ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Of the 1087 OCD and depressed patients treated with fluvoxamine maleate in controlled clinical trials conducted in North America, 22% discontinued treatment due to an adverse event. The most common events (≥ 1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate at least twice that of placebo) included:
Table 6 | Adverse Events Associated With Discontinuation Of Treatment In OCD And Depression Populations |
| Body System/ Adverse Event | Percentage Of Patients |
| Fluvoxamine | Placebo |
| Body As A Whole | | |
| Headache | 3% | 1% |
| Asthenia | 2% | < 1% |
| Abdominal Pain | 1% | 0% |
| Digestive | | |
| Nausea | 9% | 1% |
| Diarrhea | 1% | < 1% |
| Vomiting | 2% | < 1% |
| Anorexia | 1% | < 1% |
| Dyspepsia | 1% | < 1% |
| Nervous System | | |
| Insomnia | 4% | 1% |
| Somnolence | 4% | < 1% |
| Nervousness | 2% | < 1% |
| Agitation | 2% | < 1% |
| Dizziness | 2% | < 1% |
| Anxiety | 1% | < 1% |
| Dry Mouth | 1% | < 1% |
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Fluvoxamine maleate tablets have been studied in 10 week short-term controlled trials of OCD (N = 320) and depression (N = 1350). In general, adverse event rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse events associated with the use of fluvoxamine maleate tablets and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) derived from Table 7 were: abnormal ejaculation, anorexia, asthenia, dyspepsia, insomnia, nausea, nervousness, somnolence, sweating, tremor and vomiting. In a pool of two studies involving only patients with OCD, the following additional events were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion and urinary frequency. In a study of pediatric patients with OCD, the following additional events were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash.
Adverse Events Occurring at an Incidence of 1%
Table 7 enumerates adverse events that occurred in adults at a frequency of 1% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate tablets in two short-term placebo-controlled OCD trials (10 week) and depression trials (6 week) in which patients were dosed in a range of generally 100 to 300 mg/day. This table shows the percentage of patients in each group who had at least one occurrence of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors may 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 non-drug factors to the side effect incidence rate in the population studied.
Table 7 |
1 Events for which fluvoxamine maleate incidence was equal to or less than placebo are not listed in the table above, but include the following: abdominal pain, abnormal dreams, appetite increase, back pain, chest pain, confusion, dysmenorrhea, fever, infection, leg cramps, migraine, myalgia, pain, paresthesia, pharyngitis, postural hypotension, pruritus, rash, rhinitis, thirst and tinnitus.
2 Includes “toothache,” “tooth extraction and abscess,” and “caries.”
3 Mostly feeling warm, hot, or flushed.
4 Mostly “blurred vision.”
5 Mostly “delayed ejaculation.”
6 Incidence based on number of male patients.
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| Treatment-Emergent Adverse Event Incidence Rates By Body System In Adult OCD And Depression Populations Combined 1 |
| | Percentage of Patients Reporting Event |
| Body System/ Adverse Event | Fluvoxamine N = 892 | Placebo N = 778 |
| Body As Whole | | |
| Headache | 22 | 20 |
| Asthenia | 14 | 6 |
| Flu syndrome | 3 | 2 |
| Chills | 2 | 1 |
| Cardiovascular | | |
| Palpitations | 3 | 2 |
| Digestive System | | |
| Nausea | 40 | 14 |
| Diarrhea | 11 | 7 |
| Constipation | 10 | 8 |
| Dyspepsia | 10 | 5 |
| Anorexia | 6 | 2 |
| Vomiting | 5 | 2 |
| Flatulence | 4 | 3 |
| Tooth disorder2 | 3 | 1 |
| Dysphagia | 2 | 1 |
| Nervous System | | |
| Somnolence | 22 | 8 |
| Insomnia | 21 | 10 |
| Dry mouth | 14 | 10 |
| Nervousness | 12 | 5 |
| Dizziness | 11 | 6 |
| Tremor | 5 | 1 |
| Anxiety | 5 | 3 |
| Vasodilation3 | 3 | 1 |
| Hypertonia | 2 | 1 |
| Agitation | 2 | 1 |
| Decreased libido | 2 | 1 |
| Depression | 2 | 1 |
| CNS stimulation | 2 | 1 |
| Respiratory System | | |
| Upper respiratory infection | 9 | 5 |
| Dyspnea | 2 | 1 |
| Yawn | 2 | 0 |
| Skin | | |
| Sweating | 7 | 3 |
| Special Senses | | |
| Taste perversion | 3 | 1 |
| Amblyopia4 | 3 | 2 |
| Urogenital | | |
| Abnormal ejaculation5,6 | 8 | 1 |
| Urinary frequency | 3 | 2 |
| Impotence6 | 2 | 1 |
| Anorgasmia | 2 | 0 |
| Urinary retention | 1 | 0 |
Adverse Events in OCD Placebo-Controlled Studies Which are Markedly Different (defined as at least a two-fold difference) in Rate from the Pooled Event Rates in OCD and Depression Placebo-Controlled Studies
The events in OCD studies with a two-fold decrease in rate compared to event rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea.
The events in OCD studies with a two-fold increase in rate compared to event rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, infection, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia and urinary retention. These events are listed in order of decreasing rates in the OCD trials.
Other Adverse Events in OCD Pediatric Population
In pediatric patients (N = 57) treated with fluvoxamine maleate tablets, the overall profile of adverse events was generally similar to that seen in adult studies, as shown in Table 7. However, the following adverse events, not appearing in Table 7, were reported in two or more of the pediatric patients and were more frequent with fluvoxamine maleate tablets than with placebo: abnormal thinking, cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, infection, manic reaction, rash, sinusitis, and weight decrease.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.
Table 8 displays the incidence of sexual side effects reported by at least 2% of patients taking fluvoxamine tablets in placebo-controlled trials in depression and OCD.
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* Based on the number of male patients.
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| Table 8 |
| Percentage of Patients Reporting Sexual Adverse Events in Adult Placebo-Controlled Trials in OCD and Depression |
| | Fluvoxamine Maleate Tablets N = 892 | Placebo N = 778 |
| Abnormal ejaculation* | 8% | 1% |
| Impotence* | 2% | 1% |
| Decreased libido | 2% | 1% |
| Anorgasmia | 2% | 0% |
There are no adequate and well-controlled studies examining sexual dysfunction with fluvoxamine treatment.
Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of fluvoxamine.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Vital Sign Changes
Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various vital signs variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various vital signs variables revealed no important differences between fluvoxamine maleate and placebo.
Laboratory Changes
Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various serum chemistry, hematology, and urinalysis variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various serum chemistry, hematology, and urinalysis variables revealed no important differences between fluvoxamine maleate and placebo.
ECG Changes
Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) mean change from baseline on various ECG variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various ECG variables revealed no important differences between fluvoxamine maleate and placebo.
Other Events Observed During the Premarketing Evaluation of Fluvoxamine Maleate Tablets
During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for a combined total of 2737 patient exposures in patients suffering OCD or major depressive disorder. Untoward events associated with this exposure 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 untoward events into a limited (i.e., reduced) number of standard event categories.
In the tabulations which follow, a standard COSTART-based Dictionary terminology has been used to classify reported adverse events. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. The frequencies presented, therefore, represent the proportion of the 2737 patient exposures to multiple doses of fluvoxamine maleate who experienced an event of the type cited on at least one occasion while receiving fluvoxamine maleate. All reported events are included in the list below, with the following exceptions: 1) those events already listed in Table 7, which tabulates incidence rates of common adverse experiences in placebo-controlled OCD and depression clinical trials, are excluded; 2) those events for which a drug cause was considered remote (i.e., neoplasia, gastrointestinal carcinoma, herpes simplex, herpes zoster, application site reaction, and unintended pregnancy) are omitted; and 3) events which were reported in only one patient and judged to not be potentially serious are not included. It is important to emphasize that, although the events reported did occur during treatment with fluvoxamine maleate, a causal relationship to fluvoxamine maleate has not been established.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring between 1/100 and 1/1000 patients; and rare adverse events are those occurring in less than 1/1000 patients.
Body as a Whole
Frequent: Accidental injury, malaise
Infrequent: Allergic reaction, neck pain, neck rigidity, overdose, photosensitivity reaction, suicide attempt
Rare: Cyst, pelvic pain, sudden death
Cardiovascular System
Frequent: Hypertension, hypotension, syncope, tachycardia
Infrequent: Angina pectoris, bradycardia, cardiomyopathy, cardiovascular disease, cold extremities, conduction delay, heart failure, myocardial infarction, pallor, pulse irregular, ST segment changes
Rare: AV block, cerebrovascular accident, coronary artery disease, embolus, pericarditis, phlebitis, pulmonary infarction, supraventricular extrasystoles
Digestive System
Frequent: Elevated liver transaminases
Infrequent: Colitis, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, gingivitis, glossitis, hemorrhoids, melena, rectal hemorrhage, stomatitis
Rare: Biliary pain, cholecystitis, cholelithiasis, fecal incontinence, hematemesis, intestinal obstruction, jaundice
Endocrine System
Infrequent: Hypothyroidism
Rare: Goiter
Hemic and Lymphatic Systems
Infrequent: Anemia, ecchymosis, leukocytosis, lymphadenopathy, thrombocytopenia
Rare: Leukopenia, purpura
Metabolic and Nutritional Systems
Frequent: Edema, weight gain, weight loss
Infrequent: Dehydration, hypercholesterolemia
Rare: Diabetes mellitus, hyperglycemia, hyperlipidemia, hypoglycemia, hypokalemia, lactate dehydrogenase increased
Musculoskeletal System
Infrequent: Arthralgia, arthritis, bursitis, generalized muscle spasm, myasthenia, tendinous contracture, tenosynovitis
Rare: Arthrosis, myopathy, pathological fracture
Nervous System
Frequent: Amnesia, apathy, hyperkinesia, hypokinesia, manic reaction, myoclonus, psychotic reaction
Infrequent: Agoraphobia, akathisia, ataxia, CNS depression, convulsion, delirium, delusion, depersonalization, drug dependence, dyskinesia, dystonia, emotional lability, euphoria, extrapyramidal syndrome, gait unsteady, hallucinations, hemiplegia, hostility, hypersomnia, hypochondriasis, hypotonia, hysteria, incoordination, increased salivation, increased libido, neuralgia, paralysis, paranoid reaction, phobia, psychosis, sleep disorder, stupor, twitching, vertigo
Rare: Akinesia, coma, fibrillations, mutism, obsessions, reflexes decreased, slurred speech, tardive dyskinesia, torticollis, trismus, withdrawal syndrome
Respiratory System
Frequent: Cough increased, sinusitis
Infrequent: Asthma, bronchitis, epistaxis, hoarseness, hyperventilation
Rare: Apnea, congestion of upper airway, hemoptysis, hiccups, laryngismus, obstructive pulmonary disease, pneumonia
Skin
Infrequent: Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, seborrhea, skin discoloration, urticaria
Special Senses
Infrequent: Accommodation abnormal, conjunctivitis, deafness, diplopia, dry eyes, ear pain, eye pain, mydriasis, otitis media, parosmia, photophobia, taste loss, visual field defect
Rare: Corneal ulcer, retinal detachment
Urogenital System
Infrequent: Anuria, breast pain, cystitis, delayed menstruation1, dysuria, female lactation1, hematuria, menopause1, menorrhagia1, metrorrhagia1, nocturia, polyuria, premenstrual syndrome1, urinary incontinence, urinary tract infection, urinary urgency, urination impaired, vaginal hemorrhage1, vaginitis1
Rare: Kidney calculus, hematospermia2, oliguria
Postmarketing Reports
Voluntary reports of adverse events in patients taking fluvoxamine maleate tablets that have been received since market introduction and are of unknown causal relationship to fluvoxamine maleate tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, hyponatremia, ileus, laryngismus, neuropathy, pancreatitis, porphyria, priapism, serotonin syndrome, severe akinesia with fever when fluvoxamine was coadministered with antipsychotic medication, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsade de pointes).
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