Selfemra

Name: Selfemra

Selfemra Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Selfemra there are no specific foods that you must exclude from your diet when receiving Selfemra.

Inform MD

Before starting Selfemra, 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, MAOI’s (including linezolid, an antibiotic), or antipsychotics 
    • Tramadol 
    • 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 breastfeeding
 Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Selfemra and some medicines may interact with each other, may not work as well, or may cause serious side effects.  If you take Selfemra, you should not take any other medicines that contain fluoxetine including: 
  • Symbyax 
  • Sarafem 
  • Prozac Weekly

 

Selfemra Dosage

Take Selfemra exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended dose of Selfemra is 20 mg a day, either every day of the menstrual cycle or on certain days of the month. Taking it on certain days is defined as starting a daily dose 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeating with each new cycle.

Precautions While Using Selfemra

It is important that your doctor check your progress at regular visits, to allow changes in your dose and help reduce any side effects. Blood tests may be needed to check for unwanted effects.

Do not take fluoxetine with a monoamine oxidase (MAO) inhibitor (eg, isocarboxazid [Marplan®], linezolid [Zyvox®], methylene blue injection, phenelzine [Nardil®], selegiline [Eldepryl®], tranylcypromine [Parnate®]). Do not start taking fluoxetine during the 2 weeks after you stop a MAO inhibitor and wait 5 weeks after stopping fluoxetine before you start taking a MAO inhibitor. If you take them together or do not wait the proper amount of time, you may develop confusion, agitation, restlessness, stomach or intestinal symptoms, a sudden high body temperature, an extremely high blood pressure, or severe convulsions.

Do not take thioridazine (Mellaril®) with fluoxetine and wait 5 weeks after stopping fluoxetine before you start taking thioridazine. Do not use pimozide (Orap®) with fluoxetine. Using these medicines together can cause very serious heart problems.

Fluoxetine may cause a serious condition called serotonin syndrome if taken together with some medicines. Do not use fluoxetine with buspirone (Buspar®), fentanyl (Abstral®, Duragesic®), lithium (Eskalith®, Lithobid®), tryptophan, St. John's wort, amphetamines, or some pain or migraine medicines (eg, rizatriptan, sumatriptan, tramadol, Frova®, Imitrex®, Maxalt®, Relpax®, Ultram®, Zomig®). Check with your doctor first before taking any other medicines with fluoxetine.

Fluoxetine may cause some teenagers and young adults to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, tell your doctor right away. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive) or has tried to commit suicide.

Do not suddenly stop taking this medicine without checking first with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This will decrease the chance of having withdrawal symptoms such as agitation, breathing problems, chest pain, confusion, diarrhea, dizziness or lightheadedness, fast heartbeat, headache, increased sweating, muscle pain, nausea, restlessness, runny nose, trouble sleeping, trembling or shaking, unusual tiredness or weakness, vision changes, or vomiting.

Tell your doctor right away if you develop a rash or hives, swelling of the face, eyes, or mouth, or trouble breathing after taking this medicine.

This medicine may increase your risk for bleeding problems. Make sure your doctor knows if you are also taking other medicines that thin the blood, such as aspirin, nonsteroidal antiinflammatory agents, also called NSAIDs (eg, diclofenac, ibuprofen, naproxen, Advil®, Aleve®, Celebrex®, Voltaren®), or warfarin (Coumadin®, Jantoven®).

Hyponatremia (low sodium in the blood) may occur with this medicine. Check with your doctor right away if you have confusion, difficulty concentrating, headaches, memory problems, weakness, and unsteadiness.

Contact your doctor right away if you have dizziness, fainting, or a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you have ever had a heart rhythm problem, such as QT prolongation, or if you or a family member has had a heart attack, heart failure, low blood pressure, or a stroke.

The use of alcohol is not recommended in patients who are taking fluoxetine.

This medicine may affect blood sugar levels. If you are diabetic and notice a change in the results of your blood or urine sugar tests, check with your doctor.

This medicine may cause some people to become drowsy or less able to think clearly, or to have poor muscle control. Make sure you know how you react to fluoxetine before you drive, use machines, or do anything else that could be dangerous if you are not alert and well able to control your movements.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Selfemra Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Hives, itching, or skin rash
  • inability to sit still
  • restlessness
Less common
  • Chills or fever
  • joint or muscle pain
Rare
  • Anxiety
  • cold sweats
  • confusion
  • convulsions (seizures)
  • cool pale skin
  • diarrhea
  • difficulty with concentration
  • drowsiness
  • dryness of the mouth
  • excessive hunger
  • fast or irregular heartbeat
  • headache
  • increased sweating
  • increased thirst
  • lack of energy
  • mood or behavior changes
  • overactive reflexes
  • purple or red spots on the skin
  • racing heartbeat
  • shakiness or unsteady walk
  • shivering or shaking
  • talking, feeling, and acting with excitement and activity you cannot control
  • trouble with breathing
  • unusual or incomplete body or facial movements
  • unusual tiredness or weakness
Incidence not known
  • Abdominal or stomach pain
  • agitation
  • back or leg pains
  • bleeding gums
  • blindness
  • blistering, peeling, or loosening of the skin
  • bloating
  • blood in the urine or stools
  • bloody, black or tarry stools
  • blue-yellow color blindness
  • blurred vision
  • chest pain or discomfort
  • clay-colored stools
  • constipation
  • continuing vomiting
  • cough or dry cough
  • dark urine
  • decreased urine output
  • decreased vision
  • depression
  • difficulty with breathing
  • difficulty with swallowing
  • dizziness or lightheadedness
  • eye pain
  • fainting
  • fast, pounding, or irregular heartbeat or pulse
  • general body swelling
  • high fever
  • hives, itching, puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • hostility
  • indigestion
  • irregular or slow heart rate
  • irritability
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • light-colored stools
  • loss of appetite
  • loss of bladder control
  • muscle twitching
  • nausea
  • nightmares
  • no blood pressure or pulse
  • noisy breathing
  • nosebleeds
  • pain in the ankles or knees
  • painful, red lumps under the skin, mostly on the legs
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pinpoint red spots on the skin
  • rapid weight gain
  • red or irritated eyes
  • red skin lesions, often with a purple center
  • redness, tenderness, itching, burning, or peeling of the skin
  • severe muscle stiffness
  • severe sleepiness
  • slurred speech
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • stopping of heart
  • sudden shortness of breath or troubled breathing
  • sudden weakness in the arms or legs
  • sudden, severe chest pain
  • swelling of the face, ankles, or hands
  • swollen or painful glands
  • thoughts of killing oneself
  • tightness in the chest
  • tiredness
  • twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
  • unconsciousness
  • unpleasant breath odor
  • unusual bleeding or bruising
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
  • unusually pale skin
  • use of extreme physical or emotional force
  • vomiting of blood
  • yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Decreased appetite
Less common or rare
  • Abnormal dreams
  • breast enlargement or pain
  • change in sense of taste
  • changes in vision
  • feeling of warmth or heat
  • flushing or redness of the skin, especially on face and neck
  • frequent urination
  • hair loss
  • increased appetite
  • increased sensitivity of the skin to sunlight
  • menstrual pain
  • stomach cramps, gas, or pain
  • unusual secretion of milk, in females
  • weight loss
  • yawning
Incidence not known
  • Cracks in the skin
  • loss of heat from the body
  • painful or prolonged erections of the penis
  • scaly skin
  • swelling of the breasts or breast soreness in both females and males
  • unusual milk production

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Indications and Usage for Selfemra

Selfemra® is indicated for the treatment of premenstrual dysphoric disorder (PMDD).

The efficacy of fluoxetine in the treatment of PMDD was established in 3 placebo-controlled trials (see CLINICAL TRIALS).

The essential features of PMDD, according to the DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

The effectiveness of Selfemra® in long-term use, that is, for more than 6 months, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Selfemra® for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Contraindications

Selfemra® is contraindicated in patients known to be hypersensitive to it.

Monoamine Oxidase Inhibitors

There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination)] should be allowed after stopping fluoxetine before starting an MAOI.

Pimozide

Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Thioridazine

Thioridazine should not be administered with Selfemra® or within a minimum of 5 weeks after Selfemra® has been discontinued (see WARNINGS).

Precautions

General

Abnormal Bleeding

SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal 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. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

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

Anxiety and Insomnia

In 2 placebo-controlled trials of fluoxetine in PMDD, treatment-emergent adverse events were assessed. Rates were as follows for fluoxetine 20 mg (the recommended dose) continuous and intermittent pooled, fluoxetine 60 mg continuous, and pooled placebo, respectively: anxiety (3%, 9%, and 4%); nervousness (5%, 9%, and 3%); and insomnia (9%, 26%, and 7%). For individual rates for fluoxetine 20 mg given as continuous and intermittent dosing, see Table 2 and accompanying footnote under ADVERSE REACTIONS. Events associated with discontinuation for fluoxetine 20 mg continuous and intermittent pooled, fluoxetine 60 mg continuous, and pooled placebo, respectively, were: anxiety (0%, 6%, and 1%); nervousness (1%, 0%, and 0.5%); and insomnia (1%, 4%, and 0.5%). In U.S. placebo-controlled clinical trials of fluoxetine for other approved indications, anxiety, nervousness, and insomnia have been among the most commonly reported adverse events (see ADVERSEREACTIONS, Table 3).

Altered Appetite and Weight

In 2 placebo-controlled trials of fluoxetine in PMDD, rates for anorexia were as follows for fluoxetine 20 mg (the recommended dose) continuous and intermittent pooled, fluoxetine 60 mg continuous, and pooled placebo, respectively: 4%, 13%, and 2%. For individual rates for fluoxetine 20 mg continuous and intermittent, see footnote accompanying Table 2 under ADVERSE REACTIONS. In 2 placebo-controlled trials (only one of which included a dose of 60 mg/day), potentially clinically significant weight gain (≥ 7%) occurred in 8% of patients on fluoxetine 20 mg, 6% of patients on fluoxetine 60 mg, and 1% of patients on placebo. Potentially clinically significant weight loss (≥ 7%) occurred in 7% of patients on fluoxetine 20 mg, 12% of patients on fluoxetine 60 mg, and 3% of patients on placebo. In U.S. placebo-controlled clinical trials of fluoxetine for other approved indications, changes in appetite and weight have also been reported (see Table 3 and ADVERSE REACTIONS, Other Events Observed in U.S. Clinical Trials).

Activation of Mania/Hypomania

No patients treated with fluoxetine in 4 PMDD clinical trials (N = 415) reported mania/hypomania. In all U.S. fluoxetine clinical trials for conditions other than PMDD, 0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may occur with medications used to treat depression, especially in patients predisposed to Bipolar Affective Disorder.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Selfemra® was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

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.

Seizures

No patients treated with fluoxetine in 4 PMDD clinical trials (N = 415) reported seizures. In all U.S. fluoxetine clinical trials for conditions other than PMDD, 0.2% of 10,782 patients reported seizures. Antidepressant medication should be introduced with care in patients with a history of seizures.

The Long Elimination Half-Lives of Fluoxetine and its Metabolites

Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Use in Patients With Concomitant Illness

Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials for a condition other than PMDD were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances (see CLINICAL PHARMACOLOGY, Liver Disease). A lower or less frequent dose should be used in patients with cirrhosis (see DOSAGE AND ADMINISTRATION).

Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see CLINICAL PHARMACOLOGY, Renal Disease). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION).

In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.

Discontinuation of Treatment with Selfemra®

During marketing of fluoxetine and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Selfemra®. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION).

Interference With Cognitive and Motor Performance

Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Selfemra® and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for Selfemra®. The prescriber or health professional 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. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Selfemra®.

Abnormal Bleeding

Patients should be cautioned 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 PRECAUTIONS, Abnormal Bleeding).

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Selfemra® and triptans, tramadol or other serotonergic agents.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

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 (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

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, 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 and WARNINGS).

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. In addition, 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.

CNS Active Drugs

The risk of using fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, 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, Accumulation and slow elimination).

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.

Antipsychotics

Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS.

Benzodiazepines

The half-life of concurrently administered diazepam may be prolonged in some patients (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

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.

Tryptophan

Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS.

Antidepressants

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 TCA 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 CLINICAL PHARMACOLOGY, Accumulation and slow elimination and Drug Interactions, Drugs Metabolized by CYP2D6).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including Selfemra®, and the potential for serotonin syndrome, caution is advised when Selfemra® is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of Selfemra® with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan).

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Selfemra® with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Potential Effects of Coadministration of Drugs Tightly Bound to Plasma Proteins

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., warfarin, 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 (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

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 SSRIs or SNRIs 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed.

Carcinogenicity

The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity.

Mutagenicity

Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Impairment of Fertility

Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use).

Pregnancy

Teratogenic Effects

Pregnancy category C

In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis), throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).

Infants exposed to SSRIs in late 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. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Labor and Delivery

The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOXWARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Selfemra® in a child or adolescent must balance the potential risks with the clinical need.

Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures.

In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) 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, pediatric exposure at the MRD.

A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis.

In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.

Geriatric Use

The diagnosis of PMDD is not applicable to postmenopausal women.

Drug Abuse and Dependence

Controlled Substance Class

Fluoxetine is not a controlled substance.

Physical and Psychological Dependence

Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine 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, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

How is Selfemra Supplied

Selfemra®, 10 mg, contains fluoxetine hydrochloride, equivalent to 10 mg fluoxetine, and are available as hard gelatin capsules with a purple cap and purple body, filled with a white to off-white powder with small agglomerates. Both the body and cap of the #3 capsule are imprinted “93” and “7225.” They are available in blister packs of 28 (4 cards x 7 capsules).

Selfemra®, 20 mg, contains fluoxetine hydrochloride, equivalent to 20 mg fluoxetine, and are available as hard gelatin capsules with a purple cap and flesh body. Both the body and cap of the #3 capsule are imprinted “93” and “7226.” They are available in blister packs of 28 (4 cards x 7 capsules).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from light.

Prozac® is a registered trademark of Eli Lilly and Company.

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