6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
2 ) . The following additional reactions occurred: anxiety, decreased libido, myalgia, pharyngitis, and vomiting in the OCD population; and dyspepsia, dizziness, insomnia, and yawning in another studied population. gov/medwatch. 2 days).
Patients in these trials were initiated on 100 mg/day and were titrated in 50 mg increments over the first 6 weeks to within a range of 100 mg/day to 300 mg/day. The reactions listed in Table 2 show reactions from the two populations separately.
Table 3 shows reactions from the three controlled studies combined. 2 Adverse Reactions Observed in Controlled Trials Adverse Reactions Associated with Discontinuation of Treatment : Of the 124 patients with OCD and 279 patients in other studies treated with fluvoxamine maleate extended-release capsules in controlled clinical trials, 19% and 26% discontinued treatment due to an adverse reaction.
, those reactions associated with dropout at a rate at least twice that of placebo) were anorexia (including, but not limited to, loss of appetite and decreased appetite) (1%), anxiety (3%), asthenia (3%), diarrhea (2%), dizziness (4%), headache (2%), insomnia (5%), nausea (7%), nervousness (1%), somnolence (5%), and thinking abnormal (1%).
Commonly Observed Adverse Reactions:
Fluvoxamine maleate extended-release capsules have been studied in one controlled trial in patients with OCD (N = 124) and two controlled trials for another condition (N = 279). In general, adverse reaction rates were similar in the two data sets as well as in a study of pediatric patients with OCD treated with immediate-release fluvoxamine maleate tablets.
The most commonly observed treatment-emergent adverse reactions associated with the use of fluvoxamine maleate extended-release capsules and likely to be drug- related (incidence of 5% or greater and at least twice that for placebo) and derived from Table 2 were: abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating, and tremor .
In the one controlled trial in patients with OCD, the following additional reactions occurred at an incidence of 5% or greater and at least twice that for placebo: anxiety, decreased libido, myalgia, pharyngitis, and vomiting . The following additional reactions occurred in another studied population: dyspepsia, dizziness, insomnia, and yawning .
In a study evaluating immediate-release fluvoxamine maleate tablets in pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash.
Adverse Reactions Occurring at an Incidence of ≥ 2%:
Table 2 enumerates adverse reactions that occurred in adults at a frequency of 2% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate extended-release capsules in two short-term, placebo-controlled trials (12 weeks) in another population and one short-term placebo-controlled OCD trial (12 weeks) and in which patients were dosed once-a-day in a range of 100 mg/day to 300 mg/day.
This table shows the percentage of patients in each group who had at least one occurrence of a reaction at some time during their treatment. Reported adverse reactions were classified using a 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 health care provider 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 2:
TREATMENT-EMERGENT ADVERSE REACTION INCIDENCE RATES BY BODY SYSTEM IN ADULT OCD PATIENTS AND ANOTHER STUDIED POPULATION 1 1 Events for which fluvoxamine maleate incidence was equal to or less than placebo include the following for OCD patients: abdominal pain, flu syndrome, infection, palpitation, flatulence, increased appetite, weight gain, abnormal dreams, amnesia, hypertonia, nervousness, paresthesia, increased cough, dyspnea, rhinitis, and ear pain.
In the other studied population the following events were seen: abdominal pain, accidental injury, back pain, flu syndrome, infection, pain, flatulence, pharyngitis, rhinitis, rash, and dysmenorrhea. 2 Term includes body aches/pains, dental pain, pain from surgery, unspecified pain, and general pain secondary to injuries (sprains, fractures).
3 Includes, but is not limited to, loss of appetite and decreased appetite. 3 Other Adverse Reactions in OCD Pediatric Population In pediatric patients (N=57) treated with immediate-release fluvoxamine maleate tablets, the overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2.
However, the following adverse reactions, not appearing in Table 2, were reported in two or more of the pediatric patients and were more frequent with immediate-release fluvoxamine maleate tablets than with placebo: cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis, and weight decrease.
4 Male and Female Sexual Dysfunction with SSRIs Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as 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 health care providers 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 3 displays the incidence of sexual side effects reported by at least 2% of patients taking fluvoxamine maleate extended-release capsules in placebo controlled trials.
TABLE 3:
PERCENTAGE OF PATIENTS REPORTING SEXUAL ADVERSE REACTIONS IN PLACEBO-CONTROLLED TRIALS Fluvoxamine Maleate Extended-Release N = 403 Placebo N = 400 Abnormal Ejaculation 11 2 Anorgasmia Male 4 1 Female 5 0 Impotence 2 2 Libido Decreased Male 8 5 Female 4 2 Sexual Function Abnormal Male 3 1 Female 2 0 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, health care providers should routinely inquire about such possible side effects.
5 Weight and Vital Sign Changes No statistically significant differences in weight gain or loss were found between patients treated with fluvoxamine maleate extended-release capsules or placebo. Comparisons of immediate-release fluvoxamine maleate tablets or fluvoxamine maleate extended-release capsules versus placebo groups in separate short-term 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 measures of vital signs variables revealed no important differences between fluvoxamine maleate and placebo.
6 Laboratory Changes Comparisons of immediate-release fluvoxamine maleate tablets or fluvoxamine maleate extended-release capsules versus placebo groups in separate short-term 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.
7 ECG Changes Comparisons of immediate-release fluvoxamine maleate tablets or fluvoxamine maleate extended-release capsules 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.
8 Other Reactions Observed During the Premarketing Evaluation of Fluvoxamine During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate extended-release capsules or immediate-release fluvoxamine maleate tablets were administered for a combined total of 3,219 patient exposures in patients suffering OCD or other studied disorders.
These exposures include 482 patient exposures with fluvoxamine maleate extended-release capsules and 2,737 patient exposures with immediate-release fluvoxamine maleate tablets. Untoward reactions associated with this exposure were recorded by clinical investigators using descriptive terminology of their own choosing.
, reduced) number of standard reaction categories. In the tabulations that follow, a COSTART-based Dictionary terminology has been used to classify reported adverse reactions. If the COSTART term for a reaction was so general as to be uninformative, it was replaced with a more informative term when possible.
The frequencies presented, therefore, represent the proportion of the total patient exposures to multiple doses of fluvoxamine maleate who experienced a reaction of the type cited on at least one occasion while receiving fluvoxamine maleate.
Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring between 1/100 and 1/1,000 patients; and rare adverse reactions are those occurring in less than 1/1,000 patients.
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. For fluvoxamine maleate extended-release capsules, all reported events are included in the list below, with the following exclusions: 1) those events already listed in Table 2 or previous sections of this prescribing information; 2) those events for which there is no basis to suspect a causal relationship; and 3) events that were reported in only one patient and judged not to be potentially serious.
Body as a Whole:
Infrequent: chills, malaise, photosensitivity reaction, suicide attempt.
Cardiovascular System:
Infrequent: syncope.
Digestive System:
Infrequent: eructation, increased salivation.
Metabolic and Nutritional Disorders:
Frequent: weight gain.
Nervous System:
Infrequent: confusion, incoordination, sleep disorder, suicidal tendency.
Skin and Appendages:
Infrequent: eczema, urticaria.
Special Senses:
Infrequent: dry eyes, photophobia, taste loss.
Urogenital System:
Infrequent: vaginal hemorrhage 1 . 1 Based on the number of females. For immediate-release fluvoxamine tablets, all reported events are included in the list below, with the following exclusions: 1) those events already listed in Table 2, in previous sections of this prescribing information, or in the fluvoxamine maleate extended-release capsules list of Other Reactions Observed During Premarketing Evaluation; 2) those events for which there is no basis to suspect a causal relationship; and 3) events that were reported in only one patient and judged not to be potentially serious.
Body as a Whole:
Infrequent: allergic reaction, neck pain, neck rigidity, overdose; Rare: sudden death.
Cardiovascular System:
Frequent: hypotension; Infrequent: angina pectoris, bradycardia, cardiomyopathy, cardiovascular disease, cold extremities, conduction delay, myocardial infarction, pallor, pulse irregular, ST segment changes; Rare: AV block, cerebrovascular accident, embolus, pericarditis, phlebitis, pulmonary infarction, supraventricular extrasystoles.
Digestive System:
Frequent: elevated liver transaminases; Infrequent: colitis, esophagitis, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, 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: leukocytosis, lymphadenopathy, thrombocytopenia; Rare: leukopenia, purpura.
Metabolic and Nutritional Systems:
Frequent: edema; Infrequent: dehydration, hypercholesterolemia; Rare: diabetes mellitus, hyperglycemia, hyperlipidemia, hypoglycemia, hypokalemia, lactate dehydrogenase increased.
Musculoskeletal System:
Infrequent: arthralgia, arthritis, bursitis, generalized muscle spasm, myasthenia; Rare: myopathy.
Nervous System:
Frequent: amnesia, apathy, hyperkinesia, hypokinesia, manic reaction, myoclonus, psychotic reaction; Infrequent: agoraphobia, akathisia, ataxia, CNS depression, convulsion, delirium, delusion, depersonalization, dyskinesia, dystonia, emotional lability, euphoria, extrapyramidal syndrome, gait unsteady, hallucinations, hemiplegia, hostility, hypersomnia, hypochondriasis, hypotonia, hysteria, increased libido, paralysis, paranoid reaction, phobia, psychosis, 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, hoarseness, hyperventilation; Rare: apnea, congestion of upper airway, hemoptysis, hiccups, laryngismus, obstructive pulmonary disease, pneumonia.
Skin:
Infrequent: alopecia, dry skin, exfoliative dermatitis, furunculosis, seborrhea, skin discoloration.
Special Senses:
Infrequent: accommodation abnormal, conjunctivitis, diplopia, eye pain, mydriasis, otitis media, parosmia, visual field defect; Rare: corneal ulcer.
Urogenital System :
Infrequent: anuria, cystitis, delayed menstruation 1 , dysuria, female lactation 1 , hematuria, menopause 1 , metrorrhagia 1 , nocturia, premenstrual syndrome 1 , urination impaired, vaginitis 1 ; Rare: kidney calculus, hematospermia 2 , oliguria.
1 Based on the number of females. 2 Based on the number of males. 9 Postmarketing Reports The following adverse reactions have been identified during post-approval use of immediate-release fluvoxamine maleate tablets or fluvoxamine maleate extended-release capsules.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. ) These reactions include: activation syndrome, aggression, agranulocytosis, anaphylactic reaction, anger, blood glucose increased, bruxism, cardio-respiratory arrest, crying, dysarthria, dysphagia, electrocardiogram QT prolonged, fall, fatigue, feeling drunk, feeling jittery, gait disturbance, gastroesophageal reflux disease, glossodynia, hepatitis, homicidal ideation, impulsive behavior, ileus, inappropriate antidiuretic hormone secretion, interstitial lung disease, irritability, loss of consciousness, lethargy, muscular weakness, Parkinsonism, pancreatitis, pyrexia, renal impairment, rhabdomyolysis, self injurious behavior, shock, somnolence neonatal, Stevens-Johnson syndrome, tachycardia, urinary retention, ventricular arrythmia, ventricular tachycardia (including torsades de pointes known to cause cardiac arrest, sometimes fatal), vision blurred, white blood cell count decreased, anosmia, and hyposmia.