The P-I-E-N-O Parkinsn's List Drug Database
fluoxetine / ProzacTM ,LovanTM ,ZactinTM
ANTIDEPRESSANT: SSRI:
LOW RISK
Description: Fluoxetine is an oral antidepressant. It is the prototype of the selective serotonin reuptake inhibitors (SSRIs) and has the longest half-life of all the SSRIs. The SSRIs are structurally distinct from the other classes of antidepressants (e.g., tricyclic and monoamine oxidase inhibitors). Fluoxetine was originally approved by the FDA in December 1987 for the treatment of major depression and was subsequently approved February 1994 for use in obsessive-compulsive disorder (OCD). On November 11, 1994, the FDA issued an approvable letter for use of fluoxetine in the treatment of bulimia. Also in November 1994, Eli Lilly & Co., withdrew a NDA for a higher-dosage form of fluoxetine (e.g., Lovan) for the treatment of obesity. Other uses of fluoxetine have included the treatment of ethanol dependence, anorexia nervosa, borderline personality disorder, other eating disorders, and panic disorder, although these are not approved indications. Fluoxetine is the most widely prescribed antidepressant in the US. The levo-isomer of fluoxetine is currently undergoing investigation for the prevention of migraine headache.
Mechanism of Action: The precise action of SSRIs is not fully understood, but it is believed that the most important effect is the enhancement of the actions of serotonin due to highly specific serotonin reuptake blockade at the neuronal membrane. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do the tricyclic antidepressant drugs due to dramatically decreased binding to receptors of histamine, acetylcholine, and norepinephrine. Monoamine oxidase is not inhibited by any of the SSRIs. Anticholinergic activity is virtually absent. Fluoxetine is metabolized to norfluoxetine which is also active.
Pharmacokinetics: Fluoxetine is administered orally and is well absorbed from the GI tract. The presence of food can delay the rate of absorption, but not the extent. There may be some first-pass metabolism. Peak plasma concentrations occur in 6-8 hours. Steady-state plasma concentrations of fluoxetine and its principal active metabolite norfluoxetine are achieved in 2-4 weeks. Because both fluoxetine and an active metabolite, norfluoxetine, exist as enantiomers. Since these four compounds differ in kinetics and potency, no relationship between serum concentrations and clinical effect has been defined.D Fluoxetine is highly protein-bound (94.5%) to predominantly ›A-acid glycoprotein. The drug is well distributed, and it readily crosses the blood-brain barrier and presumably the placenta. It is distributed into breast milk.
Fluoxetine is demethylated in the liver to several metabolites. The only known active metabolite is norfluoxetine, which appears to be as effective as its parent in the blockade of serotonin reuptake. Fluoxetine has the slowest elimination of the SSRIs. The half-life of fluoxetine is 2-3 days and that of norfluoxetine is 7-9 days. There is considerable individual variation, which may be associated with rates of N-demethylation and hydroxylation. About 60% of an oral dose is excreted in urine within 35 days, and about 12% of the dose is excreted in the feces within 28 days. Renal impairment does not appear to affect elimination half-lives of the parent drug and its active metabolite. Neither drug is substantially removed by hemodialysis.
CONTRAINDICATIONS/PRECAUTIONS: Fluoxetine should be used with caution in patients with a history of seizure disorders as well as in debilitated patients or those taking multiple medications because of the possibility of drug-induced seizure.
Fluoxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date. Some clinicians have reported that in rare instances the induced seizure was prolonged. A possible mechanism of this seizure prolongation may be the lowering of seizure threshold caused by high concentrations of fluoxetine or its active metabolite norfluoxetine. The clinical significance of this action is unknown but should be minimal since preparations for the seizure were present.
All effective antidepressants can transform depression into mania in predisposed individuals. The usual presentation of this switch is the sudden appearance of insomnia. The antidepressant should be held and appropriate therapy to treat the manic symptoms initiated. Therapeutic doses of lithium (and possibly carbamazepine or valproate) are effective in suppressing the switch process.
All antidepressants should be used with caution in depressed patients because of the possibility of suicidal ideation. Close monitoring of the patient is essential in the initial stages of therapy and fluoxetine prescribed in the smallest quantity consistent with good management.
Fluoxetine should be used with caution in patients with hepatic disease or severe cardiac disease because metabolism can be delayed. Either lower doses or less frequent dosing may be necessary.
Fluoxetine should be used with caution in patients with severe renal impairment because excretion of metabolites can be reduced. Lower doses or less frequent dosing may be necessary.
Fluoxetine can cause a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that presents as hypoosmolarity of serum and urine, and hyponatremia. Elderly patients and those receiving diuretics appear to be more at risk.
Patients with diabetes mellitus should be treated with caution because fluoxetine can dysregulate glucose control. Dose adjustments of hypoglycemics may be necessary.
Fluoxetine should be used with caution in breast-feeding mothers because of the excretion of the drug into breast milk. Patients should advise their physician of their intention to breast-feed. Because the drug is eliminated slowly, consideration should be given to the possible presence of the drug for a prolonged period after discontinuation of therapy.
Fluoxetine should be used cautiously during pregnancy because full evaluation of its effects has not been performed. Fluoxetine is classified as FDA category B.
DRUG INTERACTIONS: Fluoxetine potentiates serotonin by inhibiting its neuronal reuptake. Since serotonin is deaminated by monoamine oxidase type A, administration of drugs that can inhibit this enzyme concurrently with fluoxetine can lead to a serious reaction known as "serotonin syndrome." This reaction may include confusion, seizures, and severe hypertension as well as less severe symptoms. Most MAOIs are non-specific inhibitors of MAO (e.g., furazolidone, pargyline, phenelzine, tranylcypromine) and, since they affect MAO type A, should not be used with fluoxetine. In addition, selegiline, although selective for MAO type B at usual doses, may inhibit MAO type A at higher doses and should also be avoided in patients receiving fluoxetine. Finally, procarbazine, an antineoplastic agent, is a weak MAOI and should also be avoided. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of fluoxetine therapy, and at least 5 weeks between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-life of fluoxetine and its principal metabolite norfluoxetine.
Fluoxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isoenzyme 2D6) pathway at therapeutic doses. This can cause substantial increases in concentrations of other drugs metabolized via the same pathway. Plasma concentrations of tricyclic antidepressants, maprotiline, and trazodone can double when used concomitantly with fluoxetine. Concomitant use of trazodone with fluoxetine can lead to excessive sedation and unstable gait. When tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine) have been used concomitantly with fluoxetine, symptoms of tricyclic toxicity (such as sedation, decreased energy, lightheadedness, psychomotor retardation, xerostomia, constipation, and memory impairment) have been reported. The clinical need for antidepressant polypharmacy is unknown and should be undertaken only after careful consideration of alternatives and with careful monitoring.
Fluoxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isozyme 2D6) pathway at therapeutic doses. This can result in substantial increases in concentrations of other drugs metabolized via the same pathway. Fluoxetine may prolong the half-life of diazepam, but the psychomotor and physiological response does not apppear to be altered. Fluoxetine has also been reported to affect the clearance and plasma concentrations of alprazolam, but had no effect on clonazepam or triazolam.
Fluoxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isozyme 2D6) pathway at therapeutic doses. This can result in substantial increases in concentrations of other drugs metabolized via the same pathway. Fluoxetine may increase the risk of adverse effects of haloperidol, loxapine, molindone, phenothiazines, phenytoin, pimozide, or thiothixene if administered with any of these agents. Serum clozapine concentrations increased substantially when fluoxetine was coadministered. The effects of fluoxetine on hepatic metabolism may persist after discontinuation of fluoxetine because of its long elimination half-life.
Visual hallucinations were reported after dextromethorphan was used in a patient taking fluoxetine. Dextromethorphan is known to be metabolized by the CYP2D6 (cytochrome P-450 isozyme 2D6) pathway, a pathway which fluoxetine inhibits. Although data is limited, dextromethorphan should be used cautiously in any patient receiving fluoxetine.
Cyproheptadine is an antagonist of serotonin in the CNS and this pharmacologic action opposes the pharmacologic actions of fluoxetine. Clinically, cyproheptadine has reportedly lead to a worsening of depression when administered to patients taking fluoxetine however, more data is necessary to confim a direct drug-drug interaction. Ondansetron, granisetron, and methysergide also antagonize serotonin (5-HT) receptors, however no drug-drug interactions have been reported with fluoxetine.
Fluoxetine used concomitantly with tryptophan may cause "serotonin syndrome" (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behaviors, nausea, abdominal cramps, diarrhea, palpitation, or chills). Discontinuation of tryptophan usually resolves these symptoms. Since sumatriptan is also an agonist at serotonin receptors, it is theoretically possible that a similar reaction could occur if sumatriptran was administered to patients receiving this type of antidepressant.
The metabolism of carbamazepine and phenytoin may be impaired by the concomitant administration of fluoxetine leading to ocular changes, vertigo, and tremor. Carbamazepine plasma concentrations should be monitored weekly and the dose of carbamazepine adjusted to compensate for the interaction. Close monitoring should be maintained until steady state has been achieved, which theoretically can require up to 8 weeks following the final fluoxetine dosage adjustment. Phenytoin toxicity has been described in several patients after the addition of fluoxetine.
The combination of buspirone with fluoxetine has produced mixed results. Pharmacologically, these two drugs exert opposing actions: buspirone decreases the synthesis and release of serotonin via its effects on serotonin receptors while fluoxetine potentiates serotonin secondary to blocking serotonin reuptake. Use of buspirone with fluoxetine in a patient with major depression, generalized anxiety disorder, and panic disorder, has been reported to have caused increased anxiety. In patients with obsessive-compulsive disorder, however, this combination has been reported to improve efficacy. Until more data is available, careful monitoring should be undertaken when this combination is used.
Although no data are available, it is possible that inhibitors of hepatic enzymes such as cimetidine may affect fluoxetine pharmacokinetics. A significant interaction has been suggested for cimetidine-paroxetine; fluoxetine may be similarly affected by cimetidine. Until more data are available, cimetidine should be used cautiously in patients receiving fluoxetine.
One report is noted of an interaction between fluoxetine and metoprolol. Bradycardia occured in a patient receiving metoprolol after fluoxetine was added. The patient had been previously well on metoprolol alone and fluoxetine alone. This response is consistent with the possible inhibition of metoprolol metabolism by fluoxetine.
Fluoxetine may increase or decrease lithium concentrations and close monitoring of lithium concentrations is advisable particularly prior to steady state. Inadequate lithium concentrations (< 0.6 mEq/L) may precipitate mania in the bipolar patient.
Although data are limited, fluoxetine may potentiate the hypoprothrombinemic effects of warfarin. One case is noted of positive challenge and positive dechallenge with fluoxetine on warfarin action. Clinicians should avoid the concomitant use of these two drugs whenever possible.
Adverse reactions: Adverse CNS reactions can occur in patients receiving fluoxetine and include anxiety, nervousness, insomnia, drowsiness, fatigue, dizziness, tremor, and headache. Headache is the most commonly reported CNS effect. Some CNS effects can diminish with therapy because they are associated with a depressed state. In severe cases, discontinuation of the drug may be necessary. Sedation is generally less of a problem with fluoxetine than with tricyclic antidepressants, but patients should exercise caution during activities requiring mental alertness until the effects of the drug are known.
All effective antidepressants can transform depression into mania in predisposed individuals. The usual presentation of this switch is the sudden appearance of insomnia. The antidepressant should be held and appropriate therapy to treat the manic symptoms initiated. Therapeutic doses of lithium (and possibly carbamazepine or valproate) are effective in suppressing the switch process.
Fluoxetine can cause drug-induced seizures, but has been reported at a very low frequency (12 of 6,000 patients). This reaction is likely to occur only following overdose, after long-term therapy, or in the presence of a preexisting seizure disorder.
Extrapyramidal symptoms (dystonia, torticollis, and akathisia) have occurred in some patients. Akathisia is the most commonly observed of these adverse reactions and is easily confused with anxiety or agitation.
All antidepressants should be used with caution because of the possibility of suicidal ideation. There is no evidence that one antidepressant has a higher potential for causing patients to attempt suicide. Close monitoring of the patient is essential during the initial stages of therapy and the drug prescribed in the smallest quantity consistent with good management.
Nausea/vomiting is the most commonly (~20%) experienced adverse reaction. Nausea usually subsides after a few weeks of therapy but occasionally is severe enough to necessitate discontinuation of the drug. Nausea occurs more frequently with fluoxetine than with tricyclic antidepressant drugs. Diarrhea, anorexia, xerostomia, and dyspepsia are also fairly common (~10%) and may require medical attention. Anorexia can result from serotonin-reuptake blockade, and tolerance to this effect does not appear to occur. Weight loss exceeding 5% of body weight has been reported in 10-15% of fluoxetine-treated patients. Higher doses are correlated with higher weight loss. Approximately 1% of patients require discontinuation due to this adverse effect. Underweight patients should have their weights monitored weekly to prevent further weight loss. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction.
Pruritus and rash occur during the first few weeks of therapy in 2-4% of patients receiving fluoxetine. Diaphoresis occurs in ~10% of patients. Only 1% of patients require discontinuation of fluoxetine due to allergic reactions. All dermatological reactions should be investigated because they could be precursors of a serious systemic reaction to the drug. In most cases, maculopapular rash or urticaria disappears with treatment with an antihistamine or corticosteroid, or upon discontinuation of the drug. Other dermatologic reactions occuring in <1% of patients include alopecia, acne, contact dermatitis, and xerosis.
Hypoglycemia has been observed rarely in patients treated with fluoxetine. Hyperglycemia has been observed following discontinuation of fluoxetine. Patients with diabetes mellitus should be monitored closely during initiation or discontinuation of fluoxetine.
Visual impairment, including blurred vision, occurs in ~3% of patients receiving fluoxetine.
Fluoxetine is substantially less cardiotoxic than are the tricyclic antidepressants. A slight sinus bradycardia of 3 beats/minute has been reported in patients taking fluoxetine. Orthostatic hypotension occurs in fewer than 1% of patients. Palpitations, hot flashes, and angina have been reported infrequently.
Back, joint, limb, or muscle pain occurs in 1-2% of patients receiving fluoxetine. Anemia has been reported in fewer than 1% of patients receiving fluoxetine. None of the hematologic effects is known to have a definite relationship to fluoxetine therapy.
Upper respiratory infection (URI) has been observed in 8% of patients treated with fluoxetine. Other respiratory effects that have been reported in 1-3% of fluoxetine treated patients include pharyngitis, nasal congestion, sinusitis, sinus headache, cough, and dyspnea.
Sexual dysfunction including ejaculation dysfunction (delayed ejaculation), impotence, orgasm dysfunction (anorgasmia, spontaneous or delayed orgasm), libido decrease, and penile anesthesia have been reported in ~2% of patients receiving fluoxetine. Although the manufacturer reports that sexual dysfunction occurs in 1.9% of patients, some believe that it may occur in as many as 75% of patients.
Fluoxetine can cause a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that presents as hypoosmolarity of serum and urine, and hyponatremia. Older patients and those receiving diuretics appear to be more at risk.
Hypothyroidism is reported in ~1% of patients receiving fluoxetine, although a causal relationship to fluoxetine therapy has not been established. Even slight hypothyroidism (thyroid-stimulating hormone (TSH) " 3) can prevent response to antidepressant therapy.
PATIENT INFORMATION:
What do fluoxetine capsules do?
Fluoxetine (ProzacTM ) is an antidepressant. It helps lift severe depression that has no obvious cause. Fluoxetine can also help patients with an obsessive compulsive disorder. It relieves the anxiety and unpleasant thoughts that make patients repeat everyday tasks (like hand-washing) many times. Fluoxetine helps to maintain a normal lifestyle. Fluoxetine is chemically different from all other antidepressant medicines. Because it acts differently, fluoxetine can help patients who get unusual or limiting side effects from other antidepressants. Generic fluoxetine capsules are not yet available.
What should my doctor, dentist, or pharmacist know before I take fluoxetine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take fluoxetine capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. You can take fluoxetine with or without food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
Safe use in children has not been established.
Elderly patients may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If you do not remember within a few hours, skip that dose and return to your normal schedule. Do not take double or extra doses.
Which other medicines may interact with fluoxetine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking fluoxetine?
Serious side effects with fluoxetine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with fluoxetine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take fluoxetine?
Visit your doctor for regular checks on your progress. Continue to take your capsules even if you do not immediately feel better. It can take 4 to 5 weeks before you feel the full effect of fluoxetine. If you get suicidal thoughts call your doctor at once.
If you have been taking fluoxetine regularly for some time, do not suddenly stop taking it. You must gradually reduce the dose or your symptoms may get worse. Ask your doctor for advice. Even after you stop taking fluoxetine it can still affect your body for several weeks; continue to heed all warnings.
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how fluoxetine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can make you more drowsy and dizzy. Avoid alcoholic drinks.
Do not treat yourself for coughs, colds or allergies without asking your doctor or pharmacist for advice. Some ingredients can increase possible side effects.
Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Throw away any unused medicine after the expiration date.
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