What is Symbyax, and how does it work?
Symbyax is a prescription medicine used for:
- short-term treatment of episodes of depression that happen with Bipolar I Disorder in people age 10 or older.
- treatment of episodes of depression that do not respond to 2 other medicines, also called treatment-resistant depression, in adults.
Symbyax contains two medicines, olanzapine and fluoxetine hydrochloride.
It is not known if Symbyax is safe and effective in children under the age of 10.
The symptoms of Bipolar I Disorder include
- alternating periods of depression and high or irritable mood,
- increased activity and restlessness,
- racing thoughts,
- talking fast,
- impulsive behavior, and
- a decreased need for sleep.
With treatment, some of your symptoms of Bipolar I Disorder may improve.
The symptoms of treatment-resistant depression include
- decreased mood,
- decreased interest,
- increased guilty feelings,
- decreased energy,
- decreased concentration,
- changes in appetite, and
- suicidal thoughts or behavior.
With treatment, some of your symptoms of treatment-resistant depression may improve.
If you do not think you are getting better, call your doctor.
What are the side effects of Symbyax?
WARNINGS
SUICIDAL THOUGHTS AND BEHAVIORS; AND INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Suicidal Thoughts and Behaviors
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
In patients of all ages who are started on antidepressant therapy, monitor
closely for worsening and emergence of suicidal thoughts and behaviors. Advise
families and caregivers of the need for close observation and communication with
the prescriber. Symbyax is not approved for use in children less than 10 years
of age.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. Symbyax (olanzapine and fluoxetine) is
not approved for the treatment of patients with dementia-related psychosis.
Other possible serious risks:
- Increased risk of death and increased incidence of stroke or "mini-strokes" called transient ischemic attacks (TIAs) in elderly people with psychosis related to dementia (a brain disorder that lessens the ability to remember, think, and reason).
Symbyax is not approved forthese patients. - Severe allergic reactions: Tell your doctor right away if you get red itchy welts (hives) or, a rash alone or with fever and joint pain, while taking
Symbyax. Call your doctor right away if you become severely ill and have some or all of these symptoms:- swelling of your face, eyes, or mouth
- trouble breathing
- Neuroleptic malignant syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including
Symbyax. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have some or all of these symptoms:- high fever
- excessive sweating
- rigid muscles
- confusion
- changes in your breathing, heartbeat, and blood pressure
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur. Features of DRESS may include rash, fever, swollen glands and other internal organ involvementsuch as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctorimmediately if you experience any of these signs.
- Tardive Dyskinesia: This condition causes body movements that keep happening and that you cannot control. These movements usually affect the face and tongue. Tardive dyskinesia may notgo away, even if you stop taking
Symbyax. It may also start after you stop taking Symbyax.Tell your doctor if you get any body movements that you cannot control. - Serotonin Syndrome: This is a condition that can be life threatening. Call your doctor right awayif you become severely ill and have some or all of these symptoms:
- Visual problems:
Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.
- eye pain
- changes in vision
- swelling or redness in or around the eye
- Abnormal bleeding: Tell your doctor if you notice any increased or unusual bruising or bleedingwhile taking
Symbyax, especially if you take one of these medicines: - Low salt (sodium) levels in the blood (hyponatremia): Call your doctor right away if you become severely ill and have some or all of these symptoms:
- headache
- feel weak
- confusion
- problems concentrating
- memory problems
- feel unsteady
- Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmiaincluding Torsade de Pointes). This condition can be life threatening. The symptoms may include:
- fast, slow, or irregular heartbeat
- shortness of breath
- dizziness or fainting
- Decreased blood pressure when you change positions, with symptoms of dizziness, fast orslow heart beat, or fainting
- Difficulty swallowing
- Seizures
- Problems with control of body temperature: You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoiddehydration. Call your doctor right away if you become severely ill and have some or all of thesesymptoms of dehydration:
Common possible side effects of
Symbyax include:
- dry mouth,
- tiredness,
- sleeping for long period of time,
- increased appetite,
- swelling of your hands and feet,
- drowsiness,
- tremors (shakes), or
- blurred vision
Tell your doctor about any side effect that bothers you or that does not go away.
These are not all the possible side effects with
Symbyax. For more information, ask your doctor orpharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.
What is the dosage for Symbyax?
Depressive Episodes Associated With Bipolar I Disorder
Adults
- Administer Symbyax once daily in the evening, generally beginning with
the 6 mg/25 mg (mg olanzapine/mg equivalent fluoxetine) capsule. - While food has no appreciable effect on the absorption of olanzapine and
fluoxetine given individually, the effect of food on the absorption of
Symbyax has not been studied. - Make dosage adjustments, if indicated, according to efficacy and
tolerability. - Antidepressant efficacy was demonstrated with Symbyax in a dose range of
olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg. - The safety of doses above 18 mg of olanzapine and 75 mg of fluoxetine has not been evaluated in adult clinical studies. Periodically reexamine the need for continued pharmacotherapy.
Children And Adolescents (10 To 17 Years Of Age)
- Administer Symbyax once daily in the evening, generally beginning with
the 3 mg/25 mg capsule, without regard to meals, with a recommended target
dose within the approved dosing range (6/25; 6/50; 12/50 mg). - The safety of doses above 12 mg of olanzapine and 50 mg of fluoxetine has not been evaluated in pediatric clinical studies.
- Periodically reexamine the need for continued pharmacotherapy.
Treatment Resistant Depression
- Administer Symbyax once daily in the evening, generally beginning with
the 6 mg/25 mg capsule. - While food has no appreciable effect on the absorption of olanzapine and
fluoxetine given individually, the effect of food on the absorption of
Symbyax has not been studied. Adjust dosage, if indicated, according to
efficacy and tolerability. - Antidepressant efficacy was demonstrated with Symbyax in a dose range of
olanzapine 6 mg to 18 mg and fluoxetine 25 mg to 50 mg. - The safety of doses above 18 mg/75 mg has not been evaluated in clinical studies. Periodically reexamine the need for continued pharmacotherapy.
Specific Populations
- Start Symbyax at 3 mg/25 mg or 6 mg/25 mg in patients with a
predisposition to hypotensive reactions, patients with hepatic impairment,
or patients who exhibit a combination of factors that may slow the
metabolism of Symbyax (female gender, geriatric age, nonsmoking status) or
those patients who may be pharmacodynamically sensitive to olanzapine. - Titrate slowly and adjust dosage as needed in patients who exhibit a
combination of factors that may slow metabolism. Symbyax has not been
systematically studied in patients >65 years of age or in patients <10 years
of age.
Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of an MAOI
intended to treat psychiatric disorders and initiation of therapy with
Symbyax. Conversely, at least 5 weeks should be allowed after stopping
Symbyax before starting an MAOI intended to treat psychiatric disorders.
Use Of Symbyax With Other MAOIs Such As Linezolid Or Methylene Blue
- Do not start Symbyax in a patient who is being treated with linezolid or
intravenous methylene blue because there is an increased risk of serotonin
syndrome. In a patient who requires more urgent treatment of a psychiatric
condition, other interventions, including hospitalization, should be
considered. - In some cases, a patient already receiving Symbyax therapy may require
urgent treatment with linezolid or intravenous methylene blue. If acceptable
alternatives to linezolid or intravenous methylene blue treatment are not
available and the potential benefits of linezolid or intravenous methylene
blue are judged to outweigh the risks of serotonin syndrome in a particular
patient, Symbyax should be stopped promptly, and linezolid or intravenous
methylene blue can be administered. The patient should be monitored for
symptoms of serotonin syndrome for five weeks or until 24 hours after the
last dose of linezolid or intravenous methylene blue, whichever comes first.
Therapy with Symbyax may be resumed 24 hours after the last dose of
linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such
as oral tablets or by local injection) or in intravenous doses much lower
than 1 mg/kg with Symbyax is unclear. - The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use.
Discontinuation Of Treatment With Symbyax
- Symptoms associated with discontinuation of fluoxetine, a component of
Symbyax, SNRIs, and SSRIs, have been reported.
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What drugs interact with Symbyax?
- The risks of using Symbyax in combination with other drugs have not been
extensively evaluated in systematic studies. - The drug-drug interactions sections of fluoxetine and olanzapine are
applicable to Symbyax. - As with all drugs, the potential for interaction by a variety of
mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or
enhancement, etc.) is a possibility. - In evaluating individual cases, consideration should be given to using
lower initial doses of the concomitantly administered drugs, using
conservative titration schedules, and monitoring of clinical status.
Monoamine Oxidase Inhibitors (MAOIs)
CNS Acting Drugs
- Caution is advised if the concomitant administration of Symbyax and other
CNS-active drugs is required. In evaluating individual cases, consideration
should be given to using lower initial doses of the concomitantly administered
drugs, using conservative titration schedules, and monitoring of clinical
status.
Serotonergic Drugs
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, Warfarin)
- Serotonin release by platelets plays an important role in hemostasis.
Epidemiological studies of the case-control and cohort design that have
demonstrated an association between use of psychotropic drugs that interfere
with serotonin reuptake and the occurrence of upper gastrointestinal bleeding
have also shown that concurrent use of an NSAID or aspirin may potentiate this
risk of bleeding. Altered anticoagulant effects, including increased bleeding,
have been reported when SNRIs or SSRIs are coadministered with warfarin. Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin. Patients receiving warfarin therapy should be carefully monitored when
Symbyax is initiated or discontinued.
Electroconvulsive Therapy (ECT)
- There are no clinical studies establishing the benefit of the combined use of
ECT and fluoxetine. - There have been rare reports of prolonged seizures in
patients on fluoxetine receiving ECT treatment.
Potential For Other Drugs To Affect Symbyax
Benzodiazepines
- Co-administration of diazepam with olanzapine potentiated the orthostatic
hypotension observed with olanzapine.
Inducers Of 1A2
- Carbamazepine therapy (200 mg BID) causes an approximate 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.
Inhibitors Of CYP1A2
- Fluvoxamine decreases the clearance of olanzapine.
- This results in a mean increase in olanzapine Cmax following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers.
- The mean increase in olanzapine AUC is 52% and 108%, respectively.
- Lower doses of the olanzapine component of Symbyax should be considered in patients receiving concomitant treatment with fluvoxamine.
The Effect Of Other Drugs On Olanzapine
- Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small
amount. - Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance.
- The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on
Symbyax has not been evaluated. - Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance.
- Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.
Potential For Symbyax To Affect Other Drugs
Pimozide
- Concomitant use of Symbyax and pimozide is contraindicated.
- Pimozide can prolong
the QT interval. Symbyax can increase the level of pimozide through inhibition
of CYP2D6. - Symbyax can also prolong the QT interval.
- Clinical studies of
pimozide with other antidepressants demonstrate an increase in drug interaction
or QTc prolongation. - While a specific study with pimozide and Symbyax has not
been conducted, the potential for drug interactions or QTc prolongation warrants
restricting the concurrent use of pimozide and Symbyax.
Carbamazepine
- Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.
Alcohol
- The coadministration of ethanol with Symbyax may potentiate sedation and
orthostatic hypotension.
Thioridazine
- Thioridazine should not be administered with Symbyax or administered within a
minimum of 5 weeks after discontinuation of Symbyax, because of the risk of QT
prolongation. - In a study of 19 healthy male subjects, which included 6
slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of
thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for
thioridazine in the slow hydroxylators compared with the rapid hydroxylators.
The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6
isozyme activity. - Thus, this study suggests that drugs that inhibit CYP2D6, such
as certain SSRIs, including fluoxetine, will produce elevated plasma levels of
thioridazine. - Thioridazine administration produces a dose-related
prolongation of the QTc interval, which is associated with serious ventricular
arrhythmias, such as torsades de pointes-type arrhythmias and sudden death. This
risk is expected to increase with fluoxetine-induced inhibition of thioridazine
metabolism. - Due to the risk of serious ventricular arrhythmias and sudden
death potentially associated with elevated thioridazine plasma levels,
thioridazine should not be administered with fluoxetine or within a minimum of 5
weeks after fluoxetine has been discontinued.
Tricyclic Antidepressants (TCAs)
- Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.
- In 2 fluoxetine studies, previously stable plasma levels of imipramine and
desipramine have increased >2- to 10fold when fluoxetine has been administered
in combination. - This influence may persist for 3 weeks or longer after
fluoxetine is discontinued. - Thus, the dose of TCA may need to be reduced and
plasma TCA concentrations may need to be monitored temporarily when Symbyax is
coadministered or has been recently discontinued.
Antihypertensive Agents
- Because of the potential for olanzapine to induce hypotension, Symbyax may
enhance the effects of certain antihypertensive agents.
Levodopa And Dopamine Agonists
- The olanzapine component of Symbyax may antagonize the effects of levodopa and dopamine agonists.
Benzodiazepines
- Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N-desmethyldiazepam.
- When concurrently administered with fluoxetine, the half-life of diazepam may be
prolonged in some patients. - Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.
Clozapine
- Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine.
Haloperidol
- Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine.
Phenytoin
- Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine.
Drugs Metabolized By CYP2D6
- In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP2D6. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by this enzyme.
- Fluoxetine inhibits the activity of CYP2D6 and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution.
- Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks.
- If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered.
- Drugs with a narrow therapeutic index represent the greatest concern (including but not limited to, flecainide, propafenone, vinblastine, and TCAs).
Drugs Metabolized By CYP3A
- In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.
- In an in vivo interaction study involving the coadministration of fluoxetine with single doses of terfenadine (a CYP3A substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.
- In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.
- These data indicate that fluoxetine's extent of inhibition of CYP3A activity is not likely to be of clinical significance.
Effect Of Olanzapine On Drugs Metabolized By Other CYP Enzymes
- In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, and CYP2C19. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.
Lithium
- Multiple doses of olanzapine did not influence the pharmacokinetics of lithium.
- There have been reports of both increased and decreased lithium levels when
lithium was used concomitantly with fluoxetine. - Cases of lithium toxicity and
increased serotonergic effects have been reported. - Lithium levels should be
monitored in patients taking Symbyax concomitantly with lithium.
Drugs Tightly Bound To Plasma Proteins
- The in vitro binding of Symbyax to human plasma proteins is similar to the
individual components. - The interaction between Symbyax and other highly
protein-bound drugs has not been fully evaluated. - Because fluoxetine is tightly
bound to plasma protein, the administration of fluoxetine to a patient taking
another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may
cause a shift in plasma concentrations potentially resulting in an adverse
effect. - Conversely, adverse effects may result from displacement of
protein-bound fluoxetine by other tightly bound drugs.
Valproate
- In vitro studies using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate.
- Further, valproate has little effect on the metabolism of olanzapine in vitro. Thus, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.
Biperiden
- Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden.
Theophylline
- Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.
Drugs That Prolong The QT Interval
- Do not use Symbyax in combination with thioridazine or pimozide. Use
Symbyax
with caution in combination with other drugs that cause QT prolongation. These
include:- specific antipsychotics (e.g., ziprasidone, iloperidone,
chlorpromazine, mesoridazine, droperidol); - specific antibiotics (e.g.,
erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); - Class 1A antiarrhythmic
medications (e.g., quinidine, procainamide); - Class III antiarrhythmics (e.g.,
amiodarone, sotalol); and - others (e.g., pentamidine, levomethadyl acetate,
methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or
tacrolimus). Fluoxetine is primarily metabolized by CYP2D6.
- specific antipsychotics (e.g., ziprasidone, iloperidone,
- Concomitant
treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine.
Concomitant use of other highly protein-bound drugs can increase the
concentration of fluoxetine.
QUESTION
Another term that has been previously used for bipolar disorder is ___________________.
See Answer
Does Symbyax cause addiction or withdrawal symptoms?
Drug Abuse And Dependence
Dependence
- Symbyax, as with fluoxetine and olanzapine, has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence.
- While the clinical studies did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.
- Consequently, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of
Symbyax (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). - In studies in rats and rhesus monkeys designed to assess abuse and dependence potential, olanzapine alone was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence at oral doses up to 15 (rat) and 8 (monkey) times the MRHD (20 mg) on a mg/m² basis.
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Is Symbyax safe to use while pregnant or breastfeeding?
- Pregnant women should notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with
Symbyax. - Symbyax use later in pregnancy may lead to extrapyramidal symptoms (tremors, abnormal muscle movements), an increased risk for neonatal complications requiring prolonged hospitalization, respiratory distress, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including
Symbyax, during pregnancy. - Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
- Advise breastfeeding women using Symbyax to monitor infants for agitation, irritability, poor weight gain, poor feeding, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs.