Approval Date.
Fluoxetine Hydrochloride Capsules Instructions
Please read the instructions carefully and use under the guidance of your physician.
Cautionary Tale
Antidepressants increase the risk of suicidal ideation and behavior among children, adolescents, and young adults in short-term studies. In adults older than 24 years, such short-term trials did not show an increased risk of suicidal ideation and behavior in patients using antidepressants; in adults 65 years and older, patients had a reduced risk with antidepressants (see [caution]Worsening symptoms and risk of suicide).
Patients of all ages starting antidepressant therapy should be closely monitored for worsening and emerging suicidal ideation and behavior. Family and caregivers should be advised to closely observe and communicate with the prescribing physician (see [precautions]Worsening symptoms and risk of suicide).
[Drug Name].
Generic Name: Fluoxetine Hydrochloride Capsules
Trade Name: Omelan®
English Name: Fluoxetine Hydrochloride Capsules
Hanyu Pinyin: Yansuan Fuxiting Jiaonang
[Ingredients
The main ingredient of this product is fluoxetine hydrochloride.
Chemical name: (±)-N-methyl-3-phenyl-3-(4-trifluoromethylphenoxy)propanamine hydrochloride;
Molecular formula: C17H18F3NO-HCl
Molecular weight: 345.79
[Properties
This product is a hard capsule, the contents of which are white or off-white granules or powder.
[Indications
Depression;
OCD;
Bulimia nervosa: as an adjunct to psychotherapy to reduce bulimic and conductive behaviors.
[Specifications
20mg (based on C17H18F3NO)
[dosage
Orally.
Depression.
Adult and geriatric patients: The recommended dose is 20 mg daily. if necessary, the drug dose is evaluated and adjusted during the first 3 to 4 weeks of treatment to achieve a clinically appropriate dose. Although higher doses may increase the likelihood of adverse effects, for some patients, the dose may be gradually increased to a maximum dose of 60 mg due to the lack of significant efficacy with the 20 mg dose. Dose adjustments must be made carefully for each patient so that the patient maintains the lowest effective dose.
Patients with depression must continue treatment for at least 6 months to ensure disappearance of symptoms.
OCD
Adult and elderly patients: The recommended dose is 20 mg/day. Although doses higher than 20 mg/day may increase the likelihood of adverse effects in some patients, the maximum dose of 60 mg can be gradually increased to 60 mg after two weeks of treatment due to the lack of significant efficacy with the 20 mg dose.
If no improvement is noted within 10 weeks, treatment with fluoxetine must be reconsidered. If good results are obtained, treatment can be continued, but dose adjustments should be made on an individual basis. Although there are no systematic studies on how long fluoxetine treatment needs to be maintained, OCD is a chronic condition and patients who are effective on treatment may be considered for an extended treatment period beyond 10 weeks. Dose adjustments must be carefully tailored to each patient so that the patient maintains the lowest effective dose. The need for treatment must be reassessed periodically. Some clinicians advocate the combination of behavioral psychotherapy for patients for whom pharmacologic therapy is effective.
The long-term efficacy (more than 24 weeks) of fluoxetine in the treatment of OCD has not been demonstrated.
Bulimia nervosa
Adult and elderly patients: The recommended dose is 60 mg daily. long-term efficacy (more than 3 months) in the treatment of bulimia nervosa patients has not been demonstrated.
Adults-all indications: The recommended dose may be increased or decreased as appropriate. Daily doses above 80 mg have not been systematically evaluated.
Fluoxetine may be given as a single dose or in divided doses, with food, or between meals.
The active ingredient remains in the body for several weeks when the drug is discontinued. This feature must be taken into account when starting and ending treatment.
Elderly people: Dose increases should be cautious and should not generally exceed 40 mg/day.
Children:As the safety and efficacy of its use in Chinese children and adolescents (under 18 years of age) are not known, it is not recommended for use in this population.
For patients with hepatic impairment (see [Pharmacokinetics]) or in combination with other drugs that may interact with fluoxetine (see [Drug Interactions]), consider reducing the drug dose or decreasing the frequency of dosing (e.g., 20 mg every other day).
Withdrawal Symptoms When Discontinuing Fluoxetine: Abrupt discontinuation of the drug should be avoided. To reduce the incidence of withdrawal reactions, fluoxetine should be discontinued with a gradual dose reduction over at least 1-2 weeks (see [PRECAUTIONS] and [ADVERSE REACTIONS]). If a patient develops symptoms of intolerance during dose reduction or discontinuation, consideration should be given to resuming the original dose. Subsequently, the physician may continue to reduce the dose at a more moderate rate.
Fluoxetine hydrochloride capsules and fluoxetine hydrochloride dispersible tablets are bioequivalent.
[Adverse Reactions
Clinical trial experience
Because clinical trials are conducted under a variety of conditions, it is not possible to compare the incidence of adverse reactions observed for one drug in a clinical trial with the incidence of adverse reactions for another drug in clinical trials, and the incidence in clinical trials does not necessarily reflect or predict the incidence of adverse reactions in clinical practice. Anyone who has a drug in a clinical trial may have an adverse effect.
10,782 patients with various diagnoses in US clinical trials received multiple doses of fluoxetine. In addition, 425 patients in clinical trials for panic disorderreceived fluoxetine administration.
If it first occurred or worsened while receiving treatment after the baseline evaluation, the reaction was considered to have occurred during treatment. .
Occurrences in placebo-controlled clinical trials for depression, OCD, bulimia, and panic disorder (except data from trial expansion phase)-Table 1 lists the U.S. treatment rates for depression, OCD, and bulimia. Obsessive-Compulsive Disorder, and Bulimia, and the most common adverse reactions associated with the use of fluoxetine during treatment in U.S. controlled clinical trials for the treatment of panic disorder (at least 5% in the fluoxetine group for at least 1 indication and at least twice the incidence of placebo). Table 3 lists adverse reactions occurring during treatment in ≥2% of patients treated with fluoxetine in controlled clinical trials for depression, obsessive-compulsive disorder, and bulimia in the United States and in controlled clinical trials for panic disorder in the United States and non-United States. Table 2 provides summary data for the clinical trials by indication separately in Table 1.
Table 1: Most common adverse reactions occurring during treatment: depression, obsessive-compulsive disorder, bulimia, and panic disorder in placebo-controlled clinical trials1,2
Percentage of patients reporting events depressionOCDBulimiaPanic disorderTorso system/
Adverse effectsFluoxetine
(N=1728)placebo
(N=975)Fluoxetine
(N=266)placebo
(N=89)Fluoxetine
(N=450)placebo
(N=267)Fluoxetine
(N=425)placebo
(N=342)The whole body as a whole Debilitating9515112197 7Influenza Syndrome3 41078355 Cardiovascular System Vasodilation325 211 Digestive system
2 Includes data from clinical trials of depression, obsessive-compulsive disorder, bulimia, and panic disorder in the United States and clinical trials of panic disorder in the non-United States. .
Discontinuation-related in placebo-controlled clinical trials for depression, OCD, bulimia, and panic disorder (except data from trial expansion phase)- Table 3 presents data from depression, OCD, bulimia, and panic disorder clinical trials and adverse reactions associated with discontinuation of fluoxetine treatment in non-U.S. panic disorder clinical trials (only primary reactions associated with discontinuation were captured, occurring at least twice as often as placebo in clinical trials and at least 1% in the fluoxetine group).
Table 3: Discontinuation-related adverse reactions in placebo-controlled clinical trials for depression, obsessive-compulsive disorder, bulimia, and panic disorder
Most common adverse reactions1
Combined data on depression, obsessive-compulsive disorder, bulimia, and panic disorder
(N=1533)Depression
(N=392)OCD
(N=266)Bulimia
(N=450)Panic disorder
(N=425)Anxiety (1%)- Anxiety (2%) Anxiety (2%)- – – Insomnia (2%)- – Nervousness (1%)- – Nervousness (1%)- – Rash (1%)- – 1 includes US clinical trials for depression, OCD, bulimia, and panic disorder and non-US clinical trials for panic disorder. .
Other Adverse Reactions in Pediatric Patients (Children and Adolescents) – Adverse reactions that occurred during treatment were collected in 322 pediatric patients (180 receiving fluoxetine treatment and 142 received placebo). The overall characteristics of adverse reactions were generally similar to those observed in the adult trials shown in Tables 2 and 3. However, the following adverse reactions (except those appearing in the table body or footnotes in Table 2 or 3 and those not present or misleading in COSTART terminology) occurred at least 2% in the fluoxetine group and were greater than placebo: thirst, hypermobility, agitation, personality disorder, rhinorrhea, dysuria, and menorrhagia. .
In 3 pediatric placebo-controlled trials (number of randomized subgroups accepted: N = 418; 228 treated with fluoxetine; 190 treated with placebo), the most common adverse reactions associated with discontinuation (in the fluoxetine group) incidence was at least 1% and greater than in the placebo group) was mania/hypomania (1.8% in patients treated with fluoxetine and 0% in patients treated with placebo). In these clinical trials, only the primary reactions associated with discontinuation were captured. .
Response Observed in Fluoxetine Weekly Capsules Clinical Trials – In the Fluoxetine Weekly Capsules clinical trial, adverse reactions that occurred during treatment with fluoxetine daily dosing Adverse reactions reported by patients in clinical trials were similar. In a placebo-controlled clinical trial, more patients taking fluoxetine weekly capsules reported diarrhea than did patients taking placebo (10% and 3%, respectively) and fluoxetine 20 mg daily (10% and 5%, respectively). .
SSRI-related sexual dysfunction in men and women – Although changes in sexual desire, sexual behavior, and sexual satisfaction are often manifestations of psychiatric disorders, they can also be the result of medication. the result of treatment. In particular, some evidence suggests that SSRIs can lead to some adverse sexual experiences. However, it is difficult to reliably estimate the incidence and severity of adverse sexual experiences (including sexual desire, sexual behavior, and sexual satisfaction), in part because patients and physicians may be reluctant to discuss these issues. Therefore, estimates of the incidence of adverse sexual experiences and sexual behaviors cited in product labeling may underestimate their actual incidence. Among patients enrolled in placebo-controlled clinical trials for depression, obsessive-compulsive disorder, and bulimia in the United States, the only side effect reported sexually by at least 2% of patients taking fluoxetine was decreased libido (4% for fluoxetine and .
There are no adequate, well-controlled trials investigating sexual dysfunction associated with fluoxetine treatment.
At some point, symptoms of sexual dysfunction persisted even after fluoxetine was discontinued.
Abnormal penile erections have been reported at one time or another during all SSRI use.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely ask about such possible adverse effects.
Other reactions
The following is a list of adverse reactions reported by patients treated with fluoxetine in clinical trials that occurred during treatment. This list does not include reactions that (1) were listed in a previous table or elsewhere in the labeling, (2) have a low probability of a drug cause, (3) are so common that they do not provide useful information, (4) are not considered clinically significant, and (5) occur at a rate less than or equal to placebo. .
Adverse reactions were categorized by body system using the following definitions: common adverse reactions occurred in at least 1 in 100 patients; occasional adverse reactions occurred in 1 in 100 to 1 in 1000 patients; rare reactions occurred in occur in less than 1/1000 patients. .
The whole body as a whole – common: chills; occasional: suicide attempts; rare: acute abdominal syndrome, photosensitivity reactions.
Cardiovascular system-common: palpitations; occasionally: arrhythmias, hypotension 1.
Digestive system-occasional: dysphagia, gastritis, gastroenteritis, black stool, gastric ulcer; rare: bloody diarrhea, duodenal ulcer, esophageal ulcers, gastrointestinal bleeding, vomiting blood, hepatitis, peptic ulcers, bleeding gastric ulcers . .
Blood and lymphatic system – Occasionally: petechiae; rarely: petechiae, purpura.
Various tests-common: prolonged QT interval (QTcF ≥450 msec)3.
Neurological-common: emotional instability; occasionally: inability to sit still, ataxia, balance disorder1, teeth grinding1, buccal tongue syndrome, depersonalization, euphoria, hypertonia, increased libido, myoclonus, paranoid reactions; rare: delusions.
Respiratory system – Rare: laryngeal edema.
Skin and appendages – Occasionally: alopecia; rarely: purpuric rash.
Special sensations-common: taste inversions; occasionally: dilated pupils.
Genitourinary system-Common: dysuria; occasionally: painful urination, gynecological bleeding2.
1 MedDRA dictionary terms from the Placebo Controlled Trials Integration Database, 15,870 subjects participated in the trial, 9,673 of whom received treatment with fluoxetine. 2A set of terms including the individual MedDRA terms: cervical bleeding, dysfunctional uterine bleeding, genital bleeding, menorrhagia, menorrhagia, frequent menstruation, postmenopausal bleeding, uterine bleeding, and vaginal bleeding. After gender adjustment.
3 QT prolongation data are based on routine ECG measurements in clinical trials.
Post-marketing experience
The following adverse reactions have been identified following approval of fluoxetine. These reactions were voluntarily reported from populations with uncertain sample sizes, making it difficult to reliably estimate the frequency of occurrence or to evaluate a causal relationship with drug exposure. .
Voluntary reports of adverse reactions received post-marketing that were temporally related to fluoxetine but may not be causally related to the drug include: aplastic anemia, atrial fibrillation 1, cataract, cerebrovascular accident 1, biliary depression jaundice, dyskinesia (including, for example, a case of a 77-year-old woman who developed buccal-tongue-chewing syndrome with unconscious tongue spitting after 5 weeks of fluoxetine treatment, which completely resolved after several months of discontinuation), eosinophilic pneumonia 1, epidermal necrosis, erythema multiforme, erythema nodosum, exfoliative dermatitis, breast overflow, mammary gland development in men, cardiac arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, renal failure, memory impairment, motor impairment (patients with risk factors include medications associated with such reactions and exacerbation of preexisting dyskinesia), optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, prolonged QT interval, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including tip-twist ventricular arrhythmias), vaginal bleeding, and violent behavior1. .
1 These terms indicate serious adverse events but do not meet the definition of an adverse drug reaction. They are listed because of their severity.
[Contraindicated
Monoamine oxidase inhibitors (MAOI)
Due to the potentially elevated risk of developing 5-hydroxytryptamine syndrome, monoamine oxidase inhibitors are contraindicated for 5 weeks in persons using fluoxetine or discontinuing fluoxetine. Fluoxetine is also contraindicated for 14 days after discontinuation of monoamine oxidase inhibitors (see [Precautions]).
Because of the potentially elevated risk of developing 5-hydroxytryptamine syndrome, the use of an MAOI such as linezolid or intravenous methylene blue is prohibited: black”>in patients treated with fluoxetine (see [precautions] 5-hydroxytryptamine syndrome).
Other contraindications
Fluoxetine is contraindicated with the following medications:
Pimozide (see [precautions] QT interval prolongation and [drug interactions] Possibility of fluoxetine affecting other drugs, drugs that prolong QT interval with drugs)
Pimozide and thioridazine can prolong the QT interval . Fluoxetine can increase blood levels of pimozide and thioridazine by inhibiting CYP2D6. Therefore , fluoxetine may also prolong the QT interval.
[Caution].
Suicidal ideation and suicidal behavior in children, adolescents, and young adults
People with depression, both adults and children, with and without antidepressants, are at risk for worsening depression and/or developing suicidal ideation or behavior (suicidal ideation) or behavioral abnormalities. And that risk may persist until the disorder being treated remits significantly. Suicide is a known risk for depression and certain other psychiatric disorders, which are themselves the strongest predictors of suicide. Yet there is a long-standing concern that antidepressants early in treatment may induce exacerbation of depression and the development of suicidal ideation in some patients. Pooled analyses of short-term placebo-controlled trials of antidepressants (SSRIs and others) have shown that these medications can increase the risk of suicidal ideation and behavior (suicidal ideation) in children, adolescents, and young adults (aged 18-24 years) with depression and other psychiatric disorders. In adults older than 24 years, short-term trials did not show an increased risk of suicide compared with placebo; in adults 65 years and older, this risk was reduced with antidepressant use compared with placebo. .
A pooled analysis of placebo-controlled trials in children and adolescents with depression, OCD, or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressants in 4400 patients. Trials. A pooled analysis of placebo-controlled trials in adults with depression or other psychiatric disorders included a total of 295 short-term trials (median duration 2 months) of 11 antidepressants in more than 77,000 patients. There was considerable variability in the risk of suicidal ideation among the different drugs, but for almost all drugs studied, the risk tended to increase in younger patients. The absolute risk of suicidal ideation varied between indications, with the highest incidence in depression. However, within the same age group and across indications, the risk differences (drug versus placebo) were relatively stable. These risk differences (differences in the number of cases of suicidal ideation per 1000 patients treated with medication versus placebo) are shown in Table 4.
Table 4: Suicidal ideation per 1000 treated patients
Age rangeDifference in the number of cases of suicidal ideation per 1000 patients treated with drugs versus placebo increase relative to placebo-treated patients<1814 more examples18-245 more examples reduction relative to placebo-treated patients25-64One less case≥65Fewer than 6 casesIn none of the pediatric trials did suicides. There were suicides in the adult trials, but the numbers were too small to draw conclusions about the effects of drugs on suicide.
It is not clear whether long-term use (i.e., longer than a few months) also poses a risk of suicide. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that antidepressant use delays the recurrence of depression. .
All patients receiving antidepressants for any indication should be monitored appropriately and closely for clinical exacerbations, suicidal ideation, and behavioral abnormalities, especially during the first few months of medication treatment , or when adjusting medication doses, either by increase or decrease. .
The following symptoms have been reported in adult and pediatric patients treated with antidepressants for depression and other psychiatric and nonpsychiatric indications: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity , inability to sit still (psychomotor restlessness), hypomania, and mania. Although a causal link between the presence of these symptoms and increased depression and/or suicidal impulses has not been established, there is concern that these symptoms may be a precursor to suicidal ideation that may accompany treatment. .
In patients with persistent exacerbation of depression or sudden onset of suicidality, or in patients presenting with symptoms that may be precursors to exacerbation of depression or suicidality, especially if these symptoms are severe, emerge suddenly, or are not part of the patient’s presenting symptoms Changes in treatment regimen, including the possibility of discontinuing medication, should be considered. .
If a decision has been made to discontinue treatment, the dose should be tapered as soon as possible, but it should be recognized that abrupt discontinuation may cause some symptoms (see [precautions] Discontinuation of Treatment). .
If a patient is receiving antidepressant medication for depression or other indications including psychosis or nonpsychosis, family and caregivers should be informed of the need to monitor the patient for agitation, irritability, behavioral and other such symptoms, as well as suicidal ideation, and to report such symptoms immediately to the health care provider. This monitoring should include daily observation by family or caregivers.
Fluoxetine should be prescribed at the lowest dose that controls the condition to reduce the risk of overdose. .
5-hydroxytryptamine syndrome
Treatment with SNRIs and SSRIs, including fluoxetine, alone, especially in combination with other 5-hydroxytryptaminergic drugs (including traptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, bupropion, amphetaminesand St. John’s wort) and drugs that inhibit 5-hydroxytryptamine metabolism (specifically, MAOIs, including those used to treat psychiatric disorders as well as other disorders such as linezolid or intravenous methylene blue), a potentially life-threatening 5-hydroxytryptamine syndrome has been reported .
Symptoms of 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, delirium and coma ), autonomic instability (e.g., tachycardia, unstable blood pressure, dizziness, sweating, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, dyskinesia), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be routinely monitored for symptoms of 5-hydroxytryptamine syndrome. .
Concurrent use of fluoxetine and MAOI for the treatment of psychiatric disorders is prohibited. Treatment with fluoxetine in patients who are on linezolid or intravenous methylene blue is also prohibited. All reports involving the route of administration of methylene blue indicated that the route of administration was intravenous and that the dose range was between 1 mg/kg and 8 mg/kg. No reports involving other routes of administration (such as oral tablets or local tissue injections) or lower doses were found. There may be an urgent need for treatment with an MAOI such as linezolid or intravenous methylene blue in patients who are using fluoxetine. Fluoxetine should be discontinued prior to starting an MAOI (see [Contraindications]). .
If a combination of fluoxetine and other 5-hydroxytryptaminergic drugs, such as tritans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, is clinically indicated bupropion, amphetamines and St. John’s wort, then patients should be made aware of the potential increased risk of developing 5-hydroxytryptamine syndrome, especially during periods of treatment initiation and dose increases.
If these reactions occur, fluoxetine with concomitant 5-hydroxytryptaminergic drugs should be discontinued immediately and supportive symptomatic therapy should be initiated. .
Allergic reactions and rash
In the U.S. clinical trial of fluoxetine, 7% of 10,782 patients developed various types of rash and/or urticaria. Almost one-third of the rash and/or urticaria cases reported in premarketing clinical trials were discontinued due to rash and/or systemic signs or symptoms associated with the rash. Reported clinical findings associated with the rash reported fever, leukocytosis, arthralgia, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild aminotransferase elevation. Most patients improved quickly after discontinuation of fluoxetine and/or use of antihistamines or steroids. Full recovery has been reported in all patients who developed these reactions. .
Severe systemic skin disease is known to have occurred in 2 patients in premarketing clinical trials. Neither patient had a definitive diagnosis, but one was considered to have leukocytoclastic vasculitis, and the other was a severe desquamation syndrome that was considered to be vasculitis or erythema multiforme. Other patients had systemic syndromes suggestive of serum disease. .
Since the opening of fluoxetine, there have been systemic reactions in patients with rashes that may be associated with vasculitis, including lupus-like syndrome. Although these reactions are rare, they may be severe, involving the lungs, kidneys, or liver. Deaths associated with these systemic reactions have been reported. .
Allergic-like reactions, including bronchospasm, angioneurotic edema, laryngospasm, and urticaria, alone or in combination, have been reported. .
Rare pulmonary reactions, including various histopathologic inflammatory processes and/or fibrosis, have been reported. The only prodromal symptom when these reactions occur is dyspnea. .
It is unclear whether these systemic reactions and rashes have a common underlying cause or are due to a different etiology or pathological process. And, no specific underlying immunologic basis for these reactions has been identified. Fluoxetine should be discontinued in the presence of a rash or other possible metaplasia if no other causative factors can be identified. .
Screening for patients with bipolar disorder and monitoring for mania/hypomania
Depressive episodes can be the initial manifestation of bipolar disorder. It is generally believed (although not confirmed in controlled trials) that treatment of such episodes with antidepressants alone may increase the likelihood of mixed/manic episodes in patients at risk for bipolar disorder. It is unclear whether some of the symptoms described by clinical exacerbation and suicide risk represent such a conversion. However, patients with depressive symptoms should be adequately screened to determine whether they are at risk for bipolar disorder before initiating treatment with antidepressants; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. .
In placebo-controlled clinical trials on depression in the United States, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and in 0.1% of patients treated with placebo. A small percentage of patients with major affective disorder have also reported mania/hypomania while receiving other marketed medications that are effective in treating depression.
In the US placebo-controlled clinical trial of OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine, but not in patients treated with placebo. In the U.S. placebo-controlled clinical trial of bulimia, no patients reported mania/hypomania. In the U.S. clinical trial of fluoxetine, 0.7% of 10,782 patients reported mania/hypomania. .
Seizures
In placebo-controlled clinical trials on depression in the United States, 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo reported convulsions (or described as a possible seizure reactions). No patients reported convulsions in placebo-controlled clinical trials of OCD or bulimia in the United States. In the U.S. clinical trial of fluoxetine, 0.2% of 10,782 patients reported convulsions. The percentages were similar to other marketed drugs that can effectively treat depression. Caution should be exercised in the use of fluoxetine in patients with a history of seizures. .
Appetite and weight change
Significant weight loss may be an adverse outcome of treatment with fluoxetine, especially in patients with low weight depression or bulimia. .
In placebo-controlled clinical trials on depression in the United States, lack of appetite (loss of appetite) was reported in 11% of patients treated with fluoxetine and 2% of patients treated with placebo. Weight loss was reported in 1.4% of patients treated with fluoxetine and 0.5% of patients treated with placebo. However, discontinuation of fluoxetine treatment due to lack of appetite or weight loss was rare. .
In the US placebo-controlled clinical trial of OCD, lack of appetite (loss of appetite) was reported in 17% of patients treated with fluoxetine and 10% of patients treated with placebo. One patient discontinued fluoxetine treatment due to lack of appetite. .
In the US placebo-controlled clinical trial of bulimia nervosa, lack of appetite (hypophagia) was reported in 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo. In the 16-week double-blind trial, patients treated with fluoxetine 60 mg lost an average of 0.45 kg and those treated with placebo gained 0.16 kg. Weight change should be monitored during treatment. .
Abnormal bleeding
SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may increase this risk. Case reports and epidemiological studies (case-control and cohort designs) have demonstrated an association between the use of drugs that interfere with 5-hydroxytryptamine reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions associated with SNRIs and SSRIs include petechiae, hematomas, rhinorrhea, and bruising, even life-threatening bleeding.
Patients should be warned of the risk of bleeding associated with concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation (see [Drug Interactions] Drugs Affecting Hemostasis) . .
Glaucoma with angle closure
Closed-angle glaucoma – Patients with anatomically narrow atrial angles who have not undergone open iridectomy are treated with multiple antidepressants (including fluoxetine) are associated with pupillary dilation, which may induce closed-angle glaucoma.
Hyponatremia
Hyponatremia has been previously reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this hyponatremia appears to be caused by the syndrome of abnormal antidiuretic secretion (SIADH). Cases with serum sodium below 110 mmol/L have been reported and are reversible after discontinuation of fluoxetine. The risk of hyponatremia may be increased in older adults treated with SNRIs and SSRIs. And, the risk may be greater in patients taking diuretics or other reductions in body fluid volume (see [Geriatric Use]). In patients with symptomatic hyponatremia, discontinuation of fluoxetine and appropriate medical intervention should be considered. .
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and swaying that may lead to falls. More severe and/or urgent cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. .
Anxiety and insomnia
In placebo-controlled clinical trials on depression in the United States, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. .
In the US placebo-controlled clinical trial on OCD, 28% of patients treated with fluoxetine and 22% of patients treated with placebo reported insomnia. Anxiety was reported by 14% of patients treated with fluoxetine and 7% of patients treated with placebo. .
In the US placebo-controlled clinical trial on bulimia nervosa, 33% of patients treated with fluoxetine 60 mg and 13% of patients treated with placebo reported insomnia. Anxiety and nervousness were reported in 15% and 11% of patients treated with fluoxetine 60 mg and 9% and 5% of patients treated with placebo, respectively. .
In US placebo-controlled fluoxetine clinical trials, the most common adverse reaction associated with discontinuation (at least twice the rate of placebo and at least 1% for fluoxetine in clinical trials where only the primary reaction associated with discontinuation was collected) was anxiety (at least twice the rate of placebo and at least 1% for fluoxetine in clinical trials where only the primary reaction associated with discontinuation was collected). 1%) were anxiety (2% in OCD), insomnia (1% after combination of indications and 2% in bulimia), and nervousness (1% in depression) (see Table 3). .
Prolonged QT interval
Postmarketing case reports of prolonged QT interval and ventricular arrhythmias including tip-twisting ventricular tachycardia have been received from patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome, a history of prolonged QT interval, a family history of long QT syndrome or sudden cardiac death, and other conditions predisposing to QT interval prolongation and ventricular arrhythmias. These conditions include concomitant use of drugs that may cause QT interval prolongation; hypokalemia or hypomagnesemia; recent myocardial infarction, decompensated heart failure, bradyarrhythmias, and other major arrhythmias; conditions that may increase fluoxetine exposure (e.g., drug overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 slow metabolizers or use of other drugs with stronger protein binding activity). Fluoxetine is primarily metabolized by CYP2D6 (see [Contraindications], [Adverse Reactions] [Drug Interactions] Potential for Fluoxetine to Affect Other Drugs and Drugs That Prolong the QT Interval, [Overdose] Human Experience, [Pharmacokinetics]).
Pimozide and thioridazine are contraindicated in combination with PROZAC. Avoid concomitant use with drugs that are known to prolong the QT interval. These include certain specific antipsychotics (e.g., ziprasidone, ibuprostone, chlorpromazine, methotrexate, and haloperidol), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, and sparfloxacin), class Ia antiarrhythmic drugs (e.g., quinidine and procainamide), class III antiarrhythmic drugs (e.g., amiodarone and sotalol), and other drugs (e.g., pentazocine, levacetylmethadone, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus, etc.) (see [Drug Interactions] Potential for fluoxetine to affect other drugs and drugs that prolong the QT interval, [Pharmacokinetics]).
Patients with prolonged QT interval and risk factors for ventricular arrhythmias should be considered for ECG evaluation and periodic ECG monitoring while on treatment with fluoxetine. If a patient develops signs or symptoms of ventricular arrhythmia, discontinuation of fluoxetine or evaluation of the patient’s cardiac function should be considered.
Use in patients with concomitant disease
There is limited clinical experience with fluoxetine in patients with concomitant disease. Caution should be exercised when using fluoxetine in patients with conditions that may affect metabolic or hemodynamic responses. .
Cardiovascular – Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. In premarket trials of the product, patients with these conditions were systematically excluded from clinical trials. However, the electrocardiograms of 312 patients who received fluoxetine in the double-blind trial were evaluated retrospectively; no conduction abnormalities leading to heart block were observed. The mean heart rate decreased by approximately 3 beats/min. .
Glucose Control – In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during treatment with fluoxetine and hyperglycemia has occurred after discontinuation of the drug. This is also true in patients with diabetes who are taking many other types of medications at the same time, and the dose of insulin and/or oral hypoglycemic agents may need to be adjusted when starting or stopping fluoxetine therapy.
Likelihood of cognitive and motor impairment
Like other medications with central nervous system activity, fluoxetine may impair judgment, thinking, or motor skills. Patients should operate dangerous machinery, including cars, with caution until they are sure that the medication has no adverse effects. .
Long elimination half-life
Because of the long elimination half-life of the parent drug and its major active metabolites, dose changes will not be fully reflected in plasma for several weeks, which can affect adjustment to the final dose and strategies for discontinuing therapy. This may be a potential consequence when discontinuation is required or when drugs that may interact with fluoxetine and desmethyl fluoxetine are prescribed after discontinuation of fluoxetine (see [Pharmacokinetics]). .
Adverse Drug Discontinuation Reactions
During the marketing of fluoxetine, SSRIs, and SNRIs, spontaneous adverse reactions have been reported following abrupt discontinuation of this class of drugs, including: agitation, irritability, agitation, dizziness, sensory disturbances (e.g., abnormal sensations like electric shock-like sensory abnormalities), anxiety, confusion, headache, drowsiness, mood swings, insomnia, and light mania. These reactions are generally self-limiting, but severe withdrawal symptoms have been reported. Patients should be monitored for these symptoms when fluoxetine is discontinued. It is recommended that the dose should be tapered if possible rather than stopped abruptly. If intolerable symptoms occur after a dose reduction or abrupt cessation of therapy, restarting the previously prescribed dose should be considered. Subsequently, the physician may continue to reduce the dose at a more moderate rate. Treatment findings suggest that a gradual reduction in plasma concentrations of fluoxetine and desmethyl fluoxetine minimizes the risk of discontinuation symptoms of this drug. .
Liver damage
In subjects with cirrhosis, the clearance of fluoxetine and its active metabolite, desmethyl fluoxetine, is reduced and thus the elimination half-life of these substances is prolonged. The dose or frequency of fluoxetine administration should be reduced when used in patients with cirrhosis. Caution should be exercised when using fluoxetine in patients with conditions that affect fluoxetine metabolism (see [Pharmacokinetics] Special Populations). .
Dependence
The potential for fluoxetine abuse, tolerance, or somatic dependence has not been systematically studied in animals or humans. Although premarketing clinical trials of fluoxetine have not shown withdrawal syndromes or trends in foraging behavior, these observations are not systematic and are unlikely to predict the extent to which a centrally active drug will be misused, diverted, and/or abused postmarketing based on these limited experiences. Therefore, physicians should carefully evaluate patients’ histories of substance abuse and closely follow such patients for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, dose increases, foraging behavior). .
Tamoxifen: Fluoxetine is a potent CYP2D6 inhibitor that causes a decrease in the concentration of 4-hydroxy-N-desmethyltamoxifen, one of the most important active metabolites of tamoxifen. Therefore, fluoxetine should be avoided as much as possible during tamoxifen therapy.
Sedentary inability/psychomotor agitation: Fluoxetine use may be accompanied by symptoms of sedentary inability, characterized by a subjective experience of unpleasant or painful agitation and the need to walk, often accompanied by an inability to sit or stand still. These conditions most often occur in the first few weeks of treatment, and patients who experience such symptoms may have them exacerbated by increasing the dose.
[For pregnant and lactating women
Pregnancy
Pregnancy Category C – Fluoxetine should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. All pregnancies are at background risk for birth defects, stillbirths, and other adverse outcomes, regardless of drug exposure. .
Treatment of pregnant women in the first trimester – There are no adequate, well-controlled clinical trials on the use of fluoxetine in pregnant women. Numerous epidemiologic studies assessing the risk of first-trimester exposure to fluoxetine have yielded inconsistent results, with more than 10 cohort and case-control studies failing to demonstrate an overall increased risk of developing congenital malformations. However, a prospective cohort study conducted by the European Teratology Information Service Network reported an increased risk of cardiovascular malformations in infants (N = 253) whose mothers were exposed to fluoxetine in the first trimester compared with infants whose mothers had no history of fluoxetine exposure (N = 1359 ). There is no specific pattern of cardiovascular malformations. However, overall, it is not possible to determine whether there is a causal relationship between the two.
Non-teratogenic effects – Neonates exposed to fluoxetine, other SSRIs, or 5 -hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs) in late gestation have had a history of requiring hospitalization , respiratory support, and tube feeding complications. Such complications may occur immediately after delivery. Reported clinical findings include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, catatonia, irritability, and persistent crying. These features are consistent with direct toxic effects of SNRIs and SSRIs or may be a discontinuation syndrome. It should be noted that in some cases, the clinical presentation is consistent with 5-hydroxytryptamine syndrome (see [caution] 5-hydroxytryptamine syndrome).
Infants exposed to SSRIs in late pregnancy are at increased risk of persistent pulmonary hypertension of the newborn (PPHN). In the general population, the incidence of PPHN is typically 1 to 2 in 1000 live births and is strongly associated with neonatal incidence and mortality. Several recent epidemiologic studies have shown a positive statistical association between SSRI use (including PROZAC) and PPHN during pregnancy. Other studies have not shown a statistically significant relationship.
Physicians should also be aware that in a prospective longitudinal study, 201 pregnant women with a history of major depression but whose symptoms had resolved were taking antidepressants or had taken antidepressants less than 12 weeks prior to their last menstrual period . Pregnant women who stopped taking antidepressants during pregnancy had a significantly higher rate of recurrence of depression compared with those who had been taking antidepressants during pregnancy.
When treating pregnant women with fluoxetine, physicians should carefully consider the potential risks of taking an SSRI, as well as the established benefits of antidepressants for depression. Decisions should be made on a case-by-case basis.
Animal Data – In the rat and rabbit embryo-fetal development trials, fluoxetine administered at doses up to 12.5 and 15 mg/kg/day, respectively , there was no evidence of teratogenicity during organogenesis (1.5 and 3.6 times the maximum recommended human dose (MRHD) of 80 mg based on mg/m2, respectively). However, in the rat reproduction assay, if mothers were exposed to 12 mg/kg/day during gestation (1.5 times the MRHD based on mg/m2) or 7.5 mg/kg/day during gestation and lactation (0.9 times the MRHD based on mg/m2), there was an increase in stillborn pups during the first 7 days postpartum , decreased pup weight, and increased pup mortality. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. For rat pup mortality, the no-effect dose was 5 mg/kg/day (0.6 times higher than MRHD based on mg/m2).
Paroxysmal pain and delivery
The effects of fluoxetine on human labor are still unknown. However, because fluoxetine penetrates the placenta and because fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor only if the potential benefit outweighs the potential risk to the fetus. .
Lactating women
Because fluoxetine can be secreted into human breast milk, breastfeeding while taking fluoxetine is not recommended. In one breast milk sample, the concentration of fluoxetine plus desmethyl fluoxetine was 70.4 ng/mL. The concentration in maternal plasma was 295.0 ng/mL. no adverse effects were reported in the infant. In another case, a newborn infant who received fluoxetine from a nursing mother developed crying, sleep disturbances, vomiting, and watery stools. On the second day of breastfeeding, the infant’s plasma drug concentration was 340 ng/mL for fluoxetine and 208 ng/mL for desmethyl fluoxetine.
[Pediatric Dosage].
As the safety and efficacy of use in Chinese children and adolescents (under 18 years of age) are not known, use in this population is not recommended.
[Geriatric use
The US fluoxetine clinical trial included 687 patients ≥65 years of age and 93 patients ≥75 years of age. Efficacy in elderly patients has been established (see [Clinical Trials]). For information on pharmacokinetics in older patients (see [Pharmacokinetics]). No overall differences in efficacy or safety were observed between these subjects and younger subjects, and no other clinical events were found to differ in response between older and younger patients, but a higher sensitivity in some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with clinically significant cases of hyponatremia in older patients, and the risk of this adverse effect may be higher in older individuals (see [Precautions]). risk may be higher (see [Caution] Hyponatremia). .
Dose increases should be cautious and generally should not exceed 40 mg/day; the maximum recommended dose is 60 mg/day (see [Dosage]).
[Drug Interactions
As with all drugs, interactions by various mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement) may exist. .
Monoamine oxidase inhibitors (MAOI)
(See [contraindications] and [precautions] for 5-hydroxytryptamine syndrome).
Drugs that act on the central nervous system
Caution is advised if fluoxetine needs to be co-administered with such medications. For each case, the concomitant drug should be considered starting at a lower initial dose, following a conservative escalation regimen and monitoring clinical status (see [Pharmacokinetics]). .
5-hydroxytryptaminergic drugs
(See [contraindications] and [precautions] for 5-hydroxytryptamine syndrome).
5-hydroxytryptamine, released by platelets, plays an important role in hemostasis. Case-control and cohort-designed epidemiological studies have demonstrated an association between the use of psychotherapeutic drugs that interfere with 5-hydroxytryptamine reuptake and the occurrence of gastrointestinal bleeding, and these studies have also shown that concomitant use of NSAIDs or aspirin may increase the risk of bleeding. altered anticoagulant effects, including bleeding, have been previously reported with SNRIs as well as SSRIs administered concomitantly with warfarin. Patients receiving warfarin therapy should be carefully monitored when starting or discontinuing fluoxetine therapy (see [PRECAUTIONS] Abnormal Bleeding).
Electroconvulsive therapy (ECT)
No clinical trials have been able to determine the benefit of ECT in combination with fluoxetine. There have been rare reports of prolonged seizures in patients treated with fluoxetine while receiving ECT. .
Likelihood of other drugs affecting fluoxetine
Drugs that bind tightly to plasma proteins – Because fluoxetine is able to bind tightly to plasma proteins, another tightly bound drug that displaces the protein-bound fluoxetine may cause adverse effects. – Because fluoxetine is able to bind to plasma proteins, another tightly bound drug that displaces protein-bound fluoxetine may cause adverse effects.
The potential for fluoxetine to affect other drugs
Pimozide – Concomitant use in patients taking pimozide is prohibited. Pimozide can prolong the QT interval. Fluoxetine can increase pimozide blood levels by inhibiting CYP2D6. Fluoxetine also prolongs the QT interval. Clinical trials of pimozide with other antidepressants have shown drug interactions or increased QTc interval. Although no clinical trials have been conducted specifically with pimozide and fluoxetine, concomitant use of pimozide and fluoxetine is contraindicated because of the potential for drug interactions or QTc prolongation (see [contraindications], [precautions] QT interval prolongation, and [drug interactions] drugs that prolong the QT interval). .
Thioridazine – Because of the risk of QT interval prolongation, thioridazine should not be given concomitantly with fluoxetine or should be given at least 5 weeks after discontinuation of fluoxetine (see [ Contraindications], [Precautions] QT interval prolongation and [Drug Interactions] Drugs that prolong the QT interval). .
In a trial with 19 healthy male subjects, including 6 slow hydroxylators and 13 fast hydroxylators of isoquinuclidine, the Cmax of 25 mg thioridazine administered orally in the slow hydroxylators was 2.4 times that of the fast hydroxylators and the AUC was 4.5 times that of the fast hydroxylators. It is believed that the rate of hydroxylation of isoquinoguanidine depends on the activity of CYP2D6 isoenzyme. This trial therefore suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, may have elevated plasma concentrations of thioridazine. .
Thioridazine administration causes a dose-related prolongation of the QTc interval, which can cause severe ventricular arrhythmias, such as tip-twist arrhythmias and sudden death. This risk is expected to be increased because fluoxetine inhibits thioridazine metabolism. .
Metabolized by CYP2D6 – Fluoxetine inhibits CYP2D6 activity and may make individuals with normal CYP2D6 metabolic activity to resemble the slow metabolizer. Caution should be exercised when fluoxetine is combined with other drugs metabolized by CYP2D6, including certain antidepressants (eg, TCA), antipsychotics (eg, phenothiazines and most atypicals), and antiarrhythmics (eg, propafenone, flecainide, and others). If a patient is receiving fluoxetine concurrently or has taken fluoxetine within the previous 5 weeks, treatment with drugs that are primarily metabolized by the CYP2D6 system and have a relatively narrow therapeutic index (see list below) should be started at the lower end of the dose range. Therefore, the dosing regimen is similar to that of the slow metabolizers. If a patient is already receiving a drug metabolized by CYP2D6, a lower dose of the original drug needs to be considered when adding fluoxetine to the regimen. Drugs with a narrow therapeutic index are of greatest concern (e.g., flecainide, propafenone, vincristine, and TCA). Because of the risk of serious arrhythmias and sudden death that may be associated with elevated thioridazine plasma concentrations, thioridazine should not be administered concomitantly with fluoxetine or should be administered at least 5 weeks after discontinuation of fluoxetine (see [Contraindications]). .
Tricyclic antidepressants (TCAs) – When co-administered with fluoxetine in 2 trials, the previously stable plasma concentrations of promethazine and desipramine were increased 2- to 10-fold. This effect may persist for 3 weeks or longer after fluoxetine administration. Therefore, concomitant administration with fluoxetine or recent administration of fluoxetine may require a dose reduction of TCA and temporary monitoring of TCA plasma concentrations (see [PRECAUTIONS] 5-hydroxytryptamine Syndrome and [PHARMACOLOGY]). .
Benzodiazepines – In some patients, the half-life of concomitantly administered benzodiazepines may be prolonged (see [Pharmacokinetics]). Concomitant administration of alprazolam with fluoxetine increases plasma concentrations of alprazolam and further decreases psychomotor behavior due to increased alprazolam concentrations. .
Antipsychotics – Certain clinical data suggest that pharmacodynamic and/or pharmacokinetic interactions may exist between SSRIs and antipsychotics. Elevated blood levels of haloperidol and clozapine have been previously observed in patients receiving concomitant fluoxetine. .
Anticonvulsants – Elevated anticonvulsant plasma concentrations and clinical anticonvulsant drug toxicity.
Lithium salts – Elevated and decreased lithium concentrations have been reported when lithium is administered concomitantly with fluoxetine. Cases of lithium toxicity and increased 5-hydroxytryptamine effects have been previously reported. Lithium concentrations should be monitored when these drugs are administered concomitantly (see [caution] 5-hydroxytryptamine syndrome). .
Drugs that bind tightly to plasma proteins – Because fluoxetine binds tightly to plasma proteins, if a patient is taking another drug that binds tightly to proteins (eg coumarin, digoxin), fluoxetine may cause fluctuations in plasma concentrations when given, which may cause adverse effects (see [Pharmacokinetics]). .
Drugs metabolized by CYP3A4 – In an in vivo interaction trial involving fluoxetine and a single dose of terfenadine (a CYP3A4 substrate ) was administered concomitantly, plasma concentrations of terfenadine were not increased by concomitant administration of fluoxetine. .
In addition, in vitro assays have demonstrated that ketoconazole is a potent inhibitor of CYP3A4 activity as an inhibitor of metabolism of several substrates of this enzyme (including astemizole, cisapride, and midazolam) at a strength of at least 100% that of fluoxetine or desmethylfluoxetine, by a factor of 100. These data suggest that the extent to which fluoxetine inhibits CYP3A4 activity is unlikely to be clinically meaningful. .
Olanzapine-fluoxetine (60 mg single dose or 60 mg daily for 8 days) resulted in a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) increase in the clearance of olanzapine. caused a small (mean 16%) decrease in the clearance of olanzapine. The magnitude of the effect of this factor was small compared with the overall interindividual variability, and thus dose adjustment is generally not recommended. .
Drugs to prolong the QT interval
Fluoxetine should not be combined with thioridazine or pimozide. Fluoxetine should be used with caution when combined with other drugs that cause prolongation of the QT interval. These include certain specific antipsychotics (e.g., ziprasidone, ibuprostone, chlorpromazine, clorazepam, and haloperidol), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, and sparfloxacin), class 1A antiarrhythmic drugs (e.g., quinidine and procainamide), class III antiarrhythmic drugs (e.g., amiodarone and sotalol), and other drugs (e.g., pentoxifylline, levacetylmethadone, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol, or tacrolimus, etc.). The metabolism of fluoxetine is primarily accomplished through CYP2D6. The use of CYP2D6 inhibitors as concomitant therapy increases the concentration of fluoxetine. Concurrent use of other drugs with high protein binding properties can also increase fluoxetine concentrations (see [contraindications], [precautions] QT interval prolongation, [drug interactions] potential for fluoxetine to affect other drugs, and [pharmacokinetics]).
Ethanol: Fluoxetine did not increase blood ethanol levels or potentiate ethanol effects in formal trials. However, SSRI treatment in combination with ethanol is not recommended.
[Drug overdose].
Human experience
Globally, the level of exposure to fluoxetine hydrochloride is estimated to exceed 38 million patients (Circa 1999). Of the 1578 cases involving fluoxetine hydrochloride overdose alone or with other drugs reported by this group, 195 deaths occurred. .
Of the 633 adult patients who overdosed with fluoxetine hydrochloride alone, 34 resulted in fatal outcomes, 378 recovered completely, and 15 patients developed sequelae after the overdose, including abnormal eye regulation, abnormal gait, consciousness confusion, nonresponse, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, dyskinesia, and light mania. Outcomes for the remaining 206 patients were not available. The most common signs and symptoms associated with nonfatal overdose were seizures, drowsiness, nausea, tachycardia, and vomiting. In adult patients, the maximum known intake of fluoxetine hydrochloride was 8 g. This patient took fluoxetine alone and later recovered. However, in a patient taking fluoxetine alone, an intake as low as 520 mg was associated with a fatal outcome, but no causal relationship was established. .
In pediatric patients (3 months to 17 years of age), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. 6 patients died, 127 patients recovered completely, 1 patient developed renal failure, and 22 patients’ outcomes were unknown. One of the 6 deaths was a 9-year-old boy with a history of obsessive-compulsive disorder, Tourette syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had received 100 mg of fluoxetine daily for 6 months in addition to colistin, methylphenidate, and promethazine. Mixed drug intake or other suicidal methods complicated the 6 children whose drug overdose resulted in death. The maximum intake in pediatric patients was 3 g, which was not fatal. .
Other important adverse reactions reported after fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (eg, junctional rhythm, prolonged QT interval, and ventricular tachycardia, including tip-twist arrhythmias ), hypotension, mania, nerve blocker malignant syndrome-like reactions, fever, miosis, and syncope.
Animal Experience
Animal studies do not provide precise or necessarily valid information in the treatment of overdose in humans. However, animal studies can provide a useful reference for possible treatment strategies. .
The median oral lethal dose was found to be 452 and 248 mg/kg in rats and mice, respectively, and high acute oral doses resulted in high irritability and convulsions in several animal species. .
Major seizures occurred in 5 of 6 dogs that were deliberately overdosed with oral fluoxetine. Seizures ceased immediately after intravenous pushing of a standard veterinary dose of diazepam. In this short-term trial, the minimum plasma concentration during seizures was only 2 times the maximum plasma concentration observed in humans on a long-term dose of 80 mg/day. .
In a separate single-dose dosing trial, the electrocardiograms of dogs receiving high-dose dosing did not show prolonged PR, QRS, or QT intervals. Increased tachycardia and blood pressure were observed. Therefore, ECG values predicting cardiotoxicity are not known. Nevertheless, ECG should generally be monitored during human overdose (see [Drug Overdose] Management of Overdose). .
Overdose management
Treatment should include the general measures used to manage any drug overdose. The possibility of multiple drug overdoses should also be considered. .
Ensure a patent airway with good oxygenation and ventilation. Monitor heart rhythm and vital signs. Use general supportive therapy and symptomatic measures. Do not recommend hyperventilation. .
Activated carbon should be given. Because of the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and blood exchange therapy are unlikely to be beneficial. A specific antidote for fluoxetine is not known. .
Particular attention should be paid to patients who are taking or have recently taken fluoxetine and may have taken an overdose of TCA. In such cases, accumulation of the parent of the tricyclic and/or its active metabolite may increase the likelihood of clinically significant sequelae and prolong the time required for close medical observation (see [Drug Interactions] Potential for Fluoxetine to Affect Other Drugs). .
[Pharmacology and Toxicology
Pharmacological effects
Fluoxetine has antidepressant effects, presumably related to its inhibition of central neuronal 5-HT reuptake. Results from animal studies showed that fluoxetine inhibited 5-HT reuptake more strongly than norepinephrine. At clinically relevant doses, fluoxetine inhibited 5-HT reuptake by human platelets.
The anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressants are related to their antagonistic effects on muscarinic, histaminic, and adrenergic a1 receptors. In vitro receptor binding assays have shown that fluoxetine binds significantly weaker than tricyclic antidepressants to these and other membrane receptors in brain tissue.
Toxicological studies
Genotoxicity
The Ames test, rat hepatocyte DNA repair test, mouse lymphoma test, and Chinese hamster bone marrow cell sister chromatid interchange test for fluoxetine and its metabolite desmethyl fluoxetine were all negative.
Reproductive toxicity
No adverse effects on fertility were seen in rats at doses of fluoxetine up to 7.5 and 12.5 mg/kg/day [in mg/m2, equivalent to approximately 0.9 and 1.5 times the maximum recommended human dose ([MRHD] 80 mg), respectively.
In embryo-fetal developmental toxicity tests, no teratogenicity was seen in rats and rabbits given fluoxetine at doses up to 12.5 and 15 mg/kg/day (1.5 and 3.6 times the MRHD in mg/m2, respectively) during the organogenesis phase.
In a perinatal toxicity test, when rats were given 12 mg/kg/day during gestation (equivalent to 1.5 times the MRHD in mg/m2) or 7.5 mg/kg/day during gestation and lactation (equivalent to 0.9 times the MRHD in mg/m2 extrapolation), an An increase in the number of stillbirths, a decrease in pup weight in the first 7 days after birth and an increase in pup mortality. In rats given 12 mg/kg/day during gestation, no neurodevelopmental toxicity was observed in the surviving pups. The no-effect dose for pup mortality was 5 mg/kg/day (0.6 times the MRHD in mg/m2).
In carcinogenicity tests in rats and mice, fluoxetine was administered by adulteration up to 10 and 12 mg/kg/day (in mg/m2, equivalent to approximately 1.2 and 0.7 times the MRHD, respectively) for 2 years, and no carcinogenicity was observed.
Other toxicity
Phospholipids were increased in some tissues after long-term administration of fluoxetine in mice, rats, and dogs, and this effect was reversible after discontinuation. Phospholipid accumulation has been observed in animals with many cationic amphiphiles (including fenfluramine, promethazine, and ranitidine). The significance of this effect in humans is unclear. .
[Pharmacokinetics].
Systemic bioavailability – In humans, peak plasma concentrations of fluoxetine observed 6 to 8 hours after a single oral dose of 40 mg was 15 to 55 ng/mL.
Bioequivalence was observed between the two dosage forms, Bacitracin bullet-type capsules and Bacitracin weekly capsules. Food has no effect on the systemic bioavailability of fluoxetine, but may delay its absorption by 1 to 2 hours, which is likely to be of no clinical significance. Therefore, fluoxetine may be taken with or without food . Pepcid Weekly Capsules, an extended-release dosage form, contains particles encapsulated in an enteric-coated formulation that resists dissolution until it reaches the portion of the gastrointestinal tract with a pH above 5.5. The enteric coating delays the absorption of fluoxetine by 1 to 2 hours relative to the immediate-release formulation. .
Protein binding – Above concentrations of 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound to human serum proteins, including albumin and α 1-glycoprotein. Interactions between fluoxetine and other drugs that bind tightly to proteins have not been fully evaluated but may be important. .
Enantiomeric-fluoxetine is a racemic mixture of the enantiomers of R-fluoxetine and S-fluoxetine (50/50). In animal models, both enantiomers are specific and potent inhibitors of 5-hydroxytryptamine uptake with nearly equivalent pharmacological activity. the enantiomeric elimination of S-fluoxetine is much slower and is the predominant enantiomer present in plasma at steady state. .
Metabolism – In the liver, fluoxetine is extensively metabolized to desmethyl fluoxetine and various other unidentified metabolites. The only identified active metabolite, desmethyl fluoxetine, is formed by the demethylation of fluoxetine. In animal models, S-desmethyl fluoxetine is a potent selective 5-hydroxytryptamine uptake inhibitor with activity nearly equivalent to that of R- or S-fluoxetine. In inhibiting 5-hydroxytryptamine uptake, R-desmethylfluoxetine is significantly less potent than the parent drug. The primary elimination pathway is hepatic metabolism, with excretion of inactivated metabolites via the kidney. .
Metabolic variability – A subset of the population (approximately 7%) has reduced activity of the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are called “slow metabolizers” of drugs, including isoquinolines, dextromethorphan, and TCA. In an assay involving labeled and unlabeled enantiomers administered as racemates, these individuals metabolized S-fluoxetine at a slower rate and were thus able to achieve higher concentrations of S-fluoxetine. As a result, S-desmethyl fluoxetine concentrations at steady state were lower. The metabolism of R-fluoxetine is normal in these slow metabolizers. In the slow metabolizers, the sum of the plasma concentrations of the four active enantiomers at steady state was not significantly higher than in the normal metabolizers. Thus, the net pharmacodynamic activity was essentially the same. In contrast, the unsaturated pathway (non-2D6) also plays a role in the metabolism of fluoxetine. This could explain how fluoxetine was able to reach steady-state concentrations rather than increasing indefinitely. .
Because like a variety of other compounds, including TCA and other selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), fluoxetine metabolism involves the CYP2D6 system, and with other drugs that are also metabolized by this enzyme system (e.g., TCA) Concomitant dosing with other drugs that are also metabolized by this enzyme system (e.g., TCA) may lead to drug interactions (see [Drug Interactions] for the potential for fluoxetine to affect other drugs). .
Accumulation and slow elimination – Fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after long-term administration) and its active metabolite, desmethyl fluoxetine ( with elimination half-lives of 4 to 16 days after acute and long-term administration) are eliminated relatively slowly, even with fixed doses, resulting in significant accumulation of these active ingredients and delayed time to steady state with long-term use (see [Caution] Long Half-Life). After 30 days of dosing at 40 mg/day, plasma concentrations were found to range from 91 to 302 ng/mL for fluoxetine and 72 to 258 ng/mL for desmethyl fluoxetine. plasma concentrations of fluoxetine were higher than those predicted by single dosing trials because the metabolism of fluoxetine is not proportional to the dose. However, desmethyl fluoxetine has linear pharmacokinetics. Its mean terminal half-life was 8.6 days after a single dose and 9.3 days after multiple doses. After long-term administration, steady-state concentrations were similar to those observed at weeks 4 to 5. .
The long elimination half-lives of fluoxetine and desmethyl fluoxetine ensure that the active pharmaceutical ingredient remains in the body for several weeks even if dosing is discontinued (depending primarily on individual patient characteristics, prior dosing regimen, length of prior therapy at the time of discontinuation). length of prior therapy at the time of discontinuation). This may be a potential consequence when discontinuation is required or when drugs that may interact with fluoxetine and desmethyl fluoxetine are prescribed after discontinuation of fluoxetine. .
Weekly Dosing – Compared with daily dosing, weekly dosing of fluoxetine weekly capsules resulted in increased fluctuations between peak and trough fluoxetine and desmethyl fluoxetine concentrations [for fluoxetine: 24% ( daily) to 164% (weekly) and for desmethylfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations do not necessarily predict clinical response. The peak concentrations of fluoxetine when administered once weekly in fluoxetine weekly capsules were within the range of the mean concentrations for 20 mg once-daily administration. Compared to the concentrations maintained by 20 mg once-daily dosing, the mean trough concentrations were 76% lower for fluoxetine and 47% lower for desmethyl fluoxetine. The mean steady-state concentrations were relatively proportional to the total dose administered for either once-daily or weekly dosing. The mean steady-state concentration of fluoxetine was approximately 50% lower following the once-daily dosing regimen compared to the once-weekly dosing regimen. .
First use of 20 mg once-daily dosing and switch to 90 mg once-weekly dosing regimen the day after discontinuation. In this regimen, the Cmax of fluoxetine after 90 mg dosing was approximately 1.7 times the Cmax of 20 mg once-daily dosing. In contrast, if 1 week elapsed between the first 90 mg weekly dose and the last 20 mg once-daily dose, the Cmax values measured after both doses were similar. Moreover, a transient increase in the mean steady-state concentration of fluoxetine was observed after switching to the once-weekly dosing regimen the day after discontinuation of once-daily dosing. From a pharmacokinetic point of view, a one-week interval between the first 90 mg weekly dose and the last 20 mg once-daily dose may be preferable. .
Special Populations
Hepatic disease – Liver damage may affect fluoxetine elimination, as can be predicted based on its use as a major site of metabolism. In a trial in patients with cirrhosis, the elimination half-life of fluoxetine was prolonged, averaging 7.6 days compared with 2 to 3 days in subjects without liver disease; the half-life of desmethyl fluoxetine was also prolonged, averaging 12 days for patients with cirrhosis compared with 7 to 9 days in normal subjects. This suggests that caution must be exercised in the use of fluoxetine in patients with liver disease. If fluoxetine is administered to patients with liver disease, the dose or frequency of administration should be reduced (see [Precautions] Liver Damage). .
Renal Disease – In depressed patients on dialysis (N = 12), fluoxetine was administered at 20 mg once daily for 2 months and achieved steady-state fluoxetine and desmethyl fluoxetine plasma concentrations were similar to those observed in patients with normal renal function. In patients with severe renal dysfunction, fluoxetine metabolites excreted via the kidneys may accumulate to higher concentrations, and although this possibility exists, a routine reduction in dose or dosing frequency is generally not required in patients with renal impairment. .
Geriatric Pharmacokinetics – In healthy elderly subjects (>65 years), drug disposition after a single dose of fluoxetine was not significantly different from that of younger normal subjects. However, because of the long half-life and nonlinear disposition of the drug, single-dose trials cannot adequately exclude the possibility of altered pharmacokinetics in older adults, especially if they have systemic disease or receive multiple medications for concomitant disease. 260 elderly but otherwise healthy depressed patients (age ≥60 years) received 20 mg fluoxetine for 6 weeks and studied the effect of age on fluoxetine metabolism. effects. At the end of 6 weeks, the concentration of fluoxetine plus desmethyl fluoxetine was 209.3 ± 85.7 ng/mL. In these elderly patients, no unusual age-related adverse effect pattern was observed. .
Pediatric Pharmacokinetics (Children and Adolescents) – In 21 pediatric patients diagnosed with depression or obsessive-compulsive disorder (10 children were between 6 and .
Mean steady-state fluoxetine and desmethyl fluoxetine concentrations observed in children were higher than in adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and desmethylfluoxetine accumulate substantially after multiple oral doses; steady-state concentrations are reached 3 to 4 weeks after daily dosing. .
[Storage].
Store under shade and seal
[Packaging
Packaged in aluminum-plastic plate; 7 capsules/box; 14 capsules/box
[Expiration date
12 months
[Executive Standard
[Approval Number].
State Drug CertificateH19980114
[Manufacturer]
Company Name: Shanghai ShangPharma Midwest Pharmaceutical Co.
Manufacturing Address: No. 446, Wai-Qingsong Highway, Jiading District, Shanghai
Postal Code: 201806
Contact Phone: 021-51653688
Fax number: 021-51653689
Website: http://www.shzxyy.com/