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Prozac Side Effects, and Drug Interactions - Fluoxetine

Prozac Side Effects, and Drug Interactions - Fluoxetine

SIDE EFFECTS

Multiple doses of fluoxetine HCl had been administered to 10,782 patients with various diagnoses in U.S. clinical trials as of May 8, 1995. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories.

In the TABLE 2A, TABLE 2B, TABLE 2C, TABLE 3, TABLE 4 and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.

The prescriber should be aware that the figures in the TABLE 2A, TABLE 2B, TABLE 2C, TABLE 3, TABLE 4 and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Incidence in U.S. Placebo-Controlled Clinical Studies (excluding data from extensions of trials)

TABLE 2A, TABLE 2B and TABLE 2C enumerate the most common treatment-emergent adverse events associated with the use of fluoxetine HCl (incidence of at least 5% for fluoxetine HCl and at least twice that for placebo within at least one of the indications) for the treatment of depression, OCD, and bulimia in U.S. controlled clinical trials. TABLE 3 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with fluoxetine HCl and with incidence greater than placebo who participated in U.S. controlled clinical trials comparing fluoxetine HCl with placebo in the treatment of depression, OCD, or bulimia. TABLE 3 provides combined data for the pool of studies that are provided separately by indication in TABLE 2A, TABLE 2B and TABLE 2C.

TABLE 2A Most Common Treatment-Emergent Adverse Events: Incidence In U.S. Depression Placebo-Controlled Clinical Trials
	Percentage of Patients Reporting Event
	Depression
Body System/Adverse Event	Fluoxetine HCl (N=1728)	Placebo (N=975)
Body as a Whole
Asthenia	9	5
Flu syndrome	3	4
Cardiovascular System
Vasodilation	3	2
Digestive System
Nausea	21	9
Anorexia	11	2
Dry mouth	10	7
Dyspepsia	7	5
Nervous System
Insomnia	16	9
Anxiety	12	7
Nervousness	14	9
Somnolence	13	6
Tremor	10	3
Libido decreased	3	--
Abnormal dreams	1	1
Respiratory System
Pharyngitis	3	3
Sinusitis	1	4
Yawn	--	--
Skin and Appendages
Sweating	8	3
Rash	4	3
Urogenital System
Impotence*	2	--
Abnormal ejaculation*	--	--
* Denominator used was males only (N=690 fluoxetine HCl depression; N=410 placebo depression; N=116 fluoxetine HCl OCD; N=43 placebo OCD; N=14 fluoxetine HCl bulimia; N=1 placebo bulimia).
¾ Incidence less than 1%.

TABLE 2B Most Common Treatment-Emergent Adverse Events: Incidence In U.S. OCD Placebo-Controlled Clinical Trials
	Percentage of Patients Reporting Event
	OCD
Body System/Adverse Event	Fluoxetine HCl (N=266)	Placebo (N=89)
Body as a Whole
Asthenia	15	11
Flu syndrome	10	7
Cardiovascular System
Vasodilation	5	--
Digestive System
Nausea	26	13
Anorexia	17	10
Dry mouth	12	3
Dyspepsia	10	4
Nervous System
Insomnia	28	22
Anxiety	14	7
Nervousness	14	15
Somnolence	17	7
Tremor	9	1
Libido decreased	11	2
Abnormal dreams	5	2
Respiratory System
Pharyngitis	11	9
Sinusitis	5	2
Yawn	7	--
Skin and Appendages
Sweating	7	--
Rash	6	3
Urogenital System
Impotence*	--	--
Abnormal ejaculation*	7	--
* Denominator used was males only (N=690 fluoxetine HCl depression; N=410 placebo depression; N=116 fluoxetine HCl OCD; N=43 placebo OCD; N=14 fluoxetine HCl bulimia; N=1 placebo bulimia).
¾ Incidence less than 1%.

TABLE 2C Most Common Treatment-Emergent Adverse Events: Incidence In U.S. Bulimia Placebo-Controlled Clinical Trials
	Percentage of Patients Reporting Event
	Bulimia
Body System/Adverse Event	Fluoxetine HCl (N=450)	Placebo (N=267)
Body as a Whole
Asthenia	21	9
Flu syndrome	8	3
Cardiovascular System
Vasodilation	2	1
Digestive System
Nausea	29	11
Anorexia	8	4
Dry mouth	9	6
Dyspepsia	10	6
Nervous System
Insomnia	33	13
Anxiety	15	9
Nervousness	11	5
Somnolence	13	5
Tremor	13	1
Libido decreased	5	1
Abnormal dreams	5	3
Respiratory System
Pharyngitis	10	5
Sinusitis	6	4
Yawn	11	--
Skin and Appendages
Sweating	8	3
Rash	4	4
Urogenital System
Impotence*	7	--
Abnormal ejaculation*	7	--
* Denominator used was males only (N=690 fluoxetine HCl depression; N=410 placebo depression; N=116 fluoxetine HCl OCD; N=43 placebo OCD; N=14 fluoxetine HCl bulimia; N=1 placebo bulimia).
¾ Incidence less than 1%.

TABLE 3 Treatment-Emergent Adverse Events: Incidence In U.S. Depression, OCD, and Bulimia Placebo-Controlled Clinical Trials
	Percentage of Patients Reporting Event
	Depression, OCD, and Bulimia
Body System/Adverse Event*	Fluoxetine HCl (N=2444)	Placebo (N=1331)
Body as a Whole
Headache	21	20
Asthenia	12	6
Flu syndrome	5	4
Fever	2	1
Cardiovascular System
Vasodilation	3	1
Palpitation	2	1
Digestive System
Nausea	23	10
Diarrhea	12	8
Anorexia	11	3
Dry mouth	10	7
Dyspepsia	8	5
Flatulence	3	2
Vomiting	3	2
Metabolic and Nutritional Disorders
Weight loss	2	1
Nervous System
Insomnia	20	11
Anxiety	13	8
Nervousness	13	9
Somnolence	13	6
Dizziness	10	7
Tremor	10	3
Libido decreased	4	--
Respiratory System
Pharyngitis	5	4
Yawn	3	--
Skin and Appendages
Sweating	8	3
Rash	4	3
Pruritus	3	2
Special Senses
Abnormal vision	3	1
* Included are events reported by at least 2% of patients taking fluoxetine HCl, except the following events, which had an incidence on placebo ³fluoxetine HCl (depression, OCD, and bulimia combined): abnormal pain, abnormal dreams, accidental injury, back pain, chest pain, constipation, cough increased, depression (includes suicidal thoughts), dysmenorrhea, gastrointestinal disorder, infection, myalgia, pain, paresthesia, rhinitis, sinusitus, thinking abnormal.
¾ Incidence less than 1%.

Associated with Discontinuation in U.S. Placebo-Controlled Clinical Studies (excluding data from extensions of trials)

TABLE 4 lists the adverse events associated with discontinuation of fluoxetine HCl treatment (incidence at least twice that for placebo and at least 1% for fluoxetine HCl in clinical trials collecting only a primary event associated with discontinuation) in depression, OCD, and bulimia.

TABLE 4 Most Common Adverse Events Associated with Discontinuation in U.S. Depression, OCD, and Bulimia Placebo-controlled Clinical Trials
Depression, OCD, and bulima combined (N=1108)	Depression (N=392)	OCD (N=266)	Bulimia (N=450)
--	--	Anxiety (2%)	--
Insomnia (1%)	¾	--	Insomnia (2%)
--	Nervousness (1%)	--	--
--	--	Rash (1%)	--

Other Events Observed in all U.S. Clinical Studies

Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in U.S. clinical trials (10,782 patients) except:

1. Those listed in the body or footnotes of TABLE 1 or TABLE 2A, TABLE 2B and TABLE 2C above or elsewhere in labeling.

2. Those for which the COSTART terms were uninformative or misleading

3. Those events for which a causal relationship to fluoxetine HCl use was considered remote

4. Events occurring in only 1 patient treated with fluoxetine HCl and which did not have a substantial probability of being acutely life-threatening.

Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients.

Body as a Whole: Frequent: Chills; Infrequent: Chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: Abdominal syndrome acute, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction.

Cardiovascular System: Frequent: Hemorrhage, hypertension; Infrequent: Angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: Atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.

Digestive System: Frequent: Increased appetite, nausea and vomiting; Infrequent: Aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: Biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.

Endocrine System: Infrequent: Hypothyroidism; Rare: Diabetic acidosis, diabetes mellitus.

Hemic and Lymphatic System: Infrequent: Anemia, ecchymosis; Rare: Blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia.

Metabolic and Nutritional: Frequent: Weight gain; Infrequent: Dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: Alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased.

Musculoskeletal System: Infrequent: Arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: Arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.

Nervous System: Frequent: Agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent: Abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder (the COSTART term for designating non-aggressive objectionable behavior), psychosis, vertigo; Rare: Abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor.

Respiratory System: Infrequent: Asthma, epistaxis, hiccup, hyperventilation; Rare: Apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.

Skin and Appendages: Infrequent: Acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: Furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.

Special Senses: Frequent: Ear pain, taste perversion, tinnitus; Infrequent: Conjunctivitis, dry eyes, mydriasis, photophobia; Rare: Blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.

Urogenital System: Frequent: Urinary frequency; Infrequent: Abortion*, albuminuria, amenorrhea*, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation*, fibrocystic breast*, hematuria, leukorrhea*, menorrhagia*, metrorrhagia*, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage*; Rare: Breast engorgement, glycosuria, hypomenorrhea*, kidney pain, oliguria, priapism*, uterine hemorrhage*, uterine fibroids enlarged*.

Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.

* Adjusted for gender.

Postintroduction Reports

Voluntary reports of adverse events temporally associated with fluoxetine HCl that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual- masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, pancreatitis, pancytopenia, priapism, pulmonary embolism, QT prolongation, Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, and violent behaviors.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class: Fluoxetine HCl is not a controlled substance.

Physical and Psychological Dependence: Fluoxetine HCl has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine HCl did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine HCl (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

DRUG INTERACTIONS

As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY, Accumulation and Slow Elimination).

Drugs Metabolized by P450IID6

Approximately 7% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme P450IID6. Such individuals have been referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants. Many drugs, such as most antidepressants, including fluoxetine and other selective uptake inhibitors of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite the sum of the plasma concentrations of the 4 active enantiomers is comparable between poor and extensive metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism).

Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble "poor metabolizers." Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index (see CNS Active Drugs - below), should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of "poor metabolizers." If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P450IID6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, vinblastine, and tricyclic antidepressants).

Drugs Metabolized by Cytochrome P450IIIA4

In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P450IIIA4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical significance.

CNS Active Drugs

The risk of using fluoxetine HCl in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of fluoxetine HCl and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see CLINICAL PHARMACOLOGY, Accumulation and Slow Elimination).

Anticonvulsants: Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Antipsychotics: Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. A single case report has suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.

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

Lithium: There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

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

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS.

Other Antidepressants: In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10-fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of tricyclic antidepressant (TCA) may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see CLINICAL PHARMACOLOGY, Accumulation and Slow Elimination and Drugs Metabolized by P450IID6).

Potential Effects of Coadministration of Drugs Tightly Bound to Plasma Proteins

Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs (see CLINICAL PHARMACOLOGY, Accumulation and Slow Elimination).

Warfarin: Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped.

Electroconvulsive Therapy: There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

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