Prescription Drug Information: Olanzapine (Page 6 of 10)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of olanzapine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine 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, stuttering 1 and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1,000 mg/dL have been reported.

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

7 DRUG INTERACTIONS

The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies.

7.1 Potential for Other Drugs to Affect Olanzapine

Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2)].

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine.

Inducers of CYP1A2 — 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.

Alcohol — 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 [see Drug Interactions (7.2)].

Inhibitors of CYP1A2

Fluvoxamine: 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.

Inhibitors of CYP2D6

Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using olanzapine and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions (7.2) ].

Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin may cause an increase in olanzapine clearance.

Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

7.2 Potential for Olanzapine to Affect Other Drugs

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

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

Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (Intramuscular) — Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular olanzapine for injection added to the somnolence observed with either drug alone [see Warnings and Precautions ( 5.7) ].

Lithium — 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 [see Warnings and Precautions (5.16)].

Valproate —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 [see Warnings and Precautions (5.16)].

Effect of Olanzapine on Drug Metabolizing Enzymes — 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.

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

Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug Interactions (7.1)].

Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Drug Interactions (7.1)].

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions (7.1)].

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

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

8 USE IN SPECIFIC POPULATIONS

When using olanzapine and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, 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 olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). 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 (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy (see Clinical Considerations).

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 (see Data).

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 olanzapine, 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 9,258 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

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 (see Clinical Considerations). 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 olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to olanzapine 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

Infertility

Females

Based on the pharmacologic action of olanzapine (D2 receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.15)].

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