When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.
Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories.
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies 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. It is important to emphasize that reactions reported during therapy were not necessarily caused by it.
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 side effect incidence rate in the population studied.
PLEASE REVIEW THE MANUFACTURER’S COMPLETE DRUG INFORMATION HERE INCLUDING TABLES RELATED TO ADVERSE REACTIONS:
Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in U.S. Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia.
There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment.
Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.
Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
6.2 Other Reactions
Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine 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 reactions are those occurring in fewer than 1/1000 patients.
Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.
Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1.
Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage.
Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura.
Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions.
Respiratory System — Rare: larynx edema.
Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash.
Special Senses — Frequent: taste perversion; Infrequent: mydriasis.
Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2.
1 MedDRA dictionary term from integrated database of placebo controlled trials of 15,870 patients, of which 9,673 patients received fluoxetine.
2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post approval use of fluoxetine. 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.
Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsade de pointes-type arrhythmias), vaginal bleeding, and violent behaviors1.
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.
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.
7.1 Monoamine Oxidase Inhibitors (MAOI)
[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2).]
7.2 CNS Acting Drugs
Caution is advised if the concomitant administration of fluoxetine and such 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 [see Clinical Pharmacology (12.3)].
7.3 Serotonergic Drugs
[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2).]
7.4 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. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)].
7.5 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.
7.6 Potential for Other Drugs to Affect Fluoxetine
Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)].
7.7 Potential for Fluoxetine to Affect Other Drugs
Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)].
Thioridazine — Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT Prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)].
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 which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine.
Thioridazine administration produces a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism.
Drugs Metabolized by CYP2D6 — 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 (see list below) 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. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)].
Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10 fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.
Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine.
Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.
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 when these drugs are administered concomitantly [see Warnings and Precautions (5.2)].
Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, 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 [see Clinical Pharmacology (12.3)].
Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.
Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 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 CYP3A4 activity is not likely to be of clinical significance.
Olanzapine — 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 fluoxetine and olanzapine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.
7.8 Drugs that Prolong the QT Interval
Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine 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. 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 [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].
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