Sarafem Online

Pharmaceutical Industries Ltd. (TEVA) said that the U.S. Food and Drug Administration has granted final approval for the Company's Abbreviated New Drug Application for Fluoxetine Capsules USP, 10 mg and 20 mg.

Shipment of the product will begin immediately. Teva has been awarded a 180-day period of marketing exclusivity.

Teva's Fluoxetine Capsules are the AB-rated generic equivalent of Eli Lilly's Sarafem Pulvules, and are indicated for the treatment of premenstrual dysphoric disorder.

According to IMS sales data, the brand product had annual sales of about $39 million in the United States for the twelve months that ended March 31, 2008.

 

In Oren Rudavsky's recent film, The Treatment, a wealthy Manhattan widow is baffled that a schoolteacher might be so anxious about speaking in public that he can't eat and suffers from stomach cramps and diarrhea. After all, surely he must speak in front of others every day. His reply is, in effect -- well, yes, but only in front of students. The schoolteacher probably wouldn't take any comfort from the popularity of his fear: According to one notorious statistic, Americans are more afraid of public speaking than of death.

I've begun with this example it points up a real enigma about our minds: How can a purely cultural experience such as public speaking translate into brain chemistry? After all, neither term in "public speaking" is straightforward. How big a group counts as "public"? Are they friends, colleagues, strangers, or a mix? Am I drunk or sober? Am I reading a prepared speech? fielding questions? participating in a judicial, civic, or religious ritual? How is it that our serotonin levels are able to make such finegrained judgments? Even if one focuses just on physical responses -- mild sweat, an elevated heart rate -- people may well attribute different meanings to those responses. (I was scared / I was in the zone / I was angry.) Despite these difficulties, some psychiatrists have proposed that "public speaking phobia" ought to receive its own diagnostic classification.

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

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 thoughts or actions?

Pharmacodynamics

The mechanism of action of fluoxetine in premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in humans have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.

Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of certain psychoactive drugs. Fluoxetine has little affinity for these receptors.

Absorption, Distribution, Metabolism, and Excretion

Systemic bioavailability — In humans, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours.

Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food.

Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see Precautions).

SARAFEM is contraindicated in patients known to be hypersensitive to it.

Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under Clinical Pharmacology)] should be allowed after stopping fluoxetine before starting an MAOI.

Pimozide — Concomitant use in patients taking pimozide is contraindicated (see Precautions).

Thioridazine — Thioridazine should not be administered with SARAFEM or within a minimum of 5 weeks after SARAFEM has been discontinued (see Warnings).

Human Experience

Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths.

Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.

Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette's syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was non-lethal.

General

Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of Sarafem with NSAIDs, aspirin, or other drugs that affect coagulation.

Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under Clinical Pharmacology).

Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see Contraindications and Warnings).

In 1 of 3 placebo-controlled, continuous-dosing trials and 1 placebo-controlled, intermittent-dosing trial of fluoxetine in PMDD, treatment-emergent adverse events reporting rates were assessed. The information from Table 2 included under ADVERSE REACTIONS is based on data from the continuous-dosing trial at the recommended dose of SARAFEM (SARAFEM 20 mg, N=104; placebo, N=108) and data from the intermittent-dosing trial of fluoxetine in PMDD (SARAFEM 20 mg, N=86; placebo, N=88). In addition, a broader set of information on treatment-emergent adverse events in the population of female patients, 18 to 45 years of age from the US placebo-controlled depression, OCD, and bulimia clinical trials, is presented for comparison (see Table 3).

Adverse events 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 events into a limited (i.e., reduced) number of standardized event categories.

In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.