Drug Safety-related Labeling Changes (SrLC)

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FLUOXETINE HYDROCHLORIDE (NDA-202133)

(FLUOXETINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/18/2023 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Increased Risk of Bleeding

(Additions and/or revisions underlined)

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the increased risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

6 Adverse Reactions

(Additions and/or revisions underlined)

• 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 [see Boxed Warning and Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Allergic Reactions and Rash [see Warnings and Precautions (5.3)]
• Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4)]
• Seizures [see Warnings and Precautions (5.5)]
• Altered Appetite and Weight [see Warnings and Precautions (5.6)]
• Increased Risk of Bleeding [see Warnings and Precautions (5.7)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval 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: anosmia, aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, drug reaction with eosinophilia and systemic symptoms (DRESS), 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, hyposmia, 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 Torsades de Pointes-type arrhythmias), vaginal bleeding, and violent behaviors.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Use of fluoxetine in children—The efficacy of fluoxetine for the treatment of MDD was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to £ 18 [see Clinical Studies (14.1)].

The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18 [see Clinical Studies (14.2)].

The safety and effectiveness in pediatric patients < 8 years of age in MDD and < 7 years of age in OCD have not been established.

Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to £ 18) with MDD or OCD [see Clinical Pharmacology (12.3)].

The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer- term adverse reaction profile observed in the 19-week MDD study (N = 219 randomized; 109 fluoxetine- treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)].

Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended.

As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels.

The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions (5.6)].

Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warning and Warnings and Precautions (5.1)]. Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need.

Junvenile Animal Toxicity Data—Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation, and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day); increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day); skeletal muscle degeneration and necrosis; decreased femur length/growth; and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in the high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine- induced muscle damage was not assessed.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Information on Medication Guide and Benefits/Risks of Fluoxetine

Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine tablets and to reread it each time the prescription is renewed.

Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine tablets and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine tablets.

…

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, opioids, lithium, buspirone, tryptophan, amphetamines, and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid).

Instruct patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)].

Allergic Reactions and Rash

Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Increased Risk of Bleeding

Inform patients about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. Advise patients to call their doctor if they experience any increased or unusual bruising or bleeding while taking fluoxetine.

Angle-closure Glaucoma

Patients should be advised that taking fluoxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open- angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.8)].

Hyponatremia

Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including fluoxetine. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.9)].

QT Prolongation

Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions (5.11)]. 

…

Use in Specific Populations

Pregnancy—Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Fluoxetine Tablets.

Advise patients that Fluoxetine Tablet 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) [see Use in Specific Populations (8.1)].

Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fluoxetine during pregnancy [see Use in Specific Populations (8.1)].

Lactation— Advise breastfeeding women using Fluoxetine Tablets to monitor infants for agitation, irritability, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

MEDICATION GUIDE FLUOXETINE TABLETS

(Additions and/or revisions underlined)

• What should I tell my healthcare provider before taking fluoxetine? Ask if you are not sure.

Before starting fluoxetine, tell your healthcare provider if you:

• are taking certain drugs or treatments such as:
• Triptans used to treat migraine headache
• Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium,SSRIs, SNRIs, MAOIs, or antipsychotics
• SSRIs, SNRIs, MAOIs, or antipsychotics
• Tramadol, fentanyl, meperidine, methadone, or other opioids
• Amphetamines
• Over-the-counter supplements such as tryptophan or St. John’s Wort
• Electroconvulsive therapy (ECT)
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• are pregnant or plan to become pregnant. Taking Fluoxetine Tablets late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
• If you become pregnant while taking Fluoxetine Tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1- 866-961-2388 or go to https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.
• are breast-feeding or plan to breast-feed. Fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if taking Fluoxetine Tablets.

08/18/2023 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; newly added section)

Risk Summary

Data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine

through breast milk (see Clinical Considerations). There are no data on the effect of fluoxetine or its metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fluoxetine Tablets and any potential adverse effects on the breastfed child from Fluoxetine Tablets or the underlying maternal condition.

Clinical Considerations

Infants exposed to Fluoxetine Tablets should be monitored for agitation, irritability, poor feeding, and poor weight gain.

Data

A study of 19 nursing mothers on fluoxetine with daily doses of 10 to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL).

09/20/2021 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.16 Sexual Dysfunction

(Newly added subsection)

Use of SSRIs, including fluoxetine, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of fluoxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

…

Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, may cause sexual problems.

Symptoms in males may include:

• Delayed ejaculation or inability to have an ejaculation

• Decreased sex drive

• Problems getting or keeping an erection

Symptoms in females may include:

• Decreased sex drive

• Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluoxetine. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

17.12 Sexual Dysfunction

Advise patients that use of fluoxetine may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.16)].

…

01/04/2017 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING:  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 for emergence of suicidal thoughts and behavior. Advise families and caregivers of the need for close observation and communication with the prescriber.

• Fluoxetine is not approved for use in children less than 7 years of age.

4 Contraindications

4.1 Monoamine Oxidase Inhibitors (MAOIs)

Additions and/or revisions underlined:

The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

4.2 Other Contraindications

Additions and/or revisions underlined:

The use of fluoxetine is contraindicated with the following:

• Pimozide

• Thioridazine

  Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval …

5 Warnings and Precautions

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Replaces prior subsection title Clinical Worsening and Suicide Risk

Patients with MDD …

5.11 QT Prolongation

Newly added subsection:

Postmarketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6.

Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

5.15 Discontinuation of Adverse Reactions

Replaces prior subsection title Discontinuation of Treatment.

During marketing of fluoxetine …

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin ( in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures …

The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI.

If concomitant use of fluoxetine with other serotonergic drugs, ie, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort, is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ...

5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

Additions and/or revisions underlined:

… However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder …

6 Adverse Reactions

Addition of the following line listing:

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
• Discontinuation Adverse Reactions

6.2 Postmarketing Experience

Addition of the following to listing of voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction: galactorrhea

7 Drug Interactions

7.6 Potential for Fluoxetine to Affect Other Drugs

Additions and/or revisions underlined:

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 …

7.7 Drugs That Prolong the QT Interval

Newly added subsection:

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 (eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg, 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.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who  remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with fluoxetine, the physician should carefully consider trimester both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis.

Animal data—In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day …

8.4 Pediatric Use

Animal data—Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation, and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the  average AUC in  pediatric patients at the  MRHD of 20 mg/day); increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day); skeletal muscle degeneration and necrosis; decreased femur length/growth; and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the  MRHD of 20 mg/day).  The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at  AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in the high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed.

These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving  3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the  MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD.

A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4-week-old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on a mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include:

• fast, slow, or irregular heartbeat
• shortness of breath
• dizziness or fainting

Do not stop fluoxetine without first talking to your healthcare provider. Stopping fluoxetine too quickly may cause serious symptoms including:

• headache, sweating, nausea, dizziness

Who should not take fluoxetine?

Do not take fluoxetine if you:

• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
• Do not take an MAOI within 5 weeks of stopping fluoxetine unless directed to do so by your physician.
• Do not start fluoxetine if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

What should I tell my healthcare provider before taking fluoxetine? Ask if you are not sure.

Before starting fluoxetine, tell your healthcare provider if you:

are taking certain drugs or treatments such as:

• Triptans used to treat migraine headache
• Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychotics
• Tramadol and fentanyl
• Over-the-counter supplements such as tryptophan or St. John’s Wort
• Electroconvulsive therapy (ECT) …

PATIENT COUNSELING INFORMATION

17.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Replaces prior subsection title Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be …

17.8 QT Prolongation

Newly added subsection:

Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia.

01/04/2017 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) …

If concomitant use of fluoxetine with other serotonergic drugs, ie, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

2.   Serotonin Syndrome. This condition can be life-threatening and may include:

Addition of the following:        

• dizziness
• flushing
• tremor
• seizures

What should I tell my healthcare provider before taking fluoxetine? Ask if you are not sure.

Before starting fluoxetine, tell your healthcare provider if you:

are taking certain drugs or treatments such as:

• Triptans used to treat migraine headache
• Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychotics
• Tramadol and fentanyl
• Amphetamines …

PATIENT COUNSELING INFORMATION

17.3 Serotonin Syndrome

Additions and/or revisions underlined:

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort …