Side Effects of Prozac (fluoxetine)

Prozac (fluoxetine) is a selective serotonin reuptake inhibitor (SSRI) antidepressant used to treat depression, bulimia, obsessive-compulsive disorder (OCD), panic disorder, and premenstrual dysphoric disorder (PMDD). It is also prescribed in combination with olanzapine (Zyprexa) to treat resistant depression and depression associated with bipolar disorder.

Prozac affects neurotransmitters, the chemicals that nerves within the brain use to communicate with each other. Neurotransmitters are manufactured and released by nerves and then travel and attach to other nearby nerves.

Serotonin is one neurotransmitter that is released by nerves in the brain. The serotonin either travels across the space between nerves and attaches to receptors on the surface of nearby nerves or it attaches to receptors on the surface of the nerve that produced it, to be taken up by the nerve and released again (a process referred to as re-uptake).

Many experts believe that an imbalance among neurotransmitters is the cause of depression. Prozac works by preventing the reuptake of serotonin by nerve cells after it has been released. Since uptake is an important mechanism for removing released neurotransmitters and terminating their actions on adjacent nerves, the reduced uptake caused by Prozac increases free serotonin that stimulates nerve cells in the brain.

Common side effects of Prozac include

• nausea,
• headaches,
• anxiety,
• insomnia,
• drowsiness,
• sexual dysfunction, and
• loss of appetite. 

Serious side effects of Prozac include

• serious skin rashes and vasculitis (inflammation of small blood vessels),
• increased blood pressure,
• seizures,
• angle-closure attacks in people with narrow-angle glaucoma, and
• increased risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders.

Some patients may experience withdrawal reactions upon stopping Prozac. Symptoms of withdrawal include anxiety, nausea, nervousness, and insomnia. 

Drug interactions of Prozac include other drugs that make you sleepy or slow your breathing such as sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxant, or medicine for anxiety, depression, or seizures because the combination can cause dangerous side effects or death.

• Check the labels on all your medicines (such as allergy or cough-and-cold products), because they may contain ingredients that cause drowsiness.
• Many drugs can interact with fluoxetine, such as L-tryptophan, blood thinners, medicines for mood disorders and thought disorders, medicines to treat mental illness, medicines to treat ADHD or narcolepsy, and migraine headache medicines.
• Taking monoamine oxidase inhibitors (MAOIs) with Prozac may cause a serious (possibly fatal) drug interaction.
• The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin such as street drugs like MDMA/"ecstasy," St. John's wort, certain antidepressants (other SSRIs, SNRIs), and tryptophan, among others.
• Many drugs besides Prozac may affect the heart rhythm (QT prolongation), including pimozide and thioridazine, among others.
• Aspirin can increase the risk of bleeding when used with Prozac. If your doctor has directed you to take low-dose aspirin for heart attack or stroke prevention, continue taking it unless your doctor instructs you otherwise.

Prozac use later in pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, 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 Prozac during pregnancy.

Prozac is excreted in breast milk. Use of Prozac while breastfeeding is not recommended.

Fluoxetine, as with most antidepressants, can cause

• nausea,
• headaches,
• anxiety,
• insomnia,
• drowsiness, and
• loss of appetite.

Fluoxetine has been implicated in serious skin rashes and vasculitis (inflammation of small blood vessels). Increased blood pressure can occur, and blood pressure should be monitored. Seizures have been reported as has sexual dysfunction. Some patients may experience withdrawal reactions upon stopping fluoxetine. Symptoms of withdrawal include

• anxiety,
• nausea,
• nervousness, and
• insomnia.

The dose of fluoxetine should be gradually reduced when therapy is discontinued. Fluoxetine and other antidepressants have been associated with angle closure attacks in people with narrow angle glaucoma.

Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with depression and other psychiatric disorders.

Anyone considering the use of fluoxetine or any other antidepressant in a child or adolescent must balance this risk of suicide with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
• Serotonin Syndrome
• Allergic Reactions and Rash
• Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
• Seizures
• Altered Appetite and Weight
• Abnormal Bleeding
• Angle-Closure Glaucoma
• Hyponatremia
• Anxiety and Insomnia
• QT Prolongation
• Potential for Cognitive and Motor Impairment
• Discontinuation Adverse Reactions

When using Prozac and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax.

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 Prozac have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered Prozac in panic clinical trials. 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.

Incidence In Major Depressive Disorder, OCD, Bulimia, And Panic Disorder Placebo-Controlled Clinical Trials (excluding data from extensions of trials)

Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of Prozac (incidence of at least 5% for Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials.

Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3.

Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials^1,2

Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials^1,2

Associated With Discontinuation In Major Depressive Disorder, OCD, Bulimia, And Panic Disorder Placebo-Controlled Clinical Trials (excluding data from extensions of trials)

Table 5 lists the adverse reactions associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials.

Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials¹

Other Adverse Reactions In Pediatric Patients (children and adolescents)

• Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated).
• The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo:
  • thirst,
  • hyperkinesia,
  • agitation,
  • personality disorder,
  • epistaxis,
  • urinary frequency, and
  • menorrhagia.
• The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected.

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 healthcare providers 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 US 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, healthcare providers should routinely inquire about such possible side effects.

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.
• Investigations - Frequent: QT interval prolongation (QTcF ≥450 msec)³.
• 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 15870 patients, of which 9673 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.
³ QT prolongation data are based on routine ECG measurements in clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Prozac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Voluntary reports of adverse reactions temporally associated with Prozac 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 pre-existing movement disorders, optic neuritis,
• pancreatitis¹,
• pancytopenia,
• pulmonary embolism,
• pulmonary hypertension,
• QT prolongation,
• Stevens-Johnson syndrome,
• thrombocytopenia¹,
•  thrombocytopenic purpura,
•  ventricular tachycardia (including Torsades 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.

Monoamine Oxidase Inhibitors (MAOI)

• See prescribing information.

CNS Acting Drugs

• Caution is advised if the concomitant administration of Prozac 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.

Serotonergic Drugs

• See prescribing information.

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.

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 Prozac

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.

Potential For Prozac 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 Prozac.

Thioridazine

• Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued, 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 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 Torsades 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.

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.

Benzodiazepines

• The half-life of concurrently administered 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.

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.

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.

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 Prozac and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Drugs That Prolong The QT Interval

• Do not use Prozac in combination with thioridazine or pimozide. Use Prozac 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).
• Prozac is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of Prozac.
• Concomitant use of other highly protein-bound drugs can increase the concentration of Prozac.

Drug Abuse And Dependence

Dependence

• Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence.
• While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or 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 Prozac (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).