physician if they become pregnantor intend to
`become pregnant during therapy with olanzapine.
`Nursing--Patients should be advised not to breast-feed an infant if they are taking olanzapine.
`Concomitant Medication--Patients should be advised to inform their physicians if they are taking, or
`plan to take, any prescription or over-the-counter drugs,since there is a potential for interactions.
`Alcohol--Patients should be advised to avoid alcohol while taking olanzapine.
`Heat Exposure and Dehydration--Patients should be advised regarding appropriate care in avoiding
`overheating and dehydration.
`Phenylketonurics--ZYPREXA ZYDIS (olanzapineorally
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`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`disintegrating tablets) contains phenylalanine (0.34, 0.45, 0.67,
`or 0.90 mg per 5, 10, 15, or 20 mg tablet, respectively).
`Laboratory Tests--Periodic assessment of transaminases 1s recommendedin patients with significant
`hepatic disease (see Transaminase Elevations).
`Drug Interactions—Therisks of using olanzapine in combination with other drugs have not been
`extensively evaluated in systematic studies. Given the primary CNSeffects of olanzapine, caution should
`be used when olanzapine is taken in combination with othercentrally acting drugs and alcohol.
`Because ofits potential for inducing hypotension, olanzapine may enhance theeffects of certain
`antihypertensive agents.
`Olanzapine may antagonize the effects of levodopa and dopamineagonists.
`The Effect of Other Drugs on Olanzapine--Agents that induce CYP1A2 or glucuronyltransferase
`enzymes, such as omeprazole and nifampin, may cause an increase in olanzapine clearance. Inhibitors of
`CYP1A2 (e.g., fluvoxamine) could potentially inhibit olanzapine elimination. Because olanzapineis
`metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease
`olanzapine clearance.
`Charcoal--The administration ofactivated charcoal (1 g) reduced the Cmax and AUC ofolanzapine
`by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing,
`charcoal may be a useful treatment for olanzapine overdose.
`Cimetidine and AntacidsC Single doses ofcimetidine (800 mg) or aluminum- and magnesium-
`containing antacids did not affect the oral bioavailability of olanzapine.
`Carbamazepine--Carbamazepine therapy (200 mg bid) causes an approximately 50%increase in the
`clearance ofolanzapine. This increaseis likely due to the fact that carbamazepineis a potent inducer of
`CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in
`olanzapine clearance.
`Ethanol--Ethanol (45 mg/70 kg single dose) did not havean effect on olanzapine pharmacokinetics.
`Fluoxetine--Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes a small (mean 16%)
`increase in the maximum concentration of olanzapine and a smal! (mean 16%) decrease in olanzapine
`clearance. The magnitude ofthe impact of this factor is small in comparison to the overall variability
`between individuals, and therefore dose modification is not routinely recommended.
`Valproate—Studies in vitro using human liver microsomes determined that olanzapine has little
`potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has
`little effect on the metabolism of olanzapine in vitro. Thus, a clinically significant pharmacokinetic
`interaction between olanzapine and valproate is unlikely.
`Warfarin--Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics.
`Effect of Olanzapine on Other Drugs—In vitro studies utilizing human liver microsomes suggest that
`olanzapinehaslittle potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus,
`olanzapineis unlikely to causeclinically important drug interactions mediated by these enzymes.
`Single doses of olanzapine did not affect the pharmacokinetics of imipramine orits active metabolite
`desipramine, and warfarin. Multiple doses of olanzapine did not influence the kinetics of diazepam and
`its active metabolite N-desmethyldiazepam,lithium, ethanol, or biperiden. However, the co-
`administration of either diazepam or ethanol with olanzapine potentiated the orthostatic hypotension
`observed with olanzapine. Multiple doses of olanzapine did not affect the pharmacokinetics of
`theophylline or its metabolites.
`
`LATUDA03187591
`
`9
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`

`

`ZYPREXA’ (Olanzapine) Tablets
`ZYPREXA“ ZYDIS/
`(Olanzapine) Orally Disintegrating Tablets
`
`Carcinogenesis, Mutagenesis, Impairmentof 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 (equivalentto 0.8-5
`times the maximum recommended human daily dose on a mg/m’ basis) and 0.25, 2, 8 mg/kg/day
`(equivalent to 0.06-2 times the maximum recommended human daily dose on a mg/n basis). Rats
`were