Zyprexa relprevv

Overdose

During premarketing clinical studies of ZYPREXA RELPREVV, adverse reactions that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV. These reactions occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These reactions were correlated with an unintentional rapid increase in serum olanzapine concentrations to supra-therapeutic ranges in some cases. While a rapid and greater than expected increase in serum olanzapine concentration has been observed in some patients with these reactions, the exact mechanism by which the drug was unintentionally introduced into the blood stream is not known. Clinical signs and symptoms included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced level of consciousness ranging from mild sedation to coma. Time after injection to event ranged from soon after injection to greater than 3 hours after injection. The majority of patients were hospitalized and some required supportive care, including intubation, in several cases. All patients had largely recovered by 72 hours. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections).

In postmarketing reports of overdose with oral olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of oral olanzapine alone. In 1 case of death, the amount of acutely ingested oral olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

Post-injection delirium/sedation syndrome may occur with each injection of ZYPREXA RELPREVV. Signs and symptoms consistent with olanzapine overdose have been observed, and access to emergency response services must be readily available for safe use.

There is no specific antidote to olanzapine. Therefore, appropriate supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.) Respiratory support, including ventilation, may be required. Close medical supervision and monitoring should continue until the patient recovers.

The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

Contraindications

None.

Undesirable effects

The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for ZYPREXA RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral olanzapine studies was reported using the COSTART and MedDRA dictionaries.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA RELPREVV.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.

In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.

Table 9: Treatment-Emergent Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV

Dose group differences have been observed for weight, fasting triglycerides and prolactin elevation for ZYPREXA RELPREVV.

A dose group difference for oral olanzapine has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation.

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 10: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia - Acute Phase

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 11: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia - Acute Phase

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients experienced treatment-emergent injection-related adverse reactions (injection site pain, buttock pain, injection site mass, induration, injection site induration) in the placebo-controlled database. The most frequently occurring treatment-emergent adverse reaction was injection site pain (2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated).

Injection site abscess has been reported in clinical trials with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

In clinical trials of oral olanzapine monotherapy for the treatment of schizophrenia in adult patients, treatment-emergent adverse reactions with an incidence of 5% or greater in the olanzapine treatment arm and at least twice that of placebo were: postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia.

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole - Infrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1.

Cardiovascular System - Infrequent: cerebrovascular accident, vasodilatation.

Digestive System - Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System - Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders - Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System - Rare: osteoporosis.

Nervous System - Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System - Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages - Infrequent: alopecia.

Special Senses - Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System - Infrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired.

ZYPREXA RELPREVV In Adults

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from placebo, were observed for the following: eosinophils, monocytes, cholesterol, low-density lipoprotein (LDL), triglycerides, and direct bilirubin. There were no statistically significant differences between ZYPREXA RELPREVV and placebo in the incidence of potentially clinically significant changes in any of the laboratory values studied.

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from oral olanzapine (in a 24-week double-blind study), were observed for the following: gammaglutamyltransferase (GGT) and sodium.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Statistically significant differences were observed between ZYPREXA RELPREVV and oral olanzapine for the incidence of treatment-emergent low platelet count (0% ZYPREXA RELPREVV vs 1% oral olanzapine); and low total bilirubin (2.8% ZYPREXA RELPREVV vs 0.7% for oral olanzapine). There was a statistically significant difference between ZYPREXA RELPREVV and oral olanzapine in potentially clinically significant changes for high leukocyte count (0% ZYPREXA RELPREVV vs 1% oral olanzapine).

Changes in aminotransferases observed with ZYPREXA RELPREVV treatment were similar to those reported with ZYPREXA treatment. In placebo-controlled ZYPREXA RELPREVV studies, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2.7% (8/291) of patients exposed to olanzapine compared to 3.2% (3/94) of the placebo patients. None of these patients experienced jaundice. In 3 of these patients, liver enzymes reverted to the normal range despite continued treatment, and in 5 cases enzymes values decreased, but were still above the normal range at the end of therapy.

Within the larger premarketing ZYPREXA RELPREVV database of 1886 patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while ZYPREXA RELPREVV treatment was continued.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy In Adults

An assessment of the premarketing experience for oral olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). 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.

In placebo-controlled oral olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Oral olanzapine administration was also associated with increases in serum prolactin , with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

Comparison of ZYPREXA RELPREVV and oral olanzapine, in a 24 week study, revealed no significant differences on ECG changes. Between-group comparisons for pooled placebo-controlled trials revealed no significant oral olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Oral olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to olanzapine's potential for inducing orthostatic changes.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea, or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

REFERENCES

1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

2 Adjusted for gender.

Zyprexa Relprevv price

Therapeutic indications

ZYPREXA RELPREVV is available only through a restricted distribution program. ZYPREXA RELPREVV must not be dispensed directly to a patient. For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

ZYPREXA RELPREVV is indicated for the treatment of schizophrenia. Efficacy was established in two clinical trials in patients with schizophrenia: one 8-week trial in adults and one maintenance trial in adults .

Pharmacodynamic properties

Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β-adrenergic receptors (Ki>10 μM).

Antagonism at receptors other than dopamine and 5HT2 may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic-like effects. Olanzapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.

Pharmacokinetic properties

The fundamental pharmacokinetic properties of olanzapine are similar for ZYPREXA RELPREVV and orally administered olanzapine. Refer to the section below describing the pharmacokinetics of orally administered olanzapine for details.

Slow dissolution of ZYPREXA RELPREVV, a practically insoluble salt, after a deep intramuscular gluteal injection of a dose of ZYPREXA RELPREVV results in prolonged systemic olanzapine plasma concentrations that are sustained over a period of weeks to months. An injection every 2 or 4 weeks provides olanzapine plasma concentrations that are similar to those achieved by daily doses of oral olanzapine. The steady-state plasma concentrations for ZYPREXA RELPREVV for doses of 150 mg to 405 mg every 2 or 4 weeks are within the range of steady-state olanzapine plasma concentration known to have been associated with oral doses of 5 mg to 20 mg olanzapine once daily. The change to a slow release, rate-controlled absorption process is the only fundamental pharmacokinetic difference between the administration of ZYPREXA RELPREVV and orally administered olanzapine. The effective half-life for olanzapine after intramuscular ZYPREXA RELPREVV administration is approximately 30 days as compared to a half-life after oral administration of approximately 30 hours. Exposure to olanzapine may persist for a period of months after a ZYPREXA RELPREVV injection. The long persistence of systemic concentrations of olanzapine may be an important consideration for the long-term clinical management of the patient. Typical systemic olanzapine plasma concentrations reach a peak within the first week after injection and are at trough level immediately prior to the next injection. The olanzapine plasma concentration fluctuation between the peak and trough is comparable to the peak and trough fluctuations associated with once daily oral dosing.

ZYPREXA RELPREVV provides a dose of 150, 210, 300, or 405 mg olanzapine. An injection of a larger dose produces a dose-proportional increase in the systemic exposure. The olanzapine exposure after doses of ZYPREXA RELPREVV corresponds to exposure for oral doses of olanzapine. A ZYPREXA RELPREVV dose of 300 mg olanzapine injected every two weeks delivers approximately 20 mg olanzapine per day and a ZYPREXA RELPREVV dose of 150 mg olanzapine injected every two weeks delivers approximately 10 mg per day. These ZYPREXA RELPREVV doses sustain steady-state olanzapine concentrations over long periods of treatment.

The switch from oral olanzapine to ZYPREXA RELPREVV changes the pharmacokinetics from an elimination-rate-controlled to an absorptionrate-controlled process. The switch to ZYPREXA RELPREVV may require treatment for a period of approximately 3 months to re-establish steady-state conditions. Initial treatment with ZYPREXA RELPREVV is recommended at a dose corresponding to the mg/day oral dose. Plasma concentrations of olanzapine during the first injection interval may be lower than those maintained by a corresponding oral dose. Even though the concentrations are lower, the olanzapine concentrations remained within a therapeutically effective range and supplementation with orally administered olanzapine was generally not necessary in clinical trials.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein.

Following a single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4'-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

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

There are two formulations of ZYPREXA which are available for intramuscular injection. One form (ZYPREXA RELPREVV) is described in this package insert. The other formulation (ZYPREXA IntraMuscular) is a solution of olanzapine. When ZYPREXA IntraMuscular is injected intramuscularly, olanzapine (as the free base) is rapidly absorbed and peak plasma concentrations occur within 15 to 45 minutes. With the exception of higher maximum plasma concentrations, the pharmacokinetics of olanzapine after ZYPREXA IntraMuscular are similar to those for orally administered olanzapine. Refer to the package insert for ZYPREXA IntraMuscular for additional information.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human daily oral dose on a mg/m² basis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m2 basis). In an oral rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended human daily oral dose on a mg/m² basis). No evidence of teratogenicity or embryo-fetal toxicity was observed in rats or rabbits with ZYPREXA RELPREVV at intramuscular doses up to 75 mg/kg (1 and 2 times the maximum recommended human dose of 300 mg every 2 weeks, respectively, on a mg/m² basis). Placental transfer of olanzapine occurred in rat pups.

There are no adequate and well-controlled trials with olanzapine in pregnant females. Four pregnancies were observed during clinical trials with ZYPREXA RELPREVV, including 1 resulting in a normal birth and 3 therapeutic abortions. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonates exposed to antipsychotic drugs (including olanzapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

ZYPREXA RELPREVV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Qualitative and quantitative composition

ZYPREXA RELPREVV is a powder for suspension for intramuscular use only. ZYPREXA RELPREVV is present as a yellow solid in a glass vial equivalent to 210, 300, or 405 mg olanzapine per vial. The diluent is a clear, colorless to slightly yellow solution in a glass vial. The reconstituted suspension will be yellow and opaque.

ZYPREXA RELPREVV convenience kit is supplied in single-use cartons. Each carton includes one vial of olanzapine pamoate monohydrate in dosage strengths that are equivalent to 210 mg olanzapine (483 mg olanzapine pamoate monohydrate), 300 mg olanzapine (690 mg olanzapine pamoate monohydrate), and 405 mg olanzapine (931 mg olanzapine pamoate monohydrate) per vial; one vial of approximately 3 mL of diluent for ZYPREXA RELPREVV used to suspend the drug product; one 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device; and two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device.

NDC 0002-7635-11 - single-use convenience kit: 210 mg vial (VL7635) with rust flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap

NDC 0002-7636-11 - single-use convenience kit: 300 mg vial (VL7636) with olive flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap

NDC 0002-7637-11 - single-use convenience kit: 405 mg vial (VL7637) with steel blue flip-off cap and 3-mL vial of sterile diluent (VL7622) with gray flip-off cap

ZYPREXA RELPREVV should be stored at room temperature not to exceed 30°C (86°F).

When the drug product is suspended in the solution for ZYPREXA RELPREVV, it may be held at room temperature for 24 hours. The vial should be agitated immediately prior to product withdrawal. Once the suspension is withdrawn into the syringe, it should be used immediately.

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Feb 2017

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

During premarketing clinical studies of ZYPREXA RELPREVV, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV. These events occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months. These events were correlated with an unintentional rapid increase in serum olanzapine concentrations to supra-therapeutic ranges in some cases. While a rapid and greater than expected increase in serum olanzapine concentration has been observed in some patients with these events, the exact mechanism by which the drug was unintentionally introduced into the blood stream is not known. Clinical signs and symptoms included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced level of consciousness ranging from mild sedation to coma. Time after injection to event ranged from soon after injection to greater than 3 hours after injection. The majority of patients were hospitalized and some required supportive care, including intubation, in several cases. All patients had largely recovered by 72 hours. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections).

Healthcare professionals are advised to discuss this potential risk with patients each time they prescribe and administer ZYPREXA RELPREVV.

ZYPREXA RELPREVV is available only through a restricted distribution program. ZYPREXA RELPREVV must not be dispensed directly to a patient. For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the ZYPREXA RELPREVV Patient Care Program. To enroll, call 1-877-772-9390.

ZYPREXA RELPREVV must be administered in a registered healthcare facility (such as a hospital, clinic, residential treatment center, or community healthcare center) with ready access to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours and must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation. If parenteral benzodiazepines are required for patient management during an event of post-injection delirium/sedation syndrome, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis.

In placebo-controlled oral olanzapine clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of oral olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral olanzapine compared to patients treated with placebo. ZYPREXA RELPREVV is not approved for the treatment of patients with dementia-related psychosis.

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (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 NMS should 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 which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered and tolerability with oral olanzapine should be established prior to initiating treatment with ZYPREXA RELPREVV. The patient should be carefully monitored, since recurrences of NMS have been reported.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue ZYPREXA RELPREVV if DRESS is suspected.

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy In Adults

In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).

Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy In Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescent patients (13-17 years), including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent oral olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Oral Olanzapine Monotherapy Studies

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended.

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy In Adults

In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in longterm studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Dose group differences with respect to increases in fasting triglycerides have been observed. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, statistically significant differences among dose groups have been observed for fasting triglycerides. Incidence of changes from normal to high levels of fasting triglycerides at any time during the trial indicated significant differences between the highest dose group (300 mg/2 weeks, 24.5% [13/53]) and the lower dose groups (150 mg/2 weeks, 6.5% [4/62]; 405 mg/4 weeks, 9.8% [13/133]).

Olanzapine Monotherapy In Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

In an analysis of 3 placebo-controlled oral olanzapine monotherapy studies of adolescents (13-17 years), including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapinetreated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Oral Olanzapine Monotherapy Studies

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight.

Olanzapine Monotherapy In Adults

In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapinetreated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults

Dose group differences with respect to weight gain have been observed in some studies. In a 24-week randomized, double-blind, fixed-dose study with ZYPREXA RELPREVV, mean baseline-to-endpoint increase in weight (150 mg/2 weeks, n=140: 0.67 kg; 405 mg/4 weeks, n=315: 0.89 kg; 300 mg/2 weeks, n=140: 1.70 kg) was observed with significant differences between the lowest and highest dose groups (150 vs 300 mg/2 weeks). In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy In Adolescents

The safety and efficacy of ZYPREXA RELPREVV have not been established in patients under the age of 18 years.

Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Oral Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuatio

Dosage (Posology) and method of administration

ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only and should not be administered intravenously or subcutaneously.

Be aware that there are two ZYPREXA intramuscular formulations with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV. Refer to the package insert for ZYPREXA IntraMuscular for more information about that product.

Establish tolerability with oral olanzapine prior to initiating treatment.

ZYPREXA RELPREVV should be administered by a healthcare professional every 2 to 4 weeks by deep intramuscular gluteal injection using a 19-gauge, 1.5-inch needle. Following insertion of the needle into the muscle, aspiration should be maintained for several seconds to ensure that no blood is drawn into the syringe. If any blood is aspirated into the syringe, it should be discarded and fresh drug should be prepared using a new convenience kit. The injection should be performed at a steady, continuous pressure. Do not massage the injection site.

The efficacy of ZYPREXA RELPREVV has been demonstrated within the range of 150 mg to 300 mg administered every 2 weeks and with 405 mg administered every 4 weeks. Dose recommendations considering oral ZYPREXA and ZYPREXA RELPREVV are shown in Table 1.

Table 1: Recommended Dosing for ZYPREXA RELPREVV Based on Correspondence to Oral ZYPREXA Doses

ZYPREXA RELPREVV doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials.

During premarketing clinical studies, adverse events that presented with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, were reported in patients following an injection of ZYPREXA RELPREVV. Patients should be informed of this risk and how to recognize related symptoms. ZYPREXA RELPREVV must be administered in a registered healthcare facility with ready access to emergency response services. After each ZYPREXA RELPREVV injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours for symptoms consistent with olanzapine overdose, including sedation (ranging from mild in severity to coma) and/or delirium (including confusion, disorientation, agitation, anxiety, and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension, and convulsion. The potential for onset of an event is greatest within the first hour. The majority of cases have occurred within the first 3 hours after injection; however, the event has occurred after 3 hours. Following the 3-hour observation period, healthcare professionals must confirm that the patient is alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome prior to being released. All patients must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, patients should not drive or operate heavy machinery, and should be advised to be vigilant for symptoms of post-injection delirium/sedation syndrome and be able to obtain medical assistance if needed. If post-injection delirium/sedation syndrome is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation.

Tolerance of oral ZYPREXA should be established prior to initiating treatment with ZYPREXA RELPREVV. The recommended starting dose is ZYPREXA RELPREVV 150 mg/4 wks in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine. When indicated, dose escalation should be undertaken with caution in these patients.

ZYPREXA RELPREVV has not been studied in subjects under 18 years of age.

Although no controlled studies have been conducted to determine how long patients should be treated with ZYPREXA RELPREVV, efficacy has been demonstrated over a period of 24 weeks in patients with stabilized schizophrenia. Additionally, oral ZYPREXA has been shown to be effective in maintenance of treatment response in schizophrenia in longer-term use. Patients should be periodically reassessed to determine the need for continued treatment.

There are no systematically collected data to specifically address how to switch patients with schizophrenia from other antipsychotics to ZYPREXA RELPREVV.

For deep intramuscular gluteal injection only. Not to be injected intravenously or subcutaneously.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Convenience kit includes:

• Vial of ZYPREXA RELPREVV powder
• 3-mL vial of diluent
• One 3-mL syringe with pre-attached 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro® needle with needle protection device
• Two 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needles with needle protection device
  • For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used for administration.

ZYPREXA RELPREVV must be suspended using only the diluent supplied in the convenience kit.

It is recommended that gloves are used when reconstituting, as ZYPREXA RELPREVV may be irritating to the skin. Flush with water if contact is made with skin.

See additional insert entitled “Instructions to Reconstitute and Administer ZYPREXA RELPREVV” (included) for more information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.

Refer to the table below to determine the amount of diluent to be added to powder for reconstitution of each vial strength.

It is important to note that there is more diluent in the vial than is needed to reconstitute.

Please read the Hypodermic Needle-Pro Instructions for Use before proceeding with Step 3. Failure to follow these instructions may result in a needlestick injury.

Loosen the powder by lightly tapping the vial.

Open the prepackaged Hypodermic Needle-Pro syringe and needle with needle protection device.

Withdraw the pre-determined diluent volume (Step 2) into the syringe.

Inject the diluent into the powder vial.

Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger in the syringe.

Remove the needle from the vial, holding the vial upright to prevent any loss of material.

Engage the needle safety device (refer to complete Hypodermic Needle-Pro Instructions for Use).

Pad a hard surface to cushion impact (see Figure 1). Tap the vial firmly and repeatedly on the surface until no powder is visible.

Figure 1: Tap firmly to mix

Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if large clumps remain (see Figure 2).

Figure 2: Check for unsuspended powder and repeat tapping if needed

Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque (see Figure 3).

Figure 3: Vigorously shake vial

If foam forms, let vial stand to allow foam to dissipate.

If the product is not used right away, it should be shaken vigorously to re-suspend. Reconstituted ZYPREXA RELPREVV remains stable for up to 24 hours in the vial.

Before administering the injection, confirm there will be someone to accompany the patient after the 3­hour observation period. If this cannot be confirmed, do not give the injection.

Refer to the table below to determine the final volume to inject. Suspension concentration is 150 mg/mL ZYPREXA RELPREVV.

Attach a new safety needle to the syringe

Slowly withdraw the desired amount into the syringe.

Some excess product will remain in the vial.

Engage the needle safety device and remove needle from syringe.

For administration, select the 19-gauge, 1.5-inch (38 mm) Hypodermic Needle-Pro needle with needle protection device. For obese patients, a 2-inch (50 mm), 19-gauge or larger needle (not included in convenience kit) may be used.

To help prevent clogging, a 19-gauge or larger needle must be used.

Attach the new safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.

For deep intramuscular gluteal injection only. Do not inject intravenously or subcutaneously.

Select and prepare a site for injection in the gluteal area. After insertion of the needle into the muscle, aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin with a new convenience kit. The injection should be performed with steady, continuous pressure.

Do not massage the injection site.

Engage the needle safety device. Dispose of the vials, needles, and syringe appropriately after injection. The vial is for single-use only.

Interaction with other medicinal products and other forms of interaction

The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for ZYPREXA RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral olanzapine studies was reported using the COSTART and MedDRA dictionaries.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA RELPREVV.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.

In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.

Table 9: Treatment-Emergent Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV

Dose group differences have been observed for weight, fasting triglycerides and prolactin elevation for ZYPREXA RELPREVV.

A dose group difference for oral olanzapine has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation.

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 10: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia - Acute Phase

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 11: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia - Acute Phase

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients experienced treatment-emergent injection-related adverse reactions (injection site pain, buttock pain, injection site mass, induration, injection site induration) in the placebo-controlled database. The most frequently occurring treatment-emergent adverse reaction was injection site pain (2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated).

Injection site abscess has been reported in clinical trials with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

In clinical trials of oral olanzapine monotherapy for the treatment of schizophrenia in adult patients, treatment-emergent adverse reactions with an incidence of 5% or greater in the olanzapine treatment arm and at least twice that of placebo were: postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia.

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole - Infrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1.

Cardiovascular System - Infrequent: cerebrovascular accident, vasodilatation.

Digestive System - Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System - Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders - Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System - Rare: osteoporosis.

Nervous System - Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System - Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages - Infrequent: alopecia.

Special Senses - Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System - Infrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired.

ZYPREXA RELPREVV In Adults

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from placebo, were observed for the following: eosinophils, monocytes, cholesterol, low-density lipoprotein (LDL), triglycerides, and direct bilirubin. There were no statistically significant differences between ZYPREXA RELPREVV and placebo in the incidence of potentially clinically significant changes in any of the laboratory values studied.

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from oral olanzapine (in a 24-week double-blind study), were observed for the following: gammaglutamyltransferase (GGT) and sodium.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Statistically significant differences were observed between ZYPREXA RELPREVV and oral olanzapine for the incidence of treatment-emergent low platelet count (0% ZYPREXA RELPREVV vs 1% oral olanzapine); and low total bilirubin (2.8% ZYPREXA RELPREVV vs 0.7% for oral olanzapine). There was a statistically significant difference between ZYPREXA RELPREVV and oral olanzapine in potentially clinically significant changes for high leukocyte count (0% ZYPREXA RELPREVV vs 1% oral olanzapine).

Changes in aminotransferases observed with ZYPREXA RELPREVV treatment were similar to those reported with ZYPREXA treatment. In placebo-controlled ZYPREXA RELPREVV studies, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2.7% (8/291) of patients exposed to olanzapine compared to 3.2% (3/94) of the placebo patients. None of these patients experienced jaundice. In 3 of these patients, liver enzymes reverted to the normal range despite continued treatment, and in 5 cases enzymes values decreased, but were still above the normal range at the end of therapy.

Within the larger premarketing ZYPREXA RELPREVV database of 1886 patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while ZYPREXA RELPREVV treatment was continued.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy In Adults

An assessment of the premarketing experience for oral olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). 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.

In placebo-controlled oral olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Oral olanzapine administration was also associated with increases in serum prolactin , with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

Comparison of ZYPREXA RELPREVV and oral olanzapine, in a 24 week study, revealed no significant differences on ECG changes. Between-group comparisons for pooled placebo-controlled trials revealed no significant oral olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Oral olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to olanzapine's potential for inducing orthostatic changes.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea, or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

REFERENCES

1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

2 Adjusted for gender.

The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine.

Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine.

Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Fluoxetine caused a small decrease in olanzapine clearance leading to a minimal change in olanzapine steady-state concentrations and, therefore dose modification is not routinely recommended.

Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics.

Omeprazole and rifampin may cause an increase in olanzapine clearance.

Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Co-administration of lorazepam does not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of lorazepam with olanzapine potentiated the somnolence observed with either drug alone.

Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium.

Olanzapine (10 mg daily for 2 weeks) did not affect the steady-state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Single doses of olanzapine did not affect the pharmacokinetics of warfarin.

Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite Ndesmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone.

Multiple doses of olanzapine did not influence the kinetics of ethanol.

Multiple doses of olanzapine did not influence the kinetics of biperiden.

Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the maximum recommended human daily oral dose (20 mg) and rhesus monkeys administered oral doses up to 8 times the maximum recommended human daily oral dose on a mg/m² basis.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Because ZYPREXA RELPREVV is to be administered by healthcare professionals, the potential for misuse or abuse by patients is low.