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Duloxetine (Oral Route) Description and Brand Names
Description and Brand Names
Drug information provided by: IBM Micromedex
US Brand Name
Duloxetine is used to treat depression and anxiety. It is also used for pain caused by nerve damage associated with diabetes (diabetic peripheral neuropathy).
Duloxetine is also used to treat fibromyalgia (muscle pain and stiffness) and chronic (long-lasting) pain that is related to muscles and bones.
Duloxetine belongs to a group of medicines known as selective serotonin and norepinephrine reuptake inhibitors (SSNRIs). These medicines are thought to work by increasing the activity of chemicals called serotonin and norepinephrine in the brain.
This medicine is available only with your doctor’s prescription.
This product is available in the following dosage forms:
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Cymbalta Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing
See also Warning section.
Nausea, dry mouth, constipation, loss of appetite, tiredness, drowsiness, or increased sweating may occur. If any of these effects persist or worsen, tell your doctor promptly.
Dizziness or lightheadedness may occur, especially when you first start or increase your dose of this drug. To reduce the risk of dizziness, lightheadedness, or falling, get up slowly when rising from a sitting or lying position.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.
Tell your doctor right away if any of these serious side effects occur: confusion, easy bruising/bleeding, decreased interest in sex, changes in sexual ability, muscle cramps/weakness, shaking (tremor), difficulty urinating, signs of liver problems (such as stomach/abdominal pain, persistent nausea, vomiting, yellowing eyes/skin, dark urine).
Get medical help right away if you have any very serious side effects, including: black/bloody stools, vomit that looks like coffee grounds, seizure, eye pain/swelling/redness, widened pupils, vision changes (such as seeing rainbows around lights at night, blurred vision).
This medication may increase serotonin and rarely cause a very serious condition called serotonin syndrome/toxicity. The risk increases if you are also taking other drugs that increase serotonin, so tell your doctor or pharmacist of all the drugs you take (see Drug Interactions section). Get medical help right away if you develop some of the following symptoms: fast heartbeat, hallucinations, loss of coordination, severe dizziness, severe nausea/vomiting/diarrhea, twitching muscles, unexplained fever, unusual agitation/restlessness.
A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing, skin blisters, mouth sores.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US –
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.
In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
Differences, similarities, and which is better for you
Drug overview & main differences | Conditions treated | Efficacy | Insurance coverage and cost comparison | Side effects | Drug interactions | Warnings | FAQ
If you or a loved one experience depression, anxiety, or other conditions that affect mental health, you are not alone. More than 16 million American adults have major depressive disorder (also called MDD, or depression), and nearly 7 million adults have generalized anxiety disorder (GAD).
Cymbalta (duloxetine) and Prozac (fluoxetine) are two popular antidepressant medications prescribed for depression and several other conditions. Both prescription drugs are approved by the United States Food and Drug Administration (FDA). Medication use with Cymbalta or Prozac is often combined with psychotherapy with a psychologist or doctor of psychiatry.
Cymbalta is classified in a group of medications called SNRIs (serotonin-norepinephrine reuptake inhibitors). They work by increasing the levels of serotonin and norepinephrine in the brain.
Prozac is part of a group of drugs called SSRIs (selective serotonin reuptake inhibitors). SSRIs work by increasing levels of serotonin in the brain.
What are the main differences between Cymbalta and Prozac?
Cymbalta (duloxetine) is an SNRI medication. It is available in both brand and generic. Cymbalta is only available in capsule form. The dosage varies, but a typical dose is 60 mg per day. Cymbalta is used in adults but may be used in younger ages for certain conditions (see chart).
Prozac (fluoxetine) is an SSRI medication. It is available in both brand and generic. Prozac is available in tablet form, capsule form, and as an oral solution. Although the dosage varies, a typical dose is 20 mg once a day. Prozac may be used in adults for all of the indications listed in the chart below. Prozac can also be used in children over 8 years old for depression or over 7 years old for OCD.
|Main differences between Cymbalta and Prozac|
|Drug class||Serotonin-norepinephrine reuptake inhibitor (SNRI)||Selective serotonin reuptake inhibitor (SSRI)|
|Brand/generic status||Brand and generic||Brand and generic|
|What is the generic name?||Duloxetine||Fluoxetine|
|What form(s) does the drug come in?||Capsules||Tablet, capsule, oral solution; also available in combination with olanzapine as Symbyax|
|What is the standard dosage?||Example: 60 mg once daily (dosage varies)||Example: 20 mg once daily (dosage varies)|
|How long is the typical treatment?||Varies||Varies|
|Who typically uses the medication?||Adults and children and adolescents 7 years and older for generalized anxiety disorder or 13 years and older for fibromyalgia||Adults and children & adolescents for depression (over 8 years old) or OCD (over 7 years old)|
Conditions treated by Cymbalta and Prozac
Cymbalta is indicated for major depressive disorder, diabetic peripheral neuropathic pain, and chronic musculoskeletal pain in adults. It can also be used for generalized anxiety disorder in adults as well as children ages 7 years and older and for fibromyalgia in adults and adolescents 13 years and older. Cymbalta is not approved for use in children for depression, diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.
Prozac is indicated for major depression and obsessive-compulsive disorder (OCD) in children, adolescents, and adults. Prozac can also treat bulimia nervosa, premenstrual dysphoric disorder, and panic disorder. Prozac is not approved for use in children under 7 years old.
Note: Symbyax is a combination drug that contains fluoxetine, the ingredient in Prozac, along with another medication called olanzapine. Symbyax can treat depressive episodes associated with bipolar I disorder or treatment-resistant depression.
Sometimes doctors prescribe these drugs off-label for other uses than what they are indicated.
|Major depressive disorder||Yes||Yes|
|Generalized anxiety disorder||Yes||Off-label|
|Diabetic peripheral neuropathic pain||Yes||Off-label|
|Chronic musculoskeletal pain||Yes||Off-label|
|Obsessive-compulsive disorder (OCD)||Off-label||Yes|
|Premenstrual dysphoric disorder||Off-label||Yes|
|In combination with olanzapine (as Symbyax) to treat depressive episodes associated with bipolar disorder OR for treatment-resistant depression||No||Yes|
|Management of anxiety disorders||Yes||Yes|
Is Cymbalta or Prozac more effective?
One study reviewed many studies comparing Cymbalta, Prozac, and another medication called Effexor, to placebo. Cymbalta and Prozac were found to be similar in efficacy and safety for patients with depression.
The diagnosis is an essential factor in deciding which medication will be more appropriate. For example, if the indication is depression, either Prozac or Cymbalta may be an appropriate option. However, if the diagnosis is OCD, Prozac is more appropriate because it is indicated to treat OCD while Cymbalta is not. And if the diagnosis is fibromyalgia, Cymbalta is more appropriate because it is indicated for fibromyalgia, while Prozac is not.
Your healthcare provider can determine which drug is more appropriate for you, taking into account your diagnosis, medical history, and other medical conditions, along with any medications you take that could interact with Cymbalta or Prozac.
Coverage and cost comparison of Cymbalta vs. Prozac
Most insurance and Medicare Part D prescription plans cover Cymbalta or Prozac—choosing the generic form will result in significant cost savings. The brand-name products have a much higher copay or may not be covered at all.
The out-of-pocket cost of Cymbalta is about $126 for 30, 60 mg generic capsules. A free SingleCare card will help you save money on generic Cymbalta, bringing the price down to as low as $15.
The out-of-pocket cost for Prozac is about $21 for #30, 20 mg generic capsules. You can save money on generic Prozac with a SingleCare card, which can bring the generic price down to approximately $4.
Contact your insurance plan for up-to-date coverage information on Cymbalta or Prozac.
|Typically covered by insurance?||Yes (generic)||Yes (generic)|
|Typically covered by Medicare Part D?||Yes (generic)||Yes (generic)|
|Quantity||30, 60 mg capsules||30, 20 mg capsules|
|Typical Medicare copay||$0-$20||$0-$20|
Common side effects of Cymbalta vs. Prozac
The most common side effects of Cymbalta are nausea, headaches, sleepiness, appetite loss, constipation, dry mouth, and dizziness.
The most common side effects of Prozac are headache, nausea, drowsiness, insomnia, appetite loss, sexual side effects, and nervousness or anxiety.
When you fill or refill your Cymbalta or Prozac prescription, you will receive a medication guide that discusses side effects, warnings, and other important information about your medication.
This is not a full list of adverse effects. Other, serious side effects may occur. Consult your healthcare provider for a complete list of side effects.
|Ejaculation disorder/sexual dysfunction||Yes||2-4%||Yes||% not reported|
Source: DailyMed (Cymbalta), DailyMed (Prozac)
Drug interactions of Cymbalta vs. Prozac
MAO inhibitor (MAOI, or monoamine oxidase inhibitor) medications should not be used while taking Cymbalta or Prozac, or for a period of time before or after taking Cymbalta or Prozac. The combination may increase the risk of serotonin syndrome, a life-threatening medical emergency due to excess serotonin. Triptans, which are migraine medications, such as Imitrex (sumatriptan), and other antidepressants, should not be used in combination with Cymbalta or Prozac due to the risk of serotonin syndrome. Also, the cough suppressant dextromethorphan, found in Robitussin-DM and many cough and cold products, should be avoided as it can also cause serotonin syndrome when combined with Cymbalta or Prozac.
Avoid alcohol when taking Cymbalta or Prozac.
This is not a full list of drug interactions. Consult your healthcare provider for a complete list of drug interactions. Tell your doctor about all the medications you take, including prescription, over-the-counter (OTC), and vitamins.
|St. John’s Wort||Supplement||Yes||Yes|
|Opioid pain relievers||Yes||Yes|
|Dextromethorphan (in many cough and cold products)||Cough suppressant||Yes||Yes|
Divalproex sodium/valproic acid
|Drugs metabolized by enzyme CYP2D6||Yes||Yes|
Warnings of Cymbalta and Prozac
Antidepressants, including Cymbalta and Prozac, have a black box warning of suicidality. A black box warning is the strongest warning required by the FDA. Children, adolescents, and young adults (up to 24 years old) taking antidepressants are at an increased risk of suicidal thoughts and behavior. Anyone who takes antidepressants should be carefully monitored.
- Serotonin syndrome is a life-threatening emergency caused by too much serotonin. Patients taking Cymbalta or Prozac should be monitored for serotonin syndrome signs and symptoms, such as hallucinations, seizures, heart rhythm or blood pressure changes (such as high blood pressure), and agitation. Seek emergency medical treatment if any of these symptoms occur. Taking other drugs that increase serotonin levels (triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, dextromethorphan, amphetamines, St. John’s Wort, and MAOIs) increase the risk of serotonin syndrome.
- When discontinuing Cymbalta or Prozac, withdrawal symptoms such as agitation may occur. Your healthcare provider can advise you on the best way to discontinue Cymbalta or Prozac, with a slow taper schedule. Never stop Cymbalta or Prozac abruptly.
- Use with caution in patients who have seizures or who have bipolar disorder.
- Hyponatremia (low sodium) due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur and can be severe. Symptoms may include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Seek emergency treatment and stop Cymbalta or Prozac if symptoms occur.
- Avoid SSRIs in patients with untreated anatomically narrow angles (angle-closure glaucoma).
- SSRIs may increase bleeding risk—this risk increases with concomitant use of aspirin, NSAIDs, or warfarin.
- Do not drive or operate machinery until you know how Cymbalta or Prozac affects you.
- Use with caution in patients with kidney problems.
- Cymbalta or Prozac may alter blood sugar levels in patients with diabetes. This requires monitoring and may require dosage adjustment to diabetes medications.
- Cymbalta or Prozac may cause weight changes. Cymbalta may cause weight gain or loss, while Prozac may cause weight loss. Monitor weight during treatment with Cymbalta or Prozac.
- Cymbalta or Prozac should only be used in pregnancy if the benefit to the mother is greater than the risk to the baby. Stopping the medication may cause a relapse of depression or anxiety. However, neonates exposed to an SNRI (like Cymbalta) or an SSRI (like Prozac) in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. If you already take Cymbalta or Prozac and find out you are pregnant, contact your healthcare provider immediately for guidance.
- Cymbalta and Prozac are on the Beers’ List (drugs that may be inappropriate in older adults). Consult your healthcare provider to see if Cymbalta or Prozac is safe for you.
Other Cymbalta warnings:
- Cymbalta capsules should be swallowed whole and can be taken with or without food. Do not chew, crush, or open the capsule.
- There have been cases of liver problems in people who take Cymbalta—these can be fatal. Consult your doctor immediately and stop taking Cymbalta if you develop signs of jaundice or liver problems. People who have liver problems and/or drink a substantial amount of alcohol should not take Cymbalta.
- Cymbalta can cause orthostatic hypotension (a drop in blood pressure when you stand up), falls, and/or fainting. Falls can lead to fractures or hospitalizations.
- Severe skin reactions may occur. They can be due to conditions called erythema multiforme or Stevens-Johnson syndrome. Stop taking Cymbalta and notify your doctor right away for guidance if you develop blisters, peeling rash, or skin lesions. If symptoms are severe, seek emergency medical treatment.
- Cymbalta may cause urinary problems. Notify your doctor if you have problems urinating.
- Monitor blood pressure while taking Cymbalta.
- Do not take Cymbalta if you have chronic liver disease or cirrhosis.
- Do not take Cymbalta if you have severe kidney disease.
Other Prozac warnings:
- In rare cases, there have been reports of rash and allergic reactions/systemic anaphylaxis reactions, which have been fatal. If you experience a rash or allergic symptoms, stop taking Prozac, and seek immediate medical treatment.
- Prozac may cause QT prolongation and ventricular arrhythmia, which can be life-threatening. Certain patients are at higher risk due to medical conditions or other medications. Ask your healthcare provider if Prozac is safe for you.
Frequently asked questions about Cymbalta vs. Prozac
What is Cymbalta?
Cymbalta, also known by its generic name duloxetine, is an SNRI, or serotonin-norepinephrine reuptake inhibitor. Cymbalta, which is available in both brand and generic form, treats depression, anxiety, fibromyalgia, pain from diabetic peripheral neuropathy, and chronic musculoskeletal pain.
What is Prozac?
Prozac, also known by its generic name, fluoxetine, is an SSRI or selective serotonin reuptake inhibitor. Prozac treats depression, obsessive-compulsive disorder, bulimia nervosa, premenstrual dysphoric disorder, and panic disorder. Prozac is available in both brand and generic form.
Are Cymbalta and Prozac the same?
Cymbalta and Prozac are similar, but not the same. Cymbalta is an SNRI or serotonin-norepinephrine reuptake inhibitor. Some other SNRIs include Effexor (venlafaxine) and Pristiq (desvenlafaxine).
Prozac is an SSRI. Other SSRI drugs you may have heard of include Celexa (citalopram), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), and Zoloft (sertraline).
Is Cymbalta or Prozac better?
Studies show that Cymbalta and Prozac are similar in terms of safety and efficacy.
The best medication for you can only be determined by your healthcare provider who can consider your diagnosis, symptoms, medical conditions, and history, along with any other medications you take that could potentially interact with Cymbalta or Prozac.
Can I use Cymbalta or Prozac while pregnant?
Neonates exposed to certain antidepressants, including Cymbalta or Prozac, in the third trimester of pregnancy have developed severe complications. These complications include lengthy hospitalizations, tube feeding, and breathing support.
If you are already taking Cymbalta or Prozac and find out that you are pregnant, consult your healthcare provider. If you are breastfeeding, consult your OB-GYN as well.
Can I use Cymbalta or Prozac with alcohol?
No. Cymbalta or Prozac should not be combined with alcohol. The combination increases the risk of respiratory depression—slowed breathing, not getting enough oxygen—and can increase sedation and drowsiness and impair alertness.
What antidepressant is better than Prozac?
All antidepressants have gone through extensive testing to show both safety and efficacy. While Prozac can be very effective, it does not work for everyone, because people respond differently to different medications. If you are taking Prozac and feel it is not working after taking it for six to eight weeks, consult your healthcare provider for medical advice.
How is Cymbalta different from other antidepressants?
SNRI medications like Cymbalta work on both serotonin and norepinephrine in the brain, while SSRI medications like Prozac work on serotonin. Cymbalta is also indicated to treat certain types of pain, like fibromyalgia, musculoskeletal pain, and diabetic neuropathic pain, in addition to depression and anxiety.
Who should not take Cymbalta?
People who take antidepressants in the monoamine oxidase inhibitor (MAOI) class of drugs should not take Cymbalta. Other medications interact with Cymbalta (see chart above). Ask your healthcare provider about serotonin syndrome, and if the medicines you take are safe in combination with Cymbalta.
Also, Cymbalta should not be used in children for depression, diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.
Duloxetine: medicine to treat depression, anxiety, nerve pain and stress urinary incontinence
For depression, anxiety and nerve pain, you’ll usually take duloxetine once a day.
For urinary incontinence, you’ll usually take duloxetine twice a day.
Swallow the capsules whole with a drink of water or juice. Do not chew them.
You can take duloxetine with or without food, but it’s best to take it at the same time each day.
How much will I take?
For depression, anxiety and nerve pain, duloxetine comes in 30mg and 60mg capsules.
For stress urinary incontinence, duloxetine comes in 20mg and 40mg capsules.
How much you take will depend on what you’re taking it for:
- depression – the starting dose is 60mg a day and can be increased to 120mg a day
- anxiety – the starting dose is 30mg a day and can be increased to 60mg a day
- nerve pain – the starting dose is 60mg a day and can be increased to 60mg twice a day
- stress urinary incontinence – the starting dose is 20mg twice a day and can be increased to 40mg twice a day after 2 weeks
What if I forget to take it?
If you usually take duloxetine:
- once a day – take the missed dose as soon as you remember, unless it’s less than 12 hours until your next dose, in which case skip the missed dose
- twice a day – take the missed dose as soon as you remember, unless it’s less than 4 hours until your next dose, in which case skip the missed dose
Never take 2 doses at the same time to make up for a forgotten one.
If you forget doses often, it may help to set an alarm to remind you.
You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.
What if I take too much?
The amount of duloxetine that can lead to an overdose varies from person to person.
Duloxetine: MedlinePlus Drug Information
A small number of children, teenagers, and young adults (up to 24 years of age) who took antidepressants (”mood elevators”) such as duloxetine during clinical studies became suicidal (thinking about harming or killing oneself or planning or trying to do so). Children, teenagers, and young adults who take antidepressants to treat depression or other mental illnesses may be more likely to become suicidal than children, teenagers, and young adults who do not take antidepressants to treat these conditions. However, experts are not sure about how great this risk is and how much it should be considered in deciding whether a child or teenager should take an antidepressant. Children younger than 18 years of age should not normally take duloxetine, but in some cases, a doctor may decide that duloxetine is the best medication to treat a child’s condition.
You should know that your mental health may change in unexpected ways when you take duloxetine or other antidepressants even if you are an adult over 24 years of age. These changes may occur even if you do not have a mental illness and you are taking duloxetine to treat a different type of condition. You may become suicidal, especially at the beginning of your treatment and any time that your dose is increased or decreased. You, your family, or caregiver should call your doctor right away if you experience any of the following symptoms: new or worsening depression; thinking about harming or killing yourself, or planning or trying to do so; extreme worry; agitation; panic attacks; difficulty falling asleep or staying asleep; aggressive or hostile behavior; irritability; acting without thinking; severe restlessness; frenzied abnormal excitement; or any other unusual changes in behavior. Be sure that your family or caregiver checks on you daily and knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
Your healthcare provider will want to see you often while you are taking duloxetine, especially at the beginning of your treatment. Be sure to keep all appointments for office visits with your doctor.
The doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with duloxetine. Read the information carefully and ask your doctor or pharmacist if you have any questions. You also can obtain the Medication Guide from the FDA website: http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm.
No matter your age, before you take an antidepressant, you, your parent, or your caregiver should talk to your doctor about the risks and benefits of treating your condition with an antidepressant or with other treatments. You should also talk about the risks and benefits of not treating your condition. You should know that having depression or another mental illness greatly increases the risk that you will become suicidal. This risk is higher if you or anyone in your family has or has ever had bipolar disorder (mood that changes from depressed to abnormally excited) or mania (frenzied, abnormally excited mood), depression, or has thought about or attempted suicide. Talk to your doctor about your condition, symptoms, and personal and family medical history. You and your doctor will decide what type of treatment is right for you.
Duloxetine (Cymbalta) for major depressive disorder
Duloxetine causes a similar range of adverse effects to those seen with venlafaxine or the SSRIs. Nausea is the most common adverse effect, and may cause some people to stop treatment. Antidepressants are associated with increased suicidality in children, adolescents and young adults, and duloxetine is unlikely to be an exception. Duloxetine may exacerbate existing liver disease, including alcohol-related liver damage. As with SSRIs, prescribers should guard against serotonin toxicity (also known as serotonin syndrome) caused by co-prescribing with other serotonergic drugs.
Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the ‘Blue Card’ distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.
Ask about suicidal thoughts and assess risk
Assessing depressive symptoms should include asking if the patient has had suicidal thoughts.6 The initial period of antidepressant treatment is recognised as a risk period for suicide attempts.6 For further information about risk assessment refer to NPS Prescribing Practice Review 27: Managing Depression.
Duloxetine should not be used in children and adolescents aged < 18 years
Duloxetine is not registered for use by people aged < 18 years, and there are no clinical trials in this age group.4Antidepressants have an uncertain balance of benefits and harms for children and adolescents with major depressive disorder: see the Adverse Drug Reactions Advisory Committee (ADRAC) advice about use of SSRI antidepressants in children and adolescents and the NPS RADAR review Selective serotonin re-uptake inhibitors in child and adolescent depression.
A comprehensive analysis of clinical trials by the US Food and Drug Administration found that antidepressants increased the risk of suicidal thinking and behaviour in children, adolescents and young adults (up to age 24). There were no completed suicides among those < 18 years, and too few among adults to draw a conclusion.16
Nausea is common when starting duloxetine
In placebo-controlled trials, 20% of participants receiving duloxetine experienced nausea4 and about 1% discontinued because of it.17 The nausea began within a few days of starting the drug and persisted for a week on average, and was mostly mild or moderate in intensity.17 Other common or very common adverse effects of duloxetine include headache, dry mouth, constipation, diarrhoea, decreased appetite, increased sweating, dizziness, fatigue, somnolence and insomnia.4
Venlafaxine or escitalopram may be better tolerated than duloxetine at the recommended starting doses
In clinical trials, duloxetine 60 mg daily caused more discontinuations due to adverse effects than either venlafaxine 150 mg daily or escitalopram 10–20 mg daily.13–15 In a pooled analysis, 12% of participants assigned to duloxetine 60 mg daily had discontinued because of adverse effects, compared with 6% of participants assigned to venlafaxine 150 mg daily, after 6 weeks of treatment.13
Duloxetine 60 mg daily caused more insomnia and constipation than escitalopram 10–20 mg daily after 8 weeks of treatment.14,15 It also caused more nausea and dizziness than venlafaxine 150 mg daily after 6 weeks of treatment.13 Starting with a lower dose of duloxetine (30 mg daily) or taking duloxetine with food may reduce nausea.
Duloxetine is contraindicated for people with hepatic impairment and should not be taken by heavy drinkers
Plasma clearance of duloxetine is slowed considerably in people with hepatic impairment. In addition, duloxetine may aggravate pre-existing liver disease.4 Postmarketing reports have described isolated cases of liver failure, including fatalities, which were possibly related to duloxetine.4,18 Most cases were in people with past or current risk factors for liver injury, including alcohol abuse.4 In trials for any indication, alanine aminotransferase (ALT) elevations to > 3 times the upper limit of normal occurred in 1% of people who took duloxetine, compared with 0.2% of placebo-treated individuals.
Evaluate the patient’s level of alcohol consumption when considering duloxetine and avoid prescribing it for heavy drinkers.
Duloxetine should not be used together with strong inhibitors of CYP1A2
Strong inhibitors of CYP1A2 (such as ciprofloxacin) may increase the plasma concentration of duloxetine by preventing its metabolism.4
Duloxetine is itself a moderate inhibitor of CYP2D6 and therefore may interact with drugs that are extensively metabolised by CYP2D6.4 This may lead to clinically significant increases in plasma levels of CYP2D6 substrates that have a narrow therapeutic index (such as metoprolol, perhexiline, phenothiazines, or flecainide).4,19,20Similarly, duloxetine has the potential to reduce the analgesic effect of codeine by preventing its activation by CYP2D6.21
Avoid co-prescribing duloxetine with other drugs that can increase serotonin levels
Duloxetine may interact with other serotonergic drugs to cause serotonin toxicity (also known as serotonin syndrome). These drugs include SSRIs, venlafaxine, tricyclic antidepressants, monoamine oxidase inhibitor (MAOI) antidepressants (including moclobemide), triptans, tramadol, pethidine, fentanyl, St John’s wort and the illicit drugs MDMA (‘ecstasy’), cocaine and LSD.4,22,23 Serotonin toxicity can range from mild to life threatening.23 The risk of toxicity and drug interactions from antidepressant combinations outweighs the marginal evidence of added efficacy in almost all cases.24
Duloxetine: Uses, Interactions, Mechanism of Action
1) Management of Major Depressive Disorder.Label
2) Management of Generalized Anxiety Disorder.Label
3) Management of diabetic peripheral neuropathy.Label
4) Management of fibromyalgia.Label
5) Management of chronic musculoskeletal pain.Label
6) Management of osteoarthritis of the knee in adults.17
7) Management of chronic lower back pain in adults.17
8) Management of stress urinary incontinence in adult women.18
Off-label uses include:
1) Management of chemotherapy-induced peripheral neuropathy.8
2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete.19
Reduce drug development failure rates
Build, train, & validate machine-learning modelswith evidence-based and structured datasets.
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Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf’s nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter.9,10 This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores.11 It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg.
Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain.10,12 This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys.13
While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained.14
Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling.Label,16
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.14 Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors.
Action on the external urinary sphincter is mediated via duloxetine’s CNS effects. Increased serotonin and norepinephrine concentrations in Onuf’s nucleus leads to increased activation of 5-HT2, 5-HT3, and α1 adrenergic receptors.9,10 5-HT2 and α1 are both Gq coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP3/PLC) pathway.16 This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT3 functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate.
Also related to duloxetine’s action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2, 5-HT3, α1-adrenergic, and α2-adrenergic receptors.12 5-HT2, 5-HT3, and α1-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT1 and α2 receptors are Gi/Go coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition.12,16 These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli.
The mechanisms involved in duloxetine’s benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect.10 It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed.
Duloxetine’s hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α1 receptors predominates, vasoconstriction results as the Gq coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction.16
Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%.7 The population absorption constant (ka) is 0.168 h-1.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time.Label Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax.7 These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.
Apparent Vd of 1620-1800 L.Label,7 Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma.7
Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein.Label,7
Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor.Label,7 It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance.
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About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites.Label Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite.Label,7 Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit.7
Mean of 12 h with a range of 8-17.Label,7
There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h.7 Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively.
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Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone.Label Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated.
Carcinogenicity & Mutagenicity
Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD).Label No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD).
No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations.
Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD).Label
An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose.Label Breast milk concentrations have been observed to peak 3 hours after administration.
|Interacting Gene/Enzyme||Allele name||Genotype(s)||Defining Change(s)||Type(s)||Description||Details|
|Cytochrome P450 2D6||CYP2D6*3||Not Available||C allele||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*4||Not Available||C allele||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*5||Not Available||Whole-gene deletion||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*6||Not Available||1707delT||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*7||Not Available||2935A>C||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*8||Not Available||1758G>T||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*11||Not Available||883G>C||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*12||Not Available||124G>A||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*13||Not Available||CYP2D7/2D6 hybrid gene structure||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*14A||Not Available||1758G>A||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*15||Not Available||137insT, 137_138insT||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*19||Not Available||2539_2542delAACT||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*20||Not Available||1973_1974insG||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*21||Not Available||2573insC||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*31||Not Available||-1770G>A / -1584C>G … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*36||Not Available||100C>T / -1426C>T … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*38||Not Available||2587_2590delGACT||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*40||Not Available||1863_1864ins(TTT CGC CCC)2||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*42||Not Available||3259_3260insGT||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*44||Not Available||2950G>C||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*47||Not Available||100C>T / -1426C>T … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*51||Not Available||-1584C>G / -1235A>G … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*56||Not Available||3201C>T||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*57||Not Available||100C>T / 310G>T … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*62||Not Available||4044C>T||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*68A||Not Available||-1426C>T / -1235A>G … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*68B||Not Available||Similar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*69||Not Available||2988G>A / -1426C>T … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*92||Not Available||1995delC||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*100||Not Available||-1426C>T / -1235A>G … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 2D6||CYP2D6*101||Not Available||-1426C>T / -1235A>G … show all||Effect Inferred||Poor drug metabolizer.||Details|
|Cytochrome P450 1A2||CYP1A2*6||Not Available||5090C>T||Effect Inferred||Poor drug metabolizer.||Details|
Fluoxetine instructions for use: indications, contraindications, side effects – description of Fluoxetine caps. 10 mg: blisters of 7, 10, 14 or 20 pcs, containers of 7, 10, 14, 20, 28, 30, 40, 50 or 100 pcs. (21151)
With simultaneous use with drugs that have a depressing effect on the central nervous system, with ethanol, a significant increase in the inhibitory effect on the central nervous system is possible, as well as an increase in the likelihood of seizures.
With simultaneous use with MAO inhibitors, furazolidone, procarbazine, tryptophan, the development of serotonin syndrome is possible (confusion, hypomania, motor restlessness, agitation, convulsions, dysarthria, hypertensive crisis, chills, tremor, nausea, vomiting)., Vomiting.
With the simultaneous use of fluoxetine inhibits the metabolism of tricyclic and tetracyclic antidepressants, trazodone, carbamazepine, diazepam, metoprolol, terfenadine, phenytoin, which leads to an increase in their concentration in the blood serum, an increase in their therapeutic and side effects.
With simultaneous use, it is possible to inhibit the biotransformation of drugs metabolized with the participation of the CYP2D6 isoenzyme.
With simultaneous use with hypoglycemic agents, their effect may be enhanced.
There are reports of increased effects of warfarin when used simultaneously with fluoxetine.
With simultaneous use with haloperidol, fluphenazine, maprotiline, metoclopramide, perphenazine, periciazine, pimozide, risperidone, sulpiride, trifluoperazine, cases of extrapyramidal symptoms and dystonia have been described; with dextromethorphan – a case of the development of hallucinations has been described; with digoxin – a case of an increase in the concentration of digoxin in the blood plasma.
With simultaneous use with lithium salts, it is possible to increase or decrease the concentration of lithium in the blood plasma.
With simultaneous use, it is possible to increase the concentration of imipramine or desipramine in blood plasma by 2-10 times (it can persist for 3 weeks after discontinuation of fluoxetine).
With simultaneous use with propofol, a case has been described in which spontaneous movements were observed; with phenylpropanolamine – a case was described in which dizziness, weight loss, hyperactivity were observed.
With simultaneous use, it is possible to enhance the effects of flecainide, mexiletine, propafenone, thioridazine, zuclopenthixol.
Poster Air: “Great Medicines” – Archive
“Prozac”. Pill of obedience
Perhaps it is difficult to find a drug that would cause as much discussion and controversy both in the medical environment and in society as Prozac. Its name has become a definite symbol of the era – an era of complex and unbalanced life at the limit of its own capabilities and therefore requiring constant correction of the emotional state, replenishment of mental and physical strength. According to statistics, “Prozac” is now accepted by more than 40 million inhabitants of the planet.
In an attempt to get away from the “grimaces of reality”, from solving any problems, from the instability of material wealth and the complexity of interpersonal relationships, people began to increasingly turn to drug treatment. Therefore, antidepressants have become one of the most popular drugs of the 20th century.
In the early 1970s, employees of the pharmaceutical company Eli Lilly and Co. Brian Molloy and Robert Rathbun worked on the creation of a new antidepressant, devoid of the side effects of the tricyclic antidepressants (TCAs) widely used at that time, in particular, orthostatic hypotension, sedation, cardiotoxicity, etc.
In parallel, another scientist from the same company, a Hong Kong-born pharmacologist David T. Wong, studied the mechanisms of serotonin reuptake by neurons in the brain, wanting to find a substance that would prevent (inhibit) such a seizure. Wong used several molecules synthesized by Molloy, and in 1972 tested a substance that showed a strong inhibitory response to serotonin uptake. In addition to the main function of selective serotonin reuptake inhibitors (SSRIs), it blocked the reuptake of norepinephrine, which made it possible to use it also as a stimulant.This substance turned out to be fluoxetine.
In 1974, fluoxetine, trade name Prozac, was registered by Eli Lilly.
It should be noted that almost from the first days of its existence, it was accompanied by a rather scandalous fame. Soon after the publication of a document titled Prozac (“Fluoxetine”, Lilly L110,140) – the first selective serotonin reuptake inhibitor and antidepressant “, which claimed the primacy of the company in its discovery, a furious scientific controversy ensued.Two years later, the authors were forced to publish an amendment, recognizing that the first drug with similar properties – zimelidine – was developed by the Swedish pharmacologist, who later became the Nobel Prize winner in physiology or medicine, Arvid Karlsson and colleagues.
This drug really heralded a new era, the emergence of a whole class of new medicines that have removed the shameful stigma of an incurable disease from depression and are helping more and more people to cope with the disease.
Prozac was submitted to the FDA in February 1977.But only more than ten years later (!), In December 1987, Eli Lilly received the final permission to sell the drug.
And here a real boom happened: the sales volume of “Prozac” in the USA during the first year reached $ 350 million! They began to enthusiastically call him nothing more than a “pill of happiness.”
The reason was its amazing property: the antidepressant effect (due to the ability to increase the concentration of the “happiness hormone” – serotonin – in the structures of the brain) was combined with the stimulating effect of norepinephrine on the nervous system.It improved mood, reduced tension, anxiety and feelings of fear, eliminated dysphoria, that is, calmed – but at the same time it inspired and gave strength.
Posters with people smiling broadly said “Prozac”. Are you ready to be happy? ”,“ I take Prozac every day! ”,“ Happy thanks to Prozac! ”,“ I can do a lot of things thanks to Prozac! ” and so on. Even Van Gogh, who, as you know, at one time was a patient of a psychiatric clinic, “took part” in the process! His self-portrait bore the inscription: “I wish I had” Prozac “!”
At the same time, the Federation of German Wholesale and Foreign Trade (BGA) in May 1984 rejected Prozac as “completely unsuitable for the treatment of depression.”
In 1985, FDA safety investigator Richard Karit warned, “Unlike the traditional tricyclic antidepressant profile, the side effects of fluoxetine are closer to stimulants than sedatives.” Adverse side effects could lead to “greater clinical impediments to the use of this drug for the treatment of depression,” he said.
Nevertheless, as soon as the drug appeared on the Belgian market in 1986, it instantly became a “hit”.And by 1994, he was already the world leader among antidepressants.
Not surprisingly, after Eli Lilly’s patent for Prozac (fluoxetine) expired in August 2001, generics flooded the market. (By the way, in an effort to stop the decline in sales of the drug, the company began to produce an analogue of Prozac – Sarafem.)
However, no matter how many consumers “voted” with any currency in the world, many scientists warned against euphoria about Prozac in particular and antidepressants generally.Peter Breggin, a member of the American Psychiatric Association, spoke about this back in 1994 in his book Commentary on Prozac.
Published in February 2008, a meta-analysis of data from 35 clinical trials of four new antidepressants, such as fluoxetine (Prozac, paroxetine (Paxil), nefazodone (Serzon), and venlafaxine (Effexor), had surprising results. The researchers concluded that the benefits of the popular drugs in patients with depression, both moderate and severe, were not superior to those of a placebo (an inactive substance).Benefit was noted only in a small group with an extremely severe form of the disease.
Articles began to appear in the press titled “Making the Prozac Myth!” and so on. And the manufacturers of coffee machines placed the slogan on their products: “Good coffee is cheaper than Prozac!”
In the next article, the meta-analysis authors noted that “unfortunately, the media often portrays our research results in the form of headlines such as ‘antidepressants don’t work’ and the like, which fundamentally distorts the more subtle structural conclusions of our report.”
Nevertheless, based on the results of this analysis, as well as a review of 42 clinical trials of six antidepressants (including four mentioned earlier), their leader, the famous American psychologist Irving Kirsch, published the book “The Emperor’s New Medicines: Breaking the Myth of Antidepressants”, where reiterated that the difference between drugs and placebo “while statistically significant, clinically meaningless.”
And although the book caused a wide resonance and was discussed both in scientific journals and in popular media, no one refused antidepressants.
According to statistics, “Prozac” is taken by more than 40 million inhabitants of the planet – even despite the fact that drugs in this group have a number of side effects and, according to doctors, can increase the risk of suicide, especially in adolescents.
At one time, the United States stirred up cases of suicide and other types of inappropriate behavior while taking fluoxetine (one of the striking examples was the “exit from the window” of Mike Hutchence, lead singer of the rock band INXS). Numerous publications in the media have been devoted to this; more than 70 lawsuits have been filed against Eli Lilly.
Some scientists have associated the occurrence of suicidal moods with such a side effect arising from taking the drug, such as akathisia.
One example of this was the story of Vice President Sales Tim Vitzak. When the constant stress at his new job began to cause him bouts of inexplicable fear, he, on the advice of a doctor, began to take the analogue of Prozac – Zoloft. As a result, along with an improvement in his mood, he developed symptoms of akathisia, which was also accompanied by intense itching.The torment was so strong that, according to his wife, death seemed to the young man the best way out.
It turned out that the ability of “Prozac” to provoke suicide was discovered during clinical trials of fluoxetine. However, Eli Lilly hid this information for a long time and attributed suicide cases to an overdose or a manifestation of depression.
However, any of the other side effects can push you to “step into the abyss.” For example, constant anxiety and irritability (especially at the beginning of therapy and when the dose is increased), insomnia, or, conversely, drowsiness, headache, sexual dysfunction, nausea, and much more.
Sometimes this decision can be influenced by the stimulatory property of the drug, which was originally considered a good.
“Did you know that depressed people most often commit suicide when Prozac starts to work and they are already on the road to recovery? In the midst of depression, you are completely lethargic, and you are reluctant to even cut your veins. You walk or lie as if in concrete setting. But when Prozac starts to work, you have enough strength to get a razor and go to the bathroom.Therefore, those who are at the very bottom of depression should take Prozac in the clinic, and it is safest if they are still tied with belts to the bed. This is to prevent them from going to the bathroom alone. However, they are quite capable of deceiving the attendants’ vigilance and sneaking onto the roof of the clinic building … ”
The reaction to an antidepressant of a fragile psyche turned out to be especially difficult. When in the United States the drug began to be prescribed to children (as so-called “obedience pills”) and sold freely in pharmacies, child crime rose sharply in the country.The teenagers shot their teachers, classmates and then committed suicide. The New York Times found out that all these teenagers were “sitting” on the “Prozac”.
Statistical analyzes subsequently carried out by two independent FDA expert groups based on the results of 295 trials of 11 antidepressants showed that the use of fluoxetine contributed to the manifestation of aggression and doubled the risk of suicide in children and adolescents, while in adults this risk was reduced by about 30% …
As a result, the FDA has mandated all antidepressant manufacturers to place a black box warning on their products (the so-called “black mark”) that the drug may increase the risk of suicide in people under 25.
At the same time, a study was published that indicated the connection between the intake of fluoxetine and similar drugs by pregnant and lactating women with psychological disorders in newborns.
In addition, physicians emphasized the importance of long-term treatment due to the peculiarities of the half-life of fluoxetine from the body (1-3 days after a single application and 4-6 days after reaching the equilibrium concentration).Therefore, the maximum clinical effect of the drug may appear several weeks after the start of its administration, but it can persist for a long time after discontinuation.
Many patients “skipped” from therapy, not waiting for improvement, many in an effort to quickly feel the improvement increased the dose, which is why the likelihood of side effects increased dramatically.
And nevertheless, the army of Prozac fans is not only not decreasing, but growing from year to year.This is due to the fact that depression is becoming an increasingly widespread phenomenon: according to the World Health Organization, it is observed in at least 350 million people. This disease is one of the main causes of disability. The American Centers for Disease Control and Prevention estimates that 9% of the US population suffers from depression.
The number of those taking psychotropic pills in America has doubled over the past ten years to 27 million. Among women from 40 to 50 years old, one in four regularly use antidepressants.And Prozac, which last year celebrated its 25th anniversary of entering the market, is still considered one of the best and is practically not inferior to the drugs of the new generation. Suffice it to say that the US Federal Aviation Administration (FAA) allows pilots to carry this drug on board.
Medical indications for the use of fluoxetine / “Prozac” are, according to the annotation, depression, bulimia nervosa, obsessive-compulsive disorders (that is, obsessive thoughts and actions).
Fluoxetine is also approved for the treatment of post-traumatic stress disorder, panic disorder, dysmorphobia, and dysphoric disorder. Can be used to treat obesity, alcohol dependence, etc.
Interestingly: In 2012, researchers at the University of California, Los Angeles, discovered that fluoxetine and various other SSRIs (selective serotonin reuptake inhibitors) can be used in therapy against enteroviruses such as polio.This discovery was called a “major breakthrough” by the American Society for Microbiology, as there is currently no cure for these diseases.
Some say about the miraculous ability of the drug to make the timid confident, impressionable – more persistent, turn pessimists into optimists. Others doubt not only the properties of the drug, but also the safety of its use, however, as well as antidepressants in general. Still others talk about practically drug addiction. Fourth – about the incorrectness of avoiding reality with the help of “pills of happiness.”Unfortunately, the comments of doctors are extremely rare here, but advanced bloggers always advise to be treated only under the supervision of a doctor.
There is a solid list of films, songs, books where this medicine is mentioned in one way or another. Many of the names do not tell us anything (except perhaps the TV series “House” and the film “The Nation of Prozac”), but one of the quotes seemed remarkable:
“He reads Balzac and drinks in one gulp” Prozac “,
It’s like a hand help, bringing amazing calmness. “
It is probably this search for a magic remedy for all problems that makes antidepressants cult drugs. And continuing to reflect on the “face of the era”, you realize: if before the heroes were people of action, now they are reflections and imbalances, doubts and anguish, anxieties and phobias. If earlier we counted on a real helping hand, now it becomes a pill. We are alone both online and in a crowd. Perhaps that is why, according to the results of a poll conducted in the United States, the emergence of “Prozac” became one of the most significant events of the twentieth century?
Fluoxetine (Prozac) | LifeBio.wiki
Fluoxetine (also known under the trade names Prozac, Sarafem, Fontex, etc.) is an antidepressant in the class of selective serotonin reuptake inhibitors (SSRIs). Fluoxetine was first registered in 1974 by scientists at Eli Lilly and Company. In February 1977, the drug was submitted to the US FDA, and in December 1987, Eli Lilly received final approval to market the drug. In August 2001, the patent for Fluoxetine expired.Fluoxetine is approved for the treatment of major depressive disorder (including childhood depression), obsessive-compulsive disorder (in both adults and children), bulimia nervosa, panic disorder, and dysphoric disorder. In addition, Fluoxetine is used to treat trichotillomania when CBT results are not satisfactory. In combination with olanzapine, it is marketed under the name Symbyax.
Despite the availability of new drugs, the popularity of Fluoxetine has not diminished.In 2010, more than 24.4 million generic prescriptions for Fluoxetine were issued in the United States alone. Fluoxetine is the third most prescribed antidepressant after Sertraline (SSRI; became generic in 2006) and Citalopram (SSRI; became generic in 2003). In 2011, there were 6 million prescriptions for Fluoxetine in the UK.
Pharmacological group: Antidepressants
Pharmacological action: Antidepressant, propylamine derivative.The mechanism of action is associated with the selective blockade of the neuronal reuptake of serotonin in the central nervous system. Fluoxetine is a weak antagonist of choline, adrenergic and histamine receptors. Unlike most antidepressants, fluoxetine does not seem to cause a decrease in the functional activity of postsynaptic β-adrenergic receptors. Improves mood, reduces feelings of fear and tension, eliminates dysphoria. Does not cause sedation. When taken in medium therapeutic doses, it practically does not affect the functions of the cardiovascular and other systems.
Systematic (IUPAC) name: (RS) -N-methyl-3-phenyl-3- [4 – (trifluoromethyl) phenoxy] propan-1-amine
Trade names: Prozac, among others
Bioavailability: 72 % (peak – after 6-8 hours)
Protein binding: 94.5%
Half-life: 1-3 days (fast), 4-6 days (slow)
Excretion: renal (80%), fecal (15%)
Formula: C 17 H 18 F 3 NO
Mol. mass: 309.33 g • mol-1
Melting point: 179-182 ° C (354-360 ° F)
Boiling point: 395 ° C (743 ° F)
Solubility in water: 14 mg / ml (20 ° C)
Selective serotonin reuptake inhibitor (SSRI), antidepressant.The chemical structure is not similar to classical antidepressants (tricyclic, tetracyclic). Does not show affinity for adrenergic receptors a1, a2 i β, serotonergic, muscarinic, histamine h2, dopaminergic receptors and GABA. After oral administration, it is well absorbed; food intake does not affect the bioavailability of the drug; tmax is 6-8 hours, steady state is achieved after several weeks of use. Binds to plasma proteins by about 95%. In the liver, it is demethylated with the participation of the isoenzyme CYP2D6, and one of the active metabolites is norfluoxetine.The t1 / 2 of fluoxetine is about 4-6 days and norfluoxetine is about 4-16 days. Detectable plasma concentrations are found several weeks after stopping the drug. It is excreted in the form of metabolites – 60% in the urine, 16% in the feces.
Depressive disorders in adults. Depression of varying severity in children and adolescents over the age of 8 years in cases where psychotherapy does not bring the expected effect. Obsessive-compulsive disorder.Bulimia.
Hypersensitivity to any component of the drug, parallel use of MAO inhibitors. Fluoxetine can be started 14 days after stopping the irreversible MAO inhibitor and at least 24 hours after stopping the reversible MAO inhibitor (eg, moclobemide). MAO inhibitor therapy can be started no earlier than 5 weeks after stopping the use of fluoxetine (if fluoxetine has been used for a long time and / or in large doses, consideration should be given to the need to observe a longer interval).Use with extreme caution in patients with pharmacologically controlled epilepsy, as well as with a history of seizures; should not be used in patients with refractory epilepsy. The drug should be discontinued if seizures develop. Use with caution in patients with a history of mania or hypomania; if the manic phase develops, the drug should be discontinued. In patients with diabetes mellitus, it may be necessary to adjust the dose of antidiabetic drugs.During the course of therapy (especially during the first week), the condition of patients suffering from depression should be carefully monitored for worsening symptoms of depression and the appearance of suicidal thoughts and / or suicide attempts. Due to the possibility of developing abnormal skin hemorrhages, it should be used with caution in patients taking SSRIs, especially in the case of concurrent use of oral anticoagulants, drugs that affect platelet function, and in persons with a history of bleeding disorders.During the first weeks of taking the drug, psychomotor agitation may develop (increasing the dose in this case can be harmful). Care must be taken when using electroconvulsive therapy – there is information about the development of prolonged epileptic seizures against its background. There have been cases of hyponatremia, usually in the elderly or in people taking diuretics. Due to the lack of sufficient clinical data, it should be used with caution in patients with concomitant cardiovascular diseases.Abrupt discontinuation of the drug may lead to the development of a withdrawal syndrome; it is recommended to reduce the dose gradually. Preparations containing lactose should not be prescribed to patients with congenital galactose intolerance, primary lactase deficiency or glucose-galactose malabsorption syndrome.
When considering the need to use a drug that interacts with fluoxetine, the long elimination period of fluoxetine and its pharmacologically active metabolite from the body should always be taken into account.Should not be used in combination with MAO-A inhibitors due to the risk of developing serotonin syndrome. During therapy in combination with an MAO-B inhibitor (for example, with selegiline), or serotonergic drugs (for example, with tramadol, triptans), care must be taken due to the possibility of developing serotonin syndrome. Lithium salts and tryptophan can enhance the effect of SSRI drugs. With the parallel use of drugs that affect the central nervous system, it is possible to change the concentration in the blood of drugs such as: carbamazepine, haloperidol, clozapine, diazepam, phenytoin, alprazolam, imipramine, desipramine; care should be taken to consider changing the dosage regimen and to observe the patient for the development of side effects.In the case of simultaneous use or use within 5 weeks after stopping the intake of fluoxetine, drugs metabolized by CYP2D6 with a narrow therapeutic index (for example, encainide, flecainide, vinblastine, carbamazepine, tricyclic antidepressants), the minimum effective dose should be used. Preparations containing the herb St. John’s wort can lead to worse side effects. There is a possibility of interaction of fluoxetine with drugs that strongly bind to plasma proteins; the concentration of digoxin administered in parallel should be monitored.In patients taking anticoagulants, it is necessary to monitor the coagulation parameters. Therapy in combination with ritonavir, saquinavir, or efavirenz may be associated with an increased risk of serotonin syndrome. No drug interactions were found between fluoxetine and chlorothiazide, secobarbital and tolbutamide. There is no information about cases of drug interaction with alcohol, but it is not recommended to use it while taking fluoxetine.
Fluoxetine and norfluoxetine inhibit many isoenzymes of the cytochrome P450 system, which makes drug metabolism possible.Both substances are potent inhibitors of CYP2D6 (the main enzyme responsible for their metabolism) and weak to moderate inhibitors of CYP1A2, CYP2B6, CYP2C9 / 2C19, and CYP3A4. In addition, they inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism. This widespread effect on the drug’s metabolic pathway in the body provides a wide potential for interactions with many commonly used drugs.Concomitant use of Fluoxetine with triptans, Tramadol, or other serotonergic drugs can lead to a rare but potentially life-threatening adverse reaction called serotonin syndrome.
Fluoxetine has been shown to have antimicrobial activity against several groups of microorganisms, mainly against gram-positive microorganisms. The drug also demonstrates synergistic action in combination with certain antibiotics against a number of bacteria.
Often: headache, dizziness, anxiety, drowsiness or insomnia, abnormal dreams, asthenia, fatigue, agitation, euphoria, nausea, vomiting, indigestion, diarrhea, dry mouth, taste disturbances, rash, itching, excessive sweating, blurred vision, frequent urination, urinary retention, sexual dysfunction, priapism, galactorrhea. Not very often: difficulty concentrating and thinking, mania, panic attacks, confusion, self-perception disorder, tremor, ataxia, tics, convulsions, psychomotor agitation, yawning, dilated blood vessels, orthostatic hypotension, pharyngitis, shortness of breath, urticaria, alopecia, hypersensitivity reactions, chills, increased sensitivity to light.Rarely: bleeding, hematomas, hyponatremia, abnormal secretion of antidiuretic hormone, symptoms of pulmonary disease (including inflammation with various histopathology and / or fibrosis), hepatic dysfunction, idiosyncratic hepatitis. Very rare: hallucinations, serotonin syndrome, arthralgia, myalgia, toxic epidermal necrolysis. After stopping taking fluoxetine – withdrawal syndrome (weakness, paresthesia, headache, anxiety, nausea). In the first weeks of treatment, the risk of suicide increases.Symptomatic and supportive therapy is recommended; there is no specific antidote.
Sexual dysfunction is a common side effect of SSRIs. In particular, side effects often include difficulty in arousal, erectile dysfunction, lack of interest in sex, and anorgasmia (inability to reach orgasm). Other possible side effects include genital anesthesia, loss or decreased response to sexual stimuli, and ejaculatory anhedonia.Although these sexual side effects are usually reversible, they can last months, years, or a lifetime after the drug is stopped completely. This phenomenon is known as “post-SSRI sexual dysfunction.”
According to Eli Lilly, the manufacturer of Prozac fluoxetine, the drug is contraindicated in people taking monoamine oxidase inhibitors, Pimozide (Orap) or Thioridazine (Mellaril). The recommendations for the use of the drug indicate that the treatment of patients with hepatic insufficiency “should be approached with caution.”In these patients, fluoxetine and its metabolite norfluoxetine are excreted approximately twice as fast from the body, which leads to a proportional increase in the effect of the drug. The use of ibuprofen in combination with fluoxetine can cause severe intestinal bleeding.
Among the common side effects associated with Fluoxetine and listed in the annotation to the drug, the largest difference with placebo is: nausea (22% versus 9% in the placebo group), insomnia (19% versus 10% in the placebo group), drowsiness (12% versus 5% in the placebo group), anorexia (10% versus 3% in the placebo group), anxiety (12% versus 6% in the placebo group), nervousness (13% versus 8% in the placebo group), asthenia (11% versus 6% in the placebo group) and tremors (9% versus 2% in the placebo group).Side effects most often leading to interruption of treatment are anxiety, insomnia and nervousness (1–2% each), and in pediatric trials, mania (2%).
Fluoxetine has sexual side effects in common with other SSRIs, including anorgasmia and decreased libido.
In addition, 7% of patients in clinical trials experienced rash or urticaria, sometimes severe, and a third of these cases experienced discontinuation of treatment. In post-marketing reports, there are several cases of complications that develop in patients with rash.Symptoms included vasculitis and a lupus-like syndrome. In addition, in some cases, these side effects have been fatal.
Akathisia, that is, internal tension, restlessness and inability to stand still, often accompanied by “constant aimless movement of the feet and legs, and severe anxiety”, is a common side effect of taking Fluoxetine. Akathisia usually begins to appear after starting treatment or increasing the dose and disappears after stopping fluoxetine, reducing the dose, or after treatment with Propranolol.There are reports of a direct link between akathisia and suicidal attempts, with patients feeling better after stopping fluoxetine; and with repeated administration of Fluoxetine, they experienced repeated development of severe akathisia. These patients reported that “the development of akathisia provoked suicidal thoughts in them and their previous suicide attempts were associated with this.” The experts note that due to the association of akathisia with suicide and the pain it creates for the patient, “it is vital to raise awareness among staff and patients of the symptoms of the disease.”Less commonly, fluoxetine is associated with movement disorders, acute dystonia, and tardive dyskinesia.
The use of Fluoxetine during pregnancy is also associated with an increase in the number of newborns with poor compensatory-adaptive response. Since Fluoxetine is excreted in mother’s milk, the use of the drug during lactation is not recommended. When studying the effects of Fluoxetine on newborn mice, it was shown that early postnatal administration of the drug in adult mice further develops depression and anxious behavior similar to induced depression, for the treatment of which Fluoxetine is used.The American Pediatric Association classifies fluoxetine as a drug with unknown effects on a nursing infant and may be of concern.
Pregnancy and lactation
Caution should be exercised when used during pregnancy, especially in the third trimester and before childbirth due to the serotonergic effect of the drug or the possibility of withdrawal symptoms in newborns (irritability, tremors, hypotension, constant crying, difficulty sucking, poor sleep).Fluoxetine passes into breast milk; consideration should be given to stopping breastfeeding; if breastfeeding continues, the lowest effective dose should be used.
Method of administration and dosage
Inside, regardless of the meal. Adults. Depressive Disorders. 20 mg daily in the morning. Clinical improvement is achieved after 1-4 weeks of taking the drug. If after 3-4 weeks there is no improvement, consideration should be given to increasing the dose to max.60 mg per day. After the symptoms disappear, treatment must be continued for at least 6 months. Obsessive-compulsive disorder. The initial dose is 20 mg per day in the morning; if improvement does not occur after several weeks of therapy, the dose should be increased to max. 60 mg per day. Bulimia. 60 mg per day. Doses> 20 mg per day are administered in 2 divided doses (morning and afternoon). The maximum dose for difficult-to-treat syndromes is 80 mg per day. Episodes of severe depression with moderate or severe course in children and adolescents over the age of 8, if psychotherapy does not work.The starting dose is 10 mg per day. After 1-2 weeks, the dose can be increased to 20 mg per day. The dose is selected individually; the minimum effective dose should be used. Treatment must be carried out in conjunction with psychotherapy. In elderly patients, the maximum dose is 60 mg per day. In patients with impaired liver function or taking other drugs that may interact with fluoxetine, the dose should be decreased or the intervals between doses increased. The drug should be discontinued gradually (over a period of at least 1-2 weeks.).
Fluoxetine does not affect intellectual or psychomotor functions, but, like other psychotropic drugs, it can cause impaired concentration both in connection with the disease itself and in connection with taking the drug. For this reason, patients should be informed that the drug adversely affects the ability to drive vehicles and maintain mechanical equipment.
Fluoxetine is often used to treat depression, obsessive-compulsive disorder, post-traumatic stress disorder, bulimia nervosa, panic disorder, body dysmorphobia (a mental disorder characterized by the patient’s belief that he or she has some kind of physical disability that doesn’t exist in reality, or a sharp overestimation of one) , dysphoric disorder and trichotillomania.Caution should be exercised when taking any SSRI for bipolar disorder, as this may increase the likelihood of mania; however, for bipolar disorder, Fluoxetine can be used in conjunction with antipsychotics (eg, Quetiapine). The drug has also been used to treat cataplexy, obesity and alcohol dependence, as well as binge eating disorder.
In a six-week, double-blind, controlled trial, Fluoxetine was shown to be effective in treating depression, reducing anxiety and improving sleep.An advantage of fluoxetine over placebo in preventing relapse of depression was demonstrated when patients who initially responded positively to fluoxetine were given it for an additional 38 weeks. Placebo-controlled studies have also demonstrated the effectiveness of Fluoxetine in the treatment of depression in the elderly and in children. However, two meta-analyzes of randomized, placebo-controlled trials suggest that the clinical efficacy of the drug is not very significant in patients with mild to moderate symptoms.Research shows that much of the resistance to SSRIs such as Paroxetine (Paxil) and Citalopram (Celexa) can be attributed to genetic variation in the glycoprotein transporter. Paroxetine and Citalopram, glycoprotein substrates, are actively transported by this protein from the brain. Fluoxetine is not a glycoprotein substrate, and thus, taking Fluoxetine instead of Paroxetine or Citalopram may be beneficial for patients who are resistant to SSRIs.
Fluoxetine was shown to be effective in treating OCD in two adults and one 13-week placebo-controlled pediatric study.An improvement in response was observed with higher doses of Fluoxetine, while an inverse relationship was observed with the treatment of depression. In two controlled studies of patients with panic disorder, fluoxetine has been shown to cause a dramatic, 40-50% reduction in the frequency of panic attacks. Fluoxetine has been shown to cause significant reductions in binge eating and bulimia episodes in three double-blind studies. With long-term treatment for one year in patients who demonstrated an initial response to fluoxetine, it has been shown that the drug has an advantage over placebo in the prevention of bulimic episodes.
In 2012, researchers at the University of California, Los Angeles discovered that fluoxetine and various other SSRIs could act as antiviral drugs in the treatment of enteroviruses such as polio. The American Society for Microbiology called this discovery a “major breakthrough” because there are currently no drugs used against enteroviruses.
Several cases of severe withdrawal symptoms after sudden discontinuation of Fluoxetine have been reported in the literature.However, various studies have shown that side effects when discontinuing Fluoxetine are rare and usually quite mild, especially when compared with Paroxetine, Venlafaxine and Fluvoxamine, which may be due to the relatively long pharmacological half-life of Fluoxetine. One of the recommended strategies for controlling the withdrawal syndrome of other SSRIs, in cases where dose reduction of the original SSRI is ineffective, is to replace the original drug with Fluoxetine.The effectiveness of this strategy is supported by data from double-blind controlled studies. Several studies have not demonstrated that the drug causes any increase in side effects when treatment with Fluoxetine was interrupted for a short time (4-8 days) and then resumed, and this result is not consistent with the slow elimination of the drug from organism.
With interruption of treatment with Sertraline (Zoloft), more side effects were observed, and with interruption of treatment with Paroxetine, significantly more.In a longer 6-week blind discontinuation study, there was a slight increase (32% versus 27%) in the overall incidence of new or worsening existing side effects in the group that stopped taking Fluoxetine compared to the group that continued on treatment. However, patients who discontinued treatment had a significant increase (4.2%) in sleepiness at 2 weeks and an increase in dizziness of 5-7% at 4-6 weeks. This long period of withdrawal symptoms and dizziness persisting until the very end of the study is also consistent with the long half-life of Fluoxetine in the body.According to a 2007 summary report of available data, fluoxetine had the lowest withdrawal rates of any antidepressant drug studied, including Paroxetine and Venlafaxine.
The FDA has now mandated all antidepressant manufacturers to place a black box warning on their products that antidepressants may increase the risk of suicide in people under the age of 25. This warning is based on statistical analyzes conducted by two independent FDA expert groups that have shown a 2-fold increase in the number of suicidal thoughts and related behaviors in children and adolescents, as well as a 1.5-fold increase in suicidal tendencies in individuals with aged 18-24.These rates were slightly lower in the over 24 group, and much lower in the 65 and over group. Donald Klein criticized this analysis, noting that suicidal tendencies, that is, suicidal thoughts and behavior, do not necessarily lead to committing suicide, and that the possibility cannot be denied that antidepressants can prevent the possibility of actual suicide despite an increase in suicidal thoughts.
There is relatively little data on fluoxetine compared to antidepressants in general.The FDA pooled 295 trials of 11 antidepressants to carry out the above analysis of antidepressants. When considered separately, the use of fluoxetine in children caused a 50% increase in the risk of suicide, while in adults this risk was reduced by about 30%. In addition, an analysis by the UK’s Medicines and Healthcare Authority (MHRA) showed a 50% increase in suicidal thoughts and behavior in children and adolescents with fluoxetine compared with placebo.According to the MHRA, in adults, fluoxetine does not change the number of self-harm and statistically significantly reduces the number of suicidal thoughts by 50%.
Psychiatrist David Healy and several active patient groups have reported cases of violent acts committed by individuals taking Fluoxetine or other SSRIs. Taking these drugs can push susceptible individuals to commit violent acts, the report says.
Serial reviews of this type have been criticized because the effects of a disease are often mistaken for treatment effects.Other studies, including randomized clinical trials and observational studies, have shown that fluoxetine and other SSRIs can reduce violence. A randomized clinical trial by the American National Institute of Mental Health found that fluoxetine caused a decrease in domestic violence in alcoholics with a history of such behavior. A second clinical trial at the University of Chicago showed that fluoxetine caused a decrease in aggressive behavior in patients with intermittent aggressive disorder.In a clinical trial, fluoxetine was found to reduce aggressive behavior in patients with borderline personality disorder. These results are indirectly supported by research showing that other SSRIs may reduce the risk of violence and violent behavior. The NBER study, which examined international trends in antidepressant benefits and crime rates in the 1990s, found that an increase in antidepressant prescriptions was associated with a decrease in violent crime.
Fluoxetine has a relatively high bioavailability (72%), and peak plasma concentrations after administration are reached within 6 to 8 hours. It binds well to plasma proteins, mainly albumin.
Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variation in the functioning of this enzyme among humans.Only one metabolite of fluoxetine, norfluoxetine (N-demethylated fluoxetine), is biologically active.
Fluoxetine and its active metabolite, norfluoxetine, are distinguished from other antidepressants by their extremely slow elimination from the body. Over time, fluoxetine and norfluoxetine inhibit their own metabolism, so that the half-life of fluoxetine instead of 1 day begins to be up to 3 days after a single dose, and from 4 to 6 days after long-term use. In addition, after prolonged use, the half-life of norfluoxetine increases (16 days).Thus, during the first few weeks of treatment, the concentration of the drug and its active metabolite in the blood continues to increase. A constant blood concentration is achieved after four weeks of use. In addition, the concentration of fluoxetine and its metabolites in the brain continues to rise for at least the first five weeks of treatment. This means that after applying the current dose, the drug will take effect in at least a month. For example, in one 6-week study, the median time to consistent response was 29 days.In addition, it can take several weeks for the drug to be completely eliminated from the body. During the first week after stopping treatment, the concentration of fluoxetine in the brain decreases by only 50%, the level of norfluoxetine in the blood 4 weeks after stopping treatment is about 80% of the level at the end of the first week of treatment, and 7 weeks after stopping norfluoxetine taking is still can be found in the blood.
The PET study compared the effects of a single dose of Fluoxetine on exclusively heterosexual and exclusively homosexual men who claimed that their past and present sexual behavior, desires and fantasies were directed exclusively to women or men, respectively.The study found that in some areas of the brain, the metabolic response of these two groups proceeded differently. “Both groups, however, show similar broadly lateralized metabolic responses to fluoxetine (versus placebo), with most brain regions in these groups responding in the same way.” These groups “did not differ in behavioral characteristics or blood levels of fluoxetine.”
Fluoxetine is a selective serotonin reuptake inhibitor and inhibits the reuptake of norepinephrine and dopamine to some extent.However, Eli Lilly’s researchers found that a single high dose of Fluoxetine in rats also saw significant increases in norepinephrine and dopamine concentrations in the brain. This effect may be mediated by 5HT2a receptors and, in particular, 5HT2, which are inhibited by higher concentrations of Fluoxetine. Scientists at Eli Lilly have also suggested that exposure to dopamine and norepinephrine receptors may enhance the antidepressant effects of fluoxetine.According to other researchers, the strength of this effect, however, remains unclear. There was no increase in dopamine and norepinephrine levels with fluoxetine at lower, more clinically relevant doses. In addition, in electrophysiological studies it was shown that only when taking large doses of Fluoxetine were changes in the activity of norepinephrinergic neurons in rats. Some authors, however, argue that these data may still be of clinical importance for the treatment of serious illnesses when taking Fluoxetine in doses exceeding therapeutic doses (60-80 mg).Compared to other SSRIs, “Fluoxetine is the least selective,” and exhibits a 10-fold difference in binding capacity between the first and second neural targets (eg, with the pumps of serotonin and norepinephrine, respectively). All values greater than a 10-fold difference result in negligible activation of secondary neural targets.
In addition to its known effects on serotonin, fluoxetine also increases the density of endogenous opioid receptors in the rat brain. It is unclear if the same occurs in humans, but if so, it may explain some of the antidepressant or side effects of Fluoxetine.
Measurements in body fluids
For monitoring during treatment, confirming the diagnosis of poisoning in hospitalized patients, or assisting in a forensic examination, the amount of fluoxetine and norfluoxetine can be quantified in blood, plasma, or serum. Concentrations of Fluoxetine in blood or plasma are typically 50-500 mcg / L in individuals taking the drug as an antidepressant, 900-3000 mcg / L in survivors of acute overdose, and 1000-7000 mcg / L in victims of fatal overdose.Concentrations of norfluoxetine are approximately equal to those of the parent drug during long-term therapy, but can be significantly lower in acute overdose, since it takes at least 1-2 weeks to reach equilibrium of the metabolite.
Mechanism of Action
Fluoxetine acts primarily as a serotonin reuptake inhibitor. Fluoxetine inhibits the reuptake of serotonin, with the result that serotonin, when released, is inhibited for a longer period.Some of the effects of fluoxetine also depend on its weak 5-HT2C receptor antagonism. In addition, fluoxetine acts as a sigma-1 receptor agonist, stronger than citalopram but weaker than fluvoxamine. However, the meaning of this property is not entirely clear.
In 1970, Eli Lilly and Company began work that eventually led to the discovery of Fluoxetine, through a collaboration between Brian Molloy and Robert Rathbun. At the time, the antihistamine diphenhydramine was known to have some antidepressant properties.The compound 3-phenoxy-3-phenylpropylamine, structurally similar to diphenhydramine, was taken as a basis. Molloy synthesized dozens of derivatives of this compound. Testing the physiological effects of these compounds in mice led to the discovery of nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments.
Later, in the hope of finding a derivative that only inhibits serotonin reuptake, another Eli Lilly scientist, David T. Wong, suggested retesting the compounds in vitro for the reuptake of serotonin, norepinephrine and dopamine.This test by Jong-Sir Horng in May 1972 showed that the compound later named Fluoxetine was the most potent and selective serotonin reuptake inhibitor of all compounds tested. In 1974, Wong published the first article on Fluoxetine. A year later, the compound was given the official chemical name “Fluoxetine”, and Eli Lilly and Company launched it under the trade name “Prozac”. In February 1977, Dista Products Company, a division of Eli Lilly and Co, submitted a new request to the US FDA for Fluoxetine.In May 1984, the German Regulatory Agency (BGA) rejected Prozac as “completely unsuitable for the treatment of depression.” In May 1985, the then FDA’s chief safety officer, Dr. Richard Karit, wrote: “Unlike the profile of the traditional tricyclic antidepressant, the side effects of Fluoxetine are closer to stimulants than sedatives.” According to him, “the specific profile of adverse side effects of Fluoxetine may in the future lead to large clinical impediments to the use of this drug for the treatment of depression.”Fluoxetine appeared on the Belgian market in 1986. More than ten years later, in December 1987, the FDA finally approved Fluoxetine, and a month later Eli Lilly began selling Prozac, which had annual sales of $ 350 million in the United States during the year.
Controversy ensued soon after the Lilly researchers published a document titled “Prozac (Fluoxetine, Lilly 110140), the first selective serotonin reuptake inhibitor and antidepressant,” which claimed that fluoxetine was the first selective serotonin reuptake inhibitor (SSRI).Two years later, the authors were forced to publish an amendment, recognizing that the first SSRI called Zimelidine was developed by Arvid Karlsson and colleagues.
Eli Lilly’s US patent for Prozac (Fluoxetine) expired in August 2001, prompting an influx of generic drugs into the market. In an attempt to stem the decline in sales of Fluoxetine by Eli Lilly following the expiration of the patent, Prozac was renamed Sarafem for the treatment of PMS.
A meta-analysis published in February 2008 collected data from 35 clinical trials of four new antidepressants (Fluoxetine, Paroxetine (Paxil), Nefazodone (Serzone), and Venlafaxine (Effexor)).These antidepressants, belonging to three different pharmacological groups, were considered collectively, that is, the authors did not analyze them separately. The authors concluded that “although the difference [between placebos and antidepressants] easily achieves statistical significance,” it does not meet the criteria for clinical significance used by the UK’s National Institute for Health and Clinical Standards, “in all but the most depressed patients.” …Articles titled “Making the Prozac Myth” and “Prozac Doesn’t Help Most Depressive Patients” began to appear in the press, in which the authors concluded from general conclusions about the relative effectiveness of antidepressants and placebo that fluoxetine was ineffective. In the next article, the authors of the meta-analysis noted that “unfortunately, the media often portray the results of our work in the form of headlines such as” antidepressants do not work “and the like, which fundamentally distorts the more subtle structural conclusions of our report.”As of April 2, 2010, Fluoxetine is one of four antidepressants that the FAA (Federal Aviation Administration) allows pilots to carry on board. Three others include Sertraline (Zoloft), Citalopram (Celexa), and Escitalopram (Lexapro).
Floxet (Hungary; Egis Pharmaceuticals Ltd.)
Flunil (India) Intas Biopharmaceuticals
Fluox (New Zealand)
Fluoxetina (Colombia, Brazil)
Fluxen – Fluxen (Ukraine)
Fontex (Denmark, Norway, Sweden)
Foxetin, Eburnate, Alental, Neupax, Sora, Lapsus (Argentina)
Flusetin (Bosnia and Herzegovina)
Biozac, Deprexetin, Fluval, Biflox, Deprexit, Sofluxen, Floxet, Ranflutin – (Bulgaria)
Flunisan, Orthon, Refloksetin, Fluoxetine – (Macedonia)
Lorien (South Africa)
Prozac in Popular Culture
The mention of the drug Prozac is found in many books, films and songs of popular culture.Among them:
• The book “Listening to Prozac”, written in 1993 by psychiatrist Peter D. Kramer.
• Memoir “The Nation of Prozac”, written in 1994 by Elizabeth Werzel, as well as the film of the same name in 2001, starring Christina Ricci as Werzel.
• The 1995 Blur song “Country House” contains the following lines: “He’s reading Balzac and knocking back Prozac / It’s the helping hand that makes you feel wonderfully bland.” / It’s like a helping hand, bringing amazing peace “).• A well-known drug criticism book, Commentary on Prozac, written by psychiatrist Peter Breggin and published in 1994 (ISBN 0312114869).
• Prozac is referenced in the Superman graphic novel The Red Son, where the Botanist uses him to control the mood of the people in Superman’s empire.
• In Alison Bechdel’s Dykes to Watch Out For comic series, Lois takes Prozac in the 1997 book Hot, Trrobbibg Dykes to Watch Out For.
• “Diary of Prozac” 1998, a confessional memoir by Lauren Slater.• “Plato, not Prozac!” is the title of a 1999 book from the self-help series by Lou Marinoff, which suggests using classical philosophy as an alternative to the conventional pro-pharmaceutical approach to psychotherapy.
• The song “1985” by the group “The Bowling For Soup” describes the nervous breakdown / crisis of a middle-aged housewife from the suburbs. It begins with the lines “Debbie just hit the wall / she never had it all / One Prozac a day / husband’s a CPA …” senior accountant … “)
• “Pets on Prozac” is the name of the UK underground house band formed in 2010.• Prosac is one of Tomcraft’s most notable progressive house works. The main text of the song is read from the pharmacological description and indications for the use of the drug.
• Bernard Sumner (musician from New Order and Joy Division) chronicled his experiences with Prozac and his influence on creativity for the BBC documentary The Prozac Diaries.
• Prozac is often mentioned in the popular comedy series “Ellie McBeal”, where in season 3 the character of the same name (played by Calista Flockheart) adopts Prozac at the conviction of his psychiatrist Dr. Shirley Flott (played by Betty White).Flott describes the miraculous benefits of Prozac on an almost Eucharistic scale, telling Ellie that she “won’t find happiness in love or God, happiness is in pills.” Flott also claims that she herself takes Prozac in suppository form. Although Ellie initially starts taking Prozac to combat her hallucinations, she is later discouraged by a friend and colleague, and Ellie ends up flushing the pills down the toilet.
• In the HBO series The Sopranos, gangster Tony Soprano (James Gandolfini) has a tendency to panic attacks.His psychiatrist Dr. Jennifer Melfi (Lorraine Bracco) prescribes Prozac for him.
• Prozac takes place in the movie Love and Other Drugs, starring Jake Gyllenhaal as a Pfizer drug dealer trying to promote Zoloft. He discards most of the Prozac party, which is subsequently picked up by vagrants and the drug, thus spreading throughout the country.
• “ProzaKc Blues” is a song by progressive rock band King Crimson from their 2000 album ConstruKction of Light.• “Prozac +” is the name of an Italian punk band.
Fluoxetine is a fairly common drug on the domestic market, used to treat various depressive conditions, which are accompanied by a feeling of fear and anxiety.