Pharmacy & Therapeutics - May 2008 - (Page 294) adverse effects in chronic use (see WARNINGS—Clinical Worsening and Suicide Risk). Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOXED WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of LUVOX CR in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use: Approximately 230 patients and 5 patients participating in controlled premarketing studies with IR fluvoxamine maleate and LUVOX CR, respectively, were 65 years of age or over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. However, SSRIs and SNRIs, including LUVOX CR, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this AE (see PRECAUTIONS—Hyponatremia). Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients (see Pharmacokinetics under CLINICAL PHARMACOLOGY), and greater sensitivity of some older individuals also cannot be ruled out. Consequently, LUVOX CR should be slowly titrated during initiation of therapy. ADVERSE REACTIONS—Associated with Discontinuation of Treatment: Of the 279 patients with SAD and 124 patients with OCD treated with LUVOX CR in controlled clinical trials, 26% and 19% discontinued treatment due to an AE. The most common AEs (≥1%) associated with discontinuation and considered to be drug related (ie those events associated with dropout at a rate at least twice that of placebo) were as follows: In patients with SAD —Body as a Whole: asthenia (4%), headache (3%), abdominal pain (1%); Digestive: nausea (8%), diarrhea (3%), anorexia (2%); Nervous System: insomnia (5%), somnolence (5%), anxiety (4%), dizziness (4%), abnormal thinking (2%), nervousness (2%), depression (1%), agitation (1%), paresthesia (1%), tremor (1%); Skin and Appendages: sweating (1%). In patients with OCD—Body as a Whole: asthenia (2%), pain (2%); Digestive: nausea (6%), diarrhea (2%), dyspepsia (2%); Nervous System: insomnia (5%), somnolence (4%), anxiety (2%), dizziness (3%). Commonly Observed AEs: LUVOX CR has been studied in 2 controlled trials of SAD (n=279) and 1 trial of OCD (n=124). In general, AE rates were similar in the 2 data sets as well as in a study of pediatric patients with OCD treated with IR fluvoxamine maleate. The most commonly observed AEs associated with the use of LUVOX CR and likely to be drug-related (incidence ≥5% and at least twice that for placebo) were nausea, somnolence, asthenia, diarrhea, anorexia, abnormal ejaculation, tremor, sweating, and anorgasmia. In addition, the following AEs occurred in the SAD population: insomnia, dizziness, dyspepsia, yawn. In the OCD population, the following additional events occurred: decreased libido, anxiety, pharyngitis, vomiting, myalgia, and accidental injury. AEs Occurring at an Incidence of 2%: The following AEs occurred in adults at a frequency of ≥2%, and were more frequent than in the placebo group, among adult patients with SAD (n=279) treated once-daily with 100 to 300 mg/day LUVOX CR in two 12-week controlled trials: Body as a Whole: headache (35%), asthenia (24%), abdominal pain (5%), chest pain (3%); Cardiovascular: palpitation (3%), vasodilatation (2%); Digestive: nausea (39%), diarrhea (14%), anorexia (14%), dyspepsia (10%), constipation (6%), liver function test abnormal (2%); Nervous System: insomnia (32%), somnolence (26%), dizziness (15%), dry mouth (11%), nervousness (10%), decreased libido (6%) [male (8%), female (4%)], anxiety (8%), tremor (8%), abnormal thinking (3%), abnormal dreams (3%), agitation (3%), hypertonia (2%), paresthesia (3%); Respiratory System: yawn (5%), bronchitis (2%); Skin and Appendages: sweating (6%); Special Senses: taste perversion (2%); Urogenital: abnormal ejaculation (11%), anorgasmia (5%) [male (4%), female (5%)], sexual function abnormal (3%) [male (2%), female (3%)], urinary tract infection (2%). The following AEs occurred at a frequency of ≥2%, and were more frequent than in the placebo group, among adult patients with OCD (n=124) treated once daily with 100 to 300 mg/day LUVOX CR in one 12-week controlled trial: Body as a Whole: headache (32%), asthenia (26%), pain (10%), accidental injury (5%), viral infection (2%); Cardiovascular: hypertension (2%); Digestive: nausea (34%), diarrhea (18%), anorexia (13%), dyspepsia (8%), constipation (4%), vomiting (6%), tooth disorder (2%), gingivitis (2%); Hemic and Lymphatic: ecchymosis (4%); Metabolic and Nutritional Disorders: weight loss (2%); Musculoskeletal: myalgia (5%); Nervous System: insomnia (35%), somnolence (27%), dizziness (12%), dry mouth (10%), decreased libido (6%) [male (10%), female (4%)], anxiety (6%), tremor (6%), abnormal thinking (3%), agitation (2%), apathy (3%), neurosis (2%), twitching (2%); Respiratory System: pharyngitis (6%), yawn (2%), laryngitis (3%), epistaxis (2%); Skin: sweating (7%), acne (2%); Special Senses: taste perversion (2%), amblyopia (2%); Urogenital: abnormal ejaculation (10%), anorgasmia (5%), [male (4%), female (5%)], menorrhagia (3%), sexual function abnormal (2%) [male (4%), female (0%)], polyuria (2%). These lists include the percentages of patients in each group who had at least 1 occurrence of an event during treatment. Reported AEs were classified using a COSTART-based Dictionary terminology. Other AEs in OCD Pediatric Population: In pediatric patients (n=57) treated with IR fluvoxamine maleate, the overall profile of AEs was generally similar to that seen in adult studies, as shown above. However, the following AEs, not shown above, were reported in 2 or more of the pediatric patients and were more frequent with IR fluvoxamine maleate than with placebo: cough increase, dysmenorrhea, emotional lability, fever, flatulence, flu syndrome, hyperkinesia, infection, manic reaction, rash, rhinitis, and sinusitis. 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 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. The following sexual side effects were reported by ≥2% of patients taking LUVOX CR in placebo-controlled trials of SAD and OCD: abnormal ejaculation (11%), anorgasmia [male (4%), female (5%)], impotence (2%), decreased libido [male (8%), female (4%)], sexual function abnormal [male (3%), female (2%)]. 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. Changes in Weight, Vital Signs, and Laboratory Tests: No statistically significant differences in weight gain or loss were found between patients treated with LUVOX CR or placebo. Comparisons of IR fluvoxamine maleate or LUVOX CR versus placebo groups in separate short-term trials on (1) median change from baseline and on (2) incidence of patients meeting criteria for potentially important changes from baseline showed no important differences on various vital signs variables or serum chemistry, hematology, and urinalysis variables. ECG Changes: Comparisons of IR fluvoxamine maleate or LUVOX CR and placeb o 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. Postmarketing Reports: Voluntary reports of AEs in patients taking IR fluvoxamine maleate that have been received since market introduction and are of unknown causal relationship to fluvoxamine 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 co-administered with anti-psychotic medication, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes). DRUG ABUSE AND DEPENDENCE: Controlled Substance Class—LUVOX CR is not a controlled substance. Physical and Psychological Dependence: The potential for abuse, tolerance, and physical dependence with IR fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of LUVOX CR were not systematically evaluated in controlled clinical trials. LUVOX CR was not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of IR fluvoxamine maleate. Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted,
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