Drug Safety-related Labeling Changes (SrLC)

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ZYPREXA ZYDIS (NDA-021086)

(OLANZAPINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/23/2020 (SUPPL-48)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of ‘salivary hypersecretion’ to the adverse reactions temporally related to ZYPREXA ZYDIS therapy.

04/21/2020 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA ZYDIS is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5), and Patient Counseling Information (17)].

5.14 Anticholinergic (antimuscarinic) Effects

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2]. In premarketing clinical trials, Zyprexa was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations, but Zyprexa ZYDIS should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].

The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%) …

7 Drug Interactions

7.1 Potential for Other Drugs to Affect Olanzapine

Newly added information following Charcoal:

Anticholinergic Drugs — Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. ZYPREXA ZYDIS should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.14)].

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

… In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)]. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance …

10/22/2019 (SUPPL-47)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Metabolic Changes

(additions and/or revisions are underlined)

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.

Hyperglycemia and Diabetes Mellitus

Healthcare providers 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.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and/or revisions are underlined)

…

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 healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied.

…

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ZYPREXA, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including ZYPREXA, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ZYPREXA, during pregnancy.

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximum recommended human dose (MRHD), based on mg/m^2 body surface area; some fetal toxicities were observed at these doses.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ZYPREXA, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

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 daily oral MRHD based on mg/m^2 body surface area, 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 daily oral MRHD based on mg/m^2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m^2 body surface area). 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 daily oral MRHD based on mg/m^2 body surface area).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk. There is no information on the effects of olanzapine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZYPREXA and any potential adverse effects on the breastfed child from ZYPREXA or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to ZYPREXA should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Infertility

Females

Based on the pharmacologic action of olanzapine (D2 receptor antagonism), treatment with ZYPREXA may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions and/or revisions are underlined)

…

 

What should I tell my doctor before taking ZYPREXA?

ZYPREXA may not be right for you. Before starting ZYPREXA, tell your doctor if you have or had:

• heart problems

• seizures

• diabetes or high blood sugar levels (hyperglycemia)

• high cholesterol or triglyceride levels in your blood

• liver problems

• low or high blood pressure

• strokes or “mini-strokes” also called transient ischemic attacks (TIAs)

• Alzheimer’s disease

• narrow-angle glaucoma

• enlarged prostate in men

• bowel obstruction

• phenylketonuria, because ZYPREXA ZYDIS contains phenylalanine

• breast cancer

• thoughts of suicide or hurting yourself

• any other medical condition

• are pregnant or plan to become pregnant. It is not known if ZYPREXA will harm your unborn baby.

  • If you become pregnant while receiving ZYPREXA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and- research-programs/pregnancyregistry/.

• are breast-feeding or plan to breast-feed. ZYPREXA passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take ZYPREXA.

Tell your doctor if you exercise a lot or are in hot places often.

The symptoms of bipolar I disorder, treatment resistant depression, or schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away.

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PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide) for the oral formulations.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA as monotherapy or in combination with fluoxetine. If you do not think you are getting better or have any concerns about your condition while taking ZYPREXA, call your doctor. When using ZYPREXA and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

 

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Concomitant Medication

Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax.

Patients should also be advised to inform their healthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions.

Alcohol

Patients should be advised to avoid alcohol while taking ZYPREXA.

Phenylketonurics

ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) contains phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet, respectively).

Use in Specific Populations

Pregnancy — Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZYPREXA. Advise patients that ZYPREXA may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZYPREXA during pregnancy.

Lactation — Advise breastfeeding women using ZYPREXA to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs.

Infertility — Advise females of reproductive potential that ZYPREXA may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible.

 

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Need for Comprehensive Treatment Program in Pediatric Patients

ZYPREXA is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder.

Effectiveness and safety of ZYPREXA have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider’s assessment of the chronicity and severity of the patient’s symptoms.

03/27/2018 (SUPPL-46)

Approved Drug Label (PDF)

6 Adverse Reactions

6.4 Postmarketing Experience

(Additions and/or revisions are underlined)

… stuttering1, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis)…

1  Stuttering was only studied in oral and long acting injection (LAI) formulations.

02/23/2017 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.8 Falls

ZYPREXA ZYDIS may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long- term antipsychotic therapy.

02/23/2017 (SUPPL-45)

Approved Drug Label (PDF)

6 Adverse Reactions

6.4 Postmarketing Experience

… Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA ZYDIS therapy include the following:

• restless legs syndrome (addition)

10/06/2016 (SUPPL-43)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

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 olanzapine if DRESS is suspected.

6 Adverse Reactions

6.4 Postmarketing Experience

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA ZYDIS therapy include the following:

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (addition underlined and added to paragraph in alphabetical order)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What are the possible side effects of ZYPREXA ZYDIS

Serious side effects may happen when you take ZYPREXA ZYDIS, including:

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with ZYPREXA ZYDIS. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.

PATIENT COUNSELING INFORMATION

17.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).