Minds On Meds

Mental Health Medications

Antidepressants

Fluvoxamine Maleate (Luvox, Faverin), Page 5

Fluvoxamine maleate (Luvox) tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD).

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 (females) or 26 (males) months. 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 human daily dose 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) prior to and during mating and gestation, fertility was impaired at oral 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 maximum recommended human dose [MRHD] on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Adult OCD Studies

The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (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, following which the dose was adjusted within a range of 100 to 300 mg/day (on a b.i.d. schedule), 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. Patients receiving fluvoxamine maleate experienced mean reductions of approximately 4 to 5 units on the Y-BOCS total score, compared to a 2 unit reduction for placebo patients.

Table 6 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined.

TABLE 6 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN POOL OF TWO ADULT OCD STUDIES
Outcome Classification Fluvoxamine (n = 120) Placebo (n = 134)
Very Much Improved 13% 2%
Much Improved 30% 10%
Minimally Improved 22% 32%
No Change 31% 51%
Worse 4% 6%

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

14.3 Pediatric OCD Study

The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a
10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages
8 to 17). 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 (on a b.i.d. schedule) 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. Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients.

Table 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.

TABLE 7 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN PEDIATRIC STUDY
Outcome Classification Fluvoxamine (n = 38) Placebo (n = 36)
Very Much Improved 21% 11%
Much Improved 18% 17%
Minimally Improved 37% 22%
No Change 16% 44%
Worse 8% 6%

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 to 11 age group and essentially no effect in the 12 to 17 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) may be indicated to achieve therapeutic benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Fluvoxamine Maleate Tablets, USP are available as:

25 mg: Off-white, oval, film-coated, biconvex, unscored tablet. Debossed with stylized b on one side and 967 on the other side. Available in bottles of 100.

50 mg: Yellow, oval, film-coated, biconvex, scored tablet. Debossed with stylized b on one side and 968/50 on the scored side. Available in bottles of 100.

100 mg: Brown, oval, film-coated, biconvex, scored tablet. Debossed with stylized b on one side and 969/100 on the scored side. Available in bottles of 100.

16.2 Storage

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from high humidity.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

17 PATIENT COUNSELING INFORMATION

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine maleate tablets and should counsel them in the appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for fluvoxamine maleate tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read 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 tablets.

17.1 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)].

17.2 Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluvoxamine and triptans, tramadol, or other serotonergic agents [see Warnings and Precautions-Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions (5.3)].

17.3 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 tablets therapy does not adversely affect their ability to engage in such activities.

17.4 Pregnancy

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

17.5 Nursing

Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast feeding an infant [see Use in Specific Populations, Nursing Mothers (8.3)].

17.6 Concomitant Medication

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 tablets.

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, Warfarin and Other Drugs That Interfere With Hemostasis (5.8)].

Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine [see Warnings and Precautions (5.5)].

Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with LotronexTM (alosetron) [see Warnings and Precautions (5.7)].

17.7 Alcohol

As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.

17.8 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 tablets.

LotronexTM is a registrered trademark of GlaxoSmithKline.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

11001665

Iss. 5/2010

______________________________________________________________________________

MEDICATION GUIDE

Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions

Fluvoxamine Maleate Tablets

Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:

  • all risks and benefits of treatment with antidepressant medicines
  • all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thought or actions?

1. Antidepressant medicines may increase suicidal thoughts and actions in some children, teenagers, and young adults within the first few months of treatment.

2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts and actions.

3. How can I watch for and try to prevent suicidal thoughts and actions in myself or family member?

  • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
  • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • trouble sleeping (insomnia)
• attempts to commit suicide • new or worse irritability
• new or worse depression • acting aggressive, being angry, or violent
• acting on dangerous impulses
• new or worse anxiety

• an extreme increase in activity and talking

• feeling very agitated or restless
• panic attacks

• other unusual changes in behavior or

What else do I need to know about antidepressant medicines?

  • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
  • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
  • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
  • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
  • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 5/2010