The generic medication fluoxetine (brand name: Prozac) is commonly prescribed to treat depression and other mental health conditions. More than 20 million Prozac prescriptions are written in the US each year. This drug is safe and effective when taken as directed. However, there are certain risks and benefits associated with its use. For example, taking fluoxetine with certain other medications can affect how it works and cause serious side effects. Please continue reading to learn about some of the drug interactions and which medications you should avoid when on fluoxetine.

What is fluoxetine (Prozac)?

Fluoxetine belongs to a group of drugs called selective serotonin reuptake inhibitors (SSRIs). It works by increasing the availability of serotonin in the brain. Serotonin is a natural substance that helps to regulate mood, appetite, and the sleep-wake cycle.

Fluoxetine comes in the form of capsules, delayed-release capsules, tablets, and a liquid. Fluoxetine capsules, tablets, and liquid are taken 1-2 times a day. The dose ranges between 10 to 120 mg per day, depending on the condition being treated.

You should take fluoxetine at the correct dose, exactly as your health care professional prescribes. If you miss a dose, take it as soon as you remember. But if it is almost time for the next dose, skip the missed dose and go back to your regular dosing schedule. Do not take an extra dose to make up for a missed one.

What is fluoxetine used to treat?

Fluoxetine (Prozac) is FDA-approved to treat:

Major depressive disorder (MDD)
Obsessive compulsive disorder (OCD)
Panic disorder and panic attacks
Certain eating disorders, such as bulimia nervosa
Premenstrual dysphoric disorder (PMDD)

It is also prescribed off-label to treat other types of mental illness, such as binge eating disorder, body dysmorphic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder (PTSD).

Fluoxetine monotherapy (fluoxetine alone) is approved to treat depression. However, for treatment-resistant depression or depressive episodes associated with bipolar disorder, fluoxetine is used in combination with olanzapine.

How does fluoxetine interact with other medications?

There are many interactions between fluoxetine and other medications; however, there are two main mechanisms behind these drug interactions. Having an awareness of these mechanisms can help in recognizing the potential drug interactions.

CYP2D6 is short for cytochrome P450 2D6. CYP2D6 is an enzyme mainly found in your liver. The CYP2D6 enzyme plays a major role in metabolizing or breaking down a large number of important medications such as antidepressants, antiarrhythmics, opioid medicine, and seizure treatment.
Why is CYP2D6 important regarding drug interactions with fluoxetine? It is because fluoxetine is a CYP2D6 inhibitor.
As mentioned, CYP2D6 is the natural body enzyme that breaks down antidepressants, opioids, and heart rhythm medications, just to name a few. By inhibiting this enzyme in your liver, fluoxetine interferes with the metabolism process of these medications; in turn, high levels of these medications are accumulated in your bloodstream leading to side effects ranging from unpleasant or bothersome to life-threatening.
Examples of medications that are broken down by the liver enzyme CYP2D6 include:
- Antidepressants such as amitriptyline, nortriptyline, and desipramine;
- Antipsychotics such as pimozide, clozapine, haloperidol, and risperidone;
- Antiarrhythmic drugs such as flecainide;
- Treatment of tardive dyskinesia such as valbenazine;
On the other hand, some medications require the liver enzyme CYP2D6 to be transformed into their active forms. By inhibiting CYP2D6, fluoxetine decreases the efficacy of these medications. Examples of drugs requiring CYP2D6 to become active and produce the intended effects are tramadol, codeine, and tamoxifen.
Keep in mind that the function of the CYP2D6 enzyme varies greatly among people due to genetics. As a result, the levels of adverse effects and toxicity differ among individuals.

Other mechanisms that can lead to drug interactions with fluoxetine

Serotonergic drugs

Serotonergic drugs are any medications that can raise serotonin levels. Combining any serotonergic drug with fluoxetine can cause high levels of serotonin in the central nervous system (CNS). Though rare, serotonin syndrome can happen. Serotonin syndrome can be life-threatening if left untreated.

Symptoms of serotonin syndrome can be mild to severe. Mild symptoms present with tremors, nausea, vomiting, diarrhea, dilated pupils, and increased sweating; severe symptoms include delirium, rapid heart rate, muscle rigidity, fever, high blood pressure, seizures, and fainting. You should contact your doctor and seek medical care immediately if you experience any of those symptoms, even if you only have mild symptoms.

The following medications can cause dangerously high levels of serotonin if taken together with fluoxetine (Prozac).

Monoamine oxidase inhibitors (MAOIs)

MAOIs are used to treat depression and Parkinson’s Disease. In addition to many side effects, this older drug class is not prescribed often anymore due to the strict dietary restrictions patients have to comply with in order to avoid undesirable adverse effects.

The FDA approved these MAOIs to treat depression: isocarboxazid (Marplan), selegiline (Emsam, Zelapar), phenelzine (Nardil), and tranylcypromine (Parnate).

You should never take fluoxetine and MAOI together.

Switching from an MAOI to Prozac (fluoxetine): If you are taking an MAOI and your doctor is switching you to Prozac (fluoxetine), a wash-out period of at least 14 days is mandatory, meaning you should wait at least 14 days after the last dose of MAOI before taking fluoxetine.
Switching from Prozac to an MAOI: a 5-week wash-out period is necessary, meaning that you need to wait at least 5 weeks after the last dose of Prozac (fluoxetine) before you start taking an MAOI.

Other drugs that can increase serotonin levels:

Blood thinners

Fluoxetine can increase your risk of bleeding; therefore, combining Prozac (fluoxetine) with any medication with blood-thinning effects can further raise this risk. The following examples are some of the commonly prescribed blood thinners:

Medications that cause heart rhythm problems

Prozac can cause heart rhythm problems because it can prolong the QT interval. QT prolongation or long QT syndrome is an abnormality of the heart’s electrical system that can be seen on an electrocardiogram (EKG or ECG). Long QT syndrome can be inherited or triggered by certain health conditions such as heart disease, stroke, hypothyroidism, and electrolyte imbalances. Combining Prozac (fluoxetine) with other medications that can cause QT prolongation can lead to abnormal heart rhythms. Though rare, some cases of QT prolongation can lead to a life-threatening arrhythmia called torsade de pointes. Examples of medications that can increase QT prolongation:

Antipsychotics such as ziprasidone (Geodo) and thioridazine
Antiarrhythmic medication such as amiodarone
Antimicrobials such as ciprofloxacin (Cipro) and fluconazole (Diflucan)
Opioid pain medicine such as methadone

What other medications interact with fluoxetine?

The following medications can have drug interactions with fluoxetine (Prozac).

Benzodiazepines such as alprazolam (Xanax) and diazepam (Valium)
Antiarrhythmic agents such as amiodarone (Pacerone, Nexterone), flecainide, procainamide, quinidine (in Nuedexta), and sotalol (Betapace, Sorine)
Heart failure and antiarrhythmic medications such as digoxin (Lanoxin)
Amphetamines such as dextroamphetamine (Dexedrine, Dextrostat, in Adderall), amphetamine (in Adderall), and methamphetamine (Desoxyn)
Certain antibiotics such as gatifloxacin, erythromycin (Eryc, E.E.S, Ery-tab), and moxifloxacin (Avelox)
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil) and naproxen (Naprosyn, Aleve)
Anticoagulants or blood thinners such as warfarin (Coumadin, Jantoven)
Antiplatelet medications such as clopidogrel (Plavix)
Diuretics or water pills
Tricyclic antidepressants such as amoxapine, amitriptyline, clomipramine (Anafranil), doxepin, desipramine (Norpramin), imipramine (Tofranil), protriptyline, nortriptyline (Pamelor), and trimipramine
Other selective serotonin-reuptake inhibitors such as sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and paroxetine (Paxil)
Serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor), desvenlafaxine (Pristiq, Khedezla), levomilnacipran (Fetzima), and duloxetine (Cymbalta)
Anti-anxiety medications such as buspirone
Medications used to prevent nausea and vomiting caused by chemotherapy, such as dolasetron (Anzemet)
Opioid pain medications such as fentanyl (Lazanda, Fentora, Subsys, others), tramadol (Qdolo, Ultram, Conzip, in Ultracet), and methadone (Methadose)
Diabetes medications, including insulin and oral drugs
Medications used to treat mental illness such as clozapine (Clozaril, Versacloz), haloperidol (Haldol), chlorpromazine, droperidol (Inapsine), ziprasidone (Geodon), and iloperidone (Fanapt)
Antimanic agents such as lithium (Lithobid)
Medications for Parkinson's disease
Triptan medications prescribed for migraine headaches, such as eletriptan (Relpax), almotriptan, sumatriptan (Imitrex), frovatriptan (Frova), rizatriptan (Maxalt), naratriptan (Amerge), and zolmitriptan (Zomig)
Antiprotozoal agents like pentamidine (Pentam)
Anti-seizure medications such as phenytoin (Dilantin, Phenytek) and carbamazepine (Tegretol, Equetro, Epitol, Teril)
Sleeping pills, sedatives, and tranquilizers
Cancer medications such as vinblastine

What other medications interact with Prozac?

The above list of medications include the known interactions with Prozac (fluoxetine). However, this list may not include all possible Prozac drug interactions. Give your doctor and pharmacist a complete list of your medications, including prescription drugs, over-the-counter (nonprescription) drugs, nutritional supplements or dietary supplements, and herbal products to lower your risk of dangerous drug interactions.

What are some of the risks of taking Prozac?

Suicidal Thoughts and Behaviors

Fluoxetine use can increase the risk of becoming suicidal. This risk is particularly high in children, adolescents, and young adults under the age of 24 years. Tell your health care professional immediately if you or your family members notice worsening depression, trouble sleeping, decreased interest in activities, unusual mood or behavior changes, or suicidal thinking and behavior.

Risk of Serotonin Syndrome

Fluoxetine is a selective serotonin reuptake inhibitor. It works by increasing serotonin levels in the brain. Taking fluoxetine with other drugs that also increase serotonin levels can lead to a potentially fatal condition called serotonin syndrome, in which there is too much serotonin in the body. Call your doctor without delay if you develop the following symptoms: nausea, vomiting, restlessness, agitation, confusion, delirium, fast or irregular heartbeat, dilated pupils, muscle twitching or rigidity, fever, and high blood pressure.

Allergic Reactions

A small number of people can develop severe allergic reactions to fluoxetine. Signs and symptoms may include skin rash, hives, itching, swelling of the lips or throat, chest pain, and trouble breathing. Stop taking fluoxetine and call your doctor immediately or get emergency medical attention if this happens.

Activation of Mania or Hypomania

If a person with bipolar disorder is given an antidepressant such as fluoxetine, it can activate the manic or hypomanic phase of the illness. Your doctor will screen you for bipolar disorder before starting you on fluoxetine and monitor you for symptoms of mania or hypomania during treatment.

Withdrawal Symptoms

Suddenly stopping fluoxetine can cause withdrawal symptoms such as irritability, headache, nausea, vomiting, nightmares, and prickling or tingling sensations. Your doctor may put you on a low dose before discontinuing Prozac.

Seizures

Fluoxetine should be used with caution in people with a history of seizures or other health conditions that can lower the seizure threshold.

Other Risks

Fluoxetine has been associated with other health complications, such as:

Difficulty concentrating and impaired judgment, thinking, and motor skills
Anxiety and insomnia
Changes in appetite and significant weight loss
Bleeding problems, including gastrointestinal bleeding
Serious medical problems such as angle-closure glaucoma
Hyponatremia (low sodium levels)
QT prolongation and ventricular arrhythmia
Changes in sexual ability
Priapism (painful or prolonged erection)
Only 1% of maternal use of SSRIs has been linked to persistent pulmonary hypertension of the newborn, a fatal condition associated with the use of antidepressants during the second half of pregnancy. You should never start or stop fluoxetine (Prozac) without discussing it with your doctor first.

References:

Protriptyline

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