Olanzapine-Fluoxetine Hcl (olanzapine/fluoxetine HCl)

Dosage of fluoxetine hydrochloride is expressed in terms of fluoxetine.

Consider prolonged elimination half-life of fluoxetine and norfluoxetine (active metabolite) when titrating dosage or discontinuing therapy. Several weeks will be required before the full effect of such alterations is realized.

Olanzapine is commercially available as the base and as the pamoate salt; the dosage of olanzapine pamoate is expressed in terms of olanzapine.

Conventional olanzapine tablets and orally disintegrating tablets of the drug are bioequivalent. However, IM administration of a 5-mg dose of the commercially available short-acting olanzapine injection results in a maximum plasma olanzapine concentration that is about 5 times higher than that resulting from a 5-mg oral dose of the drug.

Fluoxetine hydrochloride is administered orally without regard to meals.

Fluoxetine hydrochloride conventional capsules, tablets, and oral solution are administered once or twice daily; the delayed-release capsules are administered once weekly.

For the initial management of depression, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), or bulimia nervosa, fluoxetine conventional preparations generally are administered once daily in the morning. If the dosage exceeds 20 mg daily, the manufacturer states that the medication can be administered once in the morning or in 2 divided doses daily (preferably in the morning and at noon). Fluoxetine delayed-release capsules are administered once weekly as maintenance therapy for major depressive disorder.

Fluoxetine is also commercially available in fixed-combination with olanzapine for the treatment of acute depressive episodes associated with bipolar I disorder and treatment-resistant depression. See full prescribing information for dosage and administration.

Fluoxetine hydrochloride conventional capsules should be stored at 15-30degreesC and protected from light. Fluoxetine hydrochloride tablets, delayed-release capsules and oral solution should be stored at 20-25degreesC and protected from light.

Olanzapine is administered orally or by IM injection. Olanzapine pamoate is administered only by IM injection. Olanzapine is also available in fixed combination with fluoxetine or samidorphan. Refer to the prescribing information for olanzapine/samidorphan (Lybalvi(R)) for specific information on its administration and dosing.

No dosing information is available for this tab.

No dosing information is available for this tab.

Fluoxetine is extensively metabolized; it is known to inhibit cytochrome P-450 (CYP) 2D6 and to a lesser extent CYP3A4.

Olanzapine is mainly metabolized via direct glucuronidation and cytochrome P-450 (CYP)-mediated oxidation. In vitro studies suggest that CYP isoenzymes 1A2 and 2D6 and the flavin-containing monooxygenase system are involved in oxidation; however, CYP2D6-mediated oxidation appears to be a minor pathway.

In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit metabolism of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A substrates. Therefore, clinically important drug interactions between olanzapine and drugs metabolized by these isoenzymes are considered unlikely.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase inhibitor (MAOI). MAOIs are contraindicated within 5 weeks after fluoxetine discontinuation.

*Concurrent pimozide therapy.

*Concurrent thioridazine therapy. Thioridazine is contraindicated within 5 weeks after fluoxetine discontinuation.

*Known hypersensitivity to fluoxetine.

*None.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse effects reported in at least 5% of patients in clinical studies receiving fluoxetine for major depressive disorder, OCD, bulimia nervosa, or panic disorder include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn.

Adverse effects occurring in 5% or more of adult patients with schizophrenia receiving oral olanzapine monotherapy in clinical studies and with an incidence of at least twice that of placebo included postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia. In adolescents with schizophrenia, common adverse effects included sedation, increased weight, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, and dry mouth.

Adverse effects occurring in 5% or more of adult patients with manic or mixed episodes associated with bipolar I disorder receiving oral olanzapine monotherapy in clinical studies and with an incidence of at least twice that of placebo included asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, and tremor. In adolescents with manic or mixed episodes associated with bipolar I disorder, common adverse effects included sedation, increased weight, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, and pain in extremity.

When oral olanzapine was used in conjunction with lithium or valproate for treatment of manic or mixed episodes associated with bipolar I disorder in adults, adverse effects occurring in 5% or more of patients in clinical studies and with an incidence of at least twice that of placebo included dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, and paresthesia.

When short-acting IM olanzapine was used for the management of acute agitation in clinical studies in adults, somnolence was the only adverse effect that occurred in 5% or more of patients with schizophrenia or bipolar I mania and with an incidence at least twice that of placebo.

When extended-release olanzapine pamoate injection was used IM in adults with schizophrenia in a clinical study, adverse effects occurring in 5% or more of patients and more frequently than with placebo included headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of fluoxetine in pediatric patients have not been established in children <8 years of age for major depressive disorder or in children <7 years of age for obsessive-compulsive disorder (OCD).

FDA warns that antidepressants may increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders. The risk of suicidality for these medications was identified in a pooled analysis of data from short-term, placebo-controlled studies of 9 antidepressants (i.e., fluoxetine, bupropion, citalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) in over 4400 children and adolescents with major depressive disorder, OCD, or other psychiatric disorders. The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo. However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs, including fluoxetine, and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

The risk of suicidality in FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies. In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all medications studied. It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months). Anyone considering the use of fluoxetine in a child or adolescent for any clinical use must balance the potential risks of therapy with the clinical need.

As with other SSRIs, decreased weight gain has been observed in association with fluoxetine in children and adolescents. In one clinical trial in pediatric patients, height gain averaged about 1.1 cm less and weight gain averaged about 1.1 kg less after 19 weeks of fluoxetine therapy relative to placebo-treated patients. Because the safety of fluoxetine in pediatric patients has not been systematically assessed for chronic therapy longer than several months in duration and studies that directly evaluate the long-term effects of fluoxetine on the growth, development, and maturation of children and adolescents are lacking, height and weight should be monitored routinely in pediatric patients receiving fluoxetine.

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term clinical trials in adolescents (13-17 years of age). Use of oral olanzapine in such adolescents is supported by evidence from adequate and well-controlled clinical trials in which 268 adolescents received olanzapine in a dosage range of 2.5-20 mg daily. The recommended initial dosage for adolescents is lower than that for adults. Compared with adults in clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, prolactin, and hepatic transaminases.

Clinicians should consider the potential long-term risks (including weight gain and dyslipidemia) when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in such patients.

The manufacturer states that safety and efficacy of oral olanzapine for the treatment of schizophrenia or manic or mixed episodes associated with bipolar I disorder in children and adolescents younger than 13 years of age have not been established.

The safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder were established in a short-term clinical trial in pediatric patients 10-17 years of age. Use of oral olanzapine and fluoxetine in such children and adolescents is supported by evidence from a well-controlled clinical trial in which 255 pediatric patients received olanzapine in a dosage range of 3-12 mg daily. The recommended initial dosage of olanzapine in combination with fluoxetine for adolescents is lower than that for adults.

The manufacturer states that the safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of treatment-resistant depression have not been established in patients younger than 18 years of age.

The manufacturer states that the safety and efficacy of oral olanzapine in combination with fluoxetine have not been established in pediatric patients younger than 10 years of age.

The manufacturer states that the safety and efficacy of extended-release olanzapine pamoate IM injection in patients younger than 18 years of age have not been established.

A pregnancy registry is available that monitors pregnancy outcomes in females exposed to antidepressants during pregnancy. Healthcare providers can register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.

Published observational data have shown exposure to SSRIs, particularly during the month before delivery, is associated with a <2-fold increased risk of postpartum hemorrhage.

Some neonates exposed to fluoxetine and other SSRIs or SNRIs late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Clinical findings reported in neonates include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These clinical features appear to be consistent with either a direct toxic effect of the SSRI or SNRI or, possibly, a drug withdrawal syndrome. It should be noted, in some cases, the clinical picture was consistent with serotonin syndrome.

Infants exposed to SSRIs in late pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN). PPHN is a rare heart and lung condition occurring in an estimated 1-2 infants per 1000 births in the general population. Several recent epidemiologic studies suggest an association between SSRI use during pregnancy and PPHN, although others do not.

When treating a pregnant patient with fluoxetine, the clinician should carefully consider the potential risks and benefits of such therapy. Clinicians should consider that in a prospective longitudinal study of 201 females with a history of recurrent major depression who were either on antidepressant therapy or had received antidepressants <12 weeks prior to their last menstrual period and were in remission at the beginning of pregnancy, those who discontinued their antidepressant medication (SSRIs, TCAs, or others) during pregnancy were found to be substantially more likely to have a relapse of depression than females who continued to receive their antidepressant therapy while pregnant.

The effect of fluoxetine on labor and delivery is not known.

A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy. Clinicians are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/. Currently 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 outcomes in the mother or fetus. However, there are risks to the mother (e.g., risk of relapse, hospitalization, suicide) associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

In pregnant rats and rabbits receiving oral olanzapine at doses 9 to 30 times the maximum recommended human dose based on mg/m2 body surface area, no teratogenicity was observed; however, some fetal toxicities (e.g., increased or early resorptions, increased numbers of nonviable fetuses, and decreased fetal weight) were observed.

Neonates exposed to antipsychotic agents, including olanzapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.

Fluoxetine and its metabolites distribute into human milk. Crying, sleep disturbance, vomiting, and watery stools developed in an infant who was breastfed from a female receiving fluoxetine; plasma fluoxetine and norfluoxetine concentrations in the infant on the second day of feeding were 340 and 208 ng/mL, respectively. Some manufacturers state fluoxetine should not be used in nursing females and patients should notify their physician if they plan to breast-feed.

Breast-fed infants who are exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain, and should seek medical care if these signs are observed.

Olanzapine is distributed into 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 are no data on the effects of olanzapine on milk production.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for olanzapine and any potential adverse effects on the breast-fed child from the drug or from the mother's underlying condition.

Monitor infants exposed to olanzapine for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

A lower dosage of fluoxetine should be considered for geriatric patients.

The manufacturer suggests consideration of a lower starting dosage of oral olanzapine and extended-release IM olanzapine pamoate (e.g., Zyprexa(R) Relprevv) for any geriatric patient with factors present that could decrease pharmacokinetic clearance or increase pharmacodynamic response to olanzapine. When short-acting olanzapine for injection (e.g., Zyprexa(R) IntraMuscular) is used IM to treat agitation associated with schizophrenia and bipolar I mania in geriatric patients, a dose of 5 mg per injection should be considered when other clinical factors warrant.

Although no overall differences in efficacy or safety were observed between geriatric and younger patients, the possibility that some older patients may exhibit increased sensitivity to the medication cannot be ruled out.

In pooled data analyses, a reduced risk of suicidality was observed in adults >=65 years of age with antidepressant therapy compared with placebo.

SNRIs and SSRIs, including fluoxetine, have been associated with clinically significant hyponatremia in geriatric patients, who may be at an increased risk for this adverse effect due to volume depletion or use of diuretics.

In premarketing clinical studies with oral olanzapine, 11% (263 of 2500) of the patients were 65 years of age or older. Clinical experience in patients with schizophrenia generally has not revealed differences in tolerability of oral olanzapine in geriatric patients compared with younger adults.

Studies in patients with dementia-related psychosis have suggested that oral olanzapine may have a different tolerability profile in patients 65 years of age or older with this condition compared with younger patients with schizophrenia. Geriatric patients with dementia-related psychosis receiving antipsychotic agents, including olanzapine, are at an increased risk of death compared with that among patients receiving placebo. In addition, a significantly higher incidence of adverse cerebrovascular events (e.g., stroke, transient ischemic attack) was observed in patients receiving olanzapine compared with those receiving placebo in these trials. In 5 placebo-controlled studies of olanzapine in geriatric individuals with dementia-related psychosis, certain treatment-emergent adverse effects, including falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations, occurred in at least 2% of the patients and the incidence was significantly higher than in patients receiving placebo. Discontinuance of therapy because of adverse effects occurred in a significantly higher number of olanzapine-treated patients than in those receiving placebo (13% and 7%, respectively) in these studies.

The manufacturer states that olanzapine is not approved for the treatment of patients with dementia-related psychosis.

The manufacturer states that the presence of factors that might decrease the clearance of or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower initial dosage of the drug in geriatric patients.

Clinical studies of olanzapine in combination with fluoxetine did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.

Clinical studies of extended-release IM olanzapine pamoate did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.