Fluvoxamine Maleate (Page 10 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 months (females) or 26 months (males). The daily doses in the high-dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum recommended human dose (MRHD) on a mg/m2 basis.

Mutagenesis: No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation.

Impairment of Fertility: In a study in which male and female rats were administered fluvoxamine (60, 120, or 240 mg/kg) orally prior to and during mating and gestation, fertility was impaired at doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the MRHD on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Obsessive Compulsive Disorder (OCD)

The effectiveness of fluvoxamine maleate extended-release capsules for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled study of adult outpatients. Patients in this trial were titrated in 50 mg increments over the first six weeks of the study on the basis of response and tolerance from a dose of 100 mg/day to a fluvoxamine maleate dose within a range of 100 mg to 300 mg once-a-day. Patients in this study had moderate to severe OCD (DSM-IV), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total scores of 26.6 and 26.3 for fluvoxamine and placebo-treatment groups, respectively.

Patients receiving fluvoxamine maleate extended-release capsules demonstrated statistically significant improvement over placebo patients at the primary endpoint (Week 12) compared to baseline on the Y-BOCS. The mean daily dose of fluvoxamine maleate extended-release capsules administered to patients was 261 mg at end of study.

Exploratory analyses for age and gender effects on outcomes did not show any significant differential responsiveness on the basis of age or sex.

The effectiveness of immediate-release fluvoxamine maleate tablets for the treatment of OCD was demonstrated in two 10-week multicenter, parallel group studies of adult outpatients. Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first two weeks of the trial, after which the dose was adjusted within a range of 100 to 300 mg/day (given in two doses per day), on the basis of response and tolerance. Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score of 23.

14.2 Adult OCD Maintenance Study with Immediate-Release Fluvoxamine Maleate Tablets

In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score greater than or equal to 18 were titrated to an effective dose of immediate-release fluvoxamine maleate tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase. Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10. Of the patients who responded, their average duration of response was 4 weeks. Patients who responded during this initial phase were randomized either to continuation of immediate-release fluvoxamine maleate tablets (N=56) or to placebo (N=58) in a double-blind phase for observation of relapse. Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms. In the double-blind phase, patients receiving continued immediate-release fluvoxamine maleate tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo.

An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender.

14.3 Pediatric OCD Study

Fluvoxamine maleate extended-release capsules have not been evaluated in pediatric patients. However, the effectiveness of immediate-release fluvoxamine maleate tablets for the treatment of OCD was demonstrated in a 10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17 years). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (given in two doses per day) on the basis of response and tolerance. All patients had moderate-to-severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24.

Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 year to 11 year age group and essentially no effect in the 12 year to 17 year age group. While the significance of these results is not clear, the 2 to 3 fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents (see Clinical Pharmacology–Pediatric Subjects [12.3]) is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg/day) may be indicated to achieve therapeutic benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Fluvoxamine maleate extended-release capsules are available as follows:

100 mg – Each #2 capsule with olive opaque cap and gray opaque body, imprinted with ebfb06fd-figure-04 and 2848 on both cap and body in black ink contains 100 mg of fluvoxamine maleate, USP. Capsules are supplied in bottles of 30 (NDC 0228-2848-03).

150 mg – Each #1 capsule with olive opaque cap and white opaque body, imprinted with ebfb06fd-figure-05 and 2849 on both cap and body in black ink contains 150 mg of fluvoxamine maleate, USP. Capsules are supplied in bottles of 30 (NDC 0228-2849-03).

16.2 Storage

Keep out of reach of children.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Protect from high humidity and avoid exposure to temperatures above 30°C (86°F).

Dispense in tight, light-resistant container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Sexual Dysfunction

Advise patients that use of fluvoxamine maleate extended-release capsules may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.17)].

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine maleate extended-release capsules and should counsel them in the appropriate use. A patient Medication Guide discussing antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions and other important information about Fluvoxamine Maleate Extended-Release Capsules is available for fluvoxamine maleate extended-release capsules. The prescriber or health professional should instruct patients, their families, and their caregivers to read both sections of the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluvoxamine maleate extended-release capsules.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate the need for very close monitoring and possibly changes in the medication (see BOXED WARNING and Warnings and Precautions [5.1]).

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) [see Warnings and Precautions-Serotonin Syndrome (5.2)].

Contraindicated Medications

Patients should be advised that the following medications should not be used while taking fluvoxamine maleate extended-release capsules:

  • Monoamine oxidase inhibitors (MAOIs): See Contraindications (4.1) and Warnings and Precautions (5.2).
  • Thioridazine: See Contraindications (4) and Warnings and Precautions (5.4).
  • Tizanidine: See Contraindications (4) and Warnings and Precautions (5.5).
  • Pimozide: See Contraindications (4) and Warnings and Precautions (5.6).
  • Alosetron: See Contraindications (4) and Warnings and Precautions (5.7).
  • Ramelteon: See Contraindications (4) and Warnings and Precautions (5.8).

In addition, MAOIs should not be taken within 14 days (2 weeks) after stopping fluvoxamine maleate extended-release capsules, and fluvoxamine maleate extended-release capsules should not be taken within two weeks after stopping treatment with an MAOI (see Contraindications [4.1] and Warnings and Precautions [5.2]).

Other Potentially Hazardous Drug Interactions

Patients should be advised that the use of fluvoxamine maleate extended-release capsules with any of the following medications may produce clinically significant adverse reactions. Patients should inform their physician if they are taking any of these medications before starting treatment with fluvoxamine maleate extended-release capsules. Patients should also inform their physician prior to taking any of these medications while receiving fluvoxamine maleate extended-release capsule therapy.

  • Serotonergic drugs, including triptans, tramadol, and tryptophan: See Warnings and Precautions (5.2) .
  • Antipsychotic agents, including clozapine: See Warnings and Precautions (5.2, 5.9) .
  • Certain benzodiazepines: See Warnings and Precautions (5.9) .
  • Methadone: See Warnings and Precautions (5.9) .
  • Mexiletine: See Warnings and Precautions (5.9) .
  • Theophylline: See Warnings and Precautions (5.9) .
  • Warfarin and other drugs that interfere with hemostasis: Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see Warnings and Precautions [5.9, 5.11]).
  • Diuretics: See Warnings and Precautions (5.14).

In addition, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for clinically important interactions with fluvoxamine maleate extended-release capsules.

Abnormal Bleeding
Patients should be advised that fluvoxamine maleate extended-release capsules may increase the risk of bleeding events, which have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk (see Warnings and Precautions [5.9, 5.11]).

Angle Closure Glaucoma
Patients should be advised that taking fluvoxamine maleate extended-release capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible (see Warnings and Precautions [5.3])

Interference with Cognitive or Motor Performance
Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that fluvoxamine maleate extended-release capsules therapy does not adversely affect their ability to engage in such activities.

Pregnancy
Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with fluvoxamine maleate extended-release capsules (see Use in Specific Populations [8.1]) .

Nursing
Patients receiving fluvoxamine maleate extended-release capsules should be advised to notify their physicians if they are breastfeeding an infant. (See Use in Specific Populations–Nursing Mothers [8.3]).

Alcohol
As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate extended-release capsules.

Allergic Reactions
Patients should be advised to notify their physicians if they develop a rash, hives, or a related allergic phenomenon during therapy with fluvoxamine maleate extended-release capsules.

Brands listed are the trademarks of their respective owners.

Dispense with Medication Guide available at: www.tevausa.com/medguides

Manufactured For:
Teva Pharmaceuticals
Parsippany, NJ 07054

Rev. E 10/2023

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