Sarafem, Page 1

SARAFEM is indicated for the treatment of premenstrual dysphoric disorder (PMDD). The efficacy of fluoxetine in the treatment of PMDD was established in 3 placebo-controlled trials. The effectiveness of SARAFEM in long-term use, that is, for more than 6 months, has not been systematically evaluated in controlled trials.

SARAFEM- fluoxetine hydrochloride tablet
Warner Chilcott (US), LLC

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of SARAFEM or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SARAFEM is not approved for use in pediatric patients. (SeeWARNINGS: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and PRECAUTIONS: Pediatric Use)


SARAFEM® (fluoxetine hydrochloride tablets) is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is:

Fluoxetine hydrochloride molecular structure

Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.

Each SARAFEM tablet contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 15 mg (48.5 µmol) or 20 mg (64.7 µmol) of fluoxetine. Each tablet also contains microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, FD&C Yellow No. 6 aluminum lake (10 mg and 20 mg tablets) and D&C Yellow No. 10 aluminum lake (10 mg and 20 mg tablets).



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.

Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.


Absorption —Mean plasma fluoxetine concentrations following single-dose administration of SARAFEM 20 mg tablets are shown in Figure 1; fluoxetine and norfluoxetine pharmacokinetic parameters are shown in Table 1.

Graph of Mean Plasma Fluoxetine Concentrations Following Single-Dose Administration of SARAFEM 20 mg Tablets to Healthy Female Volunteers (n=23)
(click image for full-size original)

Figure 1. Mean (± SD) Plasma Fluoxetine Concentrations Following Single-Dose Administration of SARAFEM 20 mg Tablets to Healthy Female Volunteers (n=23)

Table 1.
3 subjects had longer fluoxetine elimination half-life values ranging from 100-300 hours; see Clinical issues relating to metabolism/elimination for more information on “poor metabolizers”
Summary of Mean Pharmacokinetic Parameters Following Single-Dose Administration of SARAFEM 20 mg Tablets to Healthy Female Volunteers (n = 23) (Cmax and AUC(0-t): shown as Mean (% Coefficient of Variation); Tmax and T1/2 : shown as median (range))





SARAFEM 20 mgFluoxetine13.2 (22)8.0 (2.0-10.0)722.4 (138)26.5 (15.7-310.0)
Norfluoxetine9.7 (37)48.0 (11.0-144.0)2114.3 (41)110.4 (66.8-308.0)

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.

Distribution — 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 (seePRECAUTIONS).

Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R– or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake.

Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use.

Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit.

Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (seeDrug InteractionsunderPRECAUTIONS).

Excretion — The primary route of elimination of fluoxetine appears to be hepatic metabolism to inactive metabolites that are then excreted by the kidney.

Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady-state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.

The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of SARAFEM.

Special Populations

Liver disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see Use in Patients with Concomitant Illness underPRECAUTIONS, GeneralandDOSAGE AND ADMINISTRATION).

Renal disease — In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness underPRECAUTIONS, GeneralandDOSAGE AND ADMINISTRATION).

Pediatric: Safety and effectiveness in the pediatric population have not been established (seeBOXED WARNING and WARNINGS, Clinical Worsening and Suicide Risk, Pediatric use).

Geriatric: The diagnosis of PMDD is not applicable to postmenopausal women.


Premenstrual Dysphoric Disorder (PMDD)

The effectiveness of SARAFEM for the treatment of PMDD was established in 3 placebo-controlled trials (1 intermittent and 2 continuous dosing). In an intermittent dosing trial described below, patients met Diagnostic and Statistical Manual-4th edition (DSM-IV) criteria for PMDD. In the continuous dosing trials described below, patients met Diagnostic and Statistical Manual-3rd edition revised (DSM-IIIR) criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as PMDD in the DSM-IV. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of fluoxetine in combination with oral contraceptives for the treatment of PMDD is unknown.

In an intermittent dosing double-blind, parallel group study of 3 months duration, patients (N = 260 randomized) were treated with fluoxetine 10 mg/day, fluoxetine 20 mg/day, or placebo. Fluoxetine or placebo was started 14 days prior to the anticipated onset of menstruation and was continued through the first full day of menses. Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Fluoxetine 20 mg/day was shown to be significantly more effective than placebo as measured by the DRSP total score. Fluoxetine 10 mg/day was not shown to be significantly more effective than placebo on this outcome. The average DRSP total score decreased 38% on fluoxetine 20 mg/day, 35% on fluoxetine 10 mg/day, and 30% on placebo.

In the first continuous dosing double-blind, parallel group study of 6 months duration involving N = 320 patients, fixed doses of fluoxetine 20 and 60 mg/day given daily throughout the menstrual cycle were shown to be significantly more effective than placebo as measured by a Visual Analogue Scale (VAS) total score (including mood and physical symptoms). The average total VAS score decreased 7% on placebo treatment, 36% on 20 mg, and 39% on 60 mg fluoxetine. The difference between the 20 and 60 mg doses was not statistically significant. The following table shows the percentage of patients meeting criteria for either moderate or marked improvement on the VAS total score:

Percentage of Patients Moderately and Markedly Improved (>50% and 75% reduction, respectively, from baseline Luteal Phase VAS total score)
Improvement N Placebo N Fluoxetine 20 mg N Fluoxetine 60 mg
Moderate 94 11% 95 37% 85 38%
Marked 94 4% 95 6% 85 18%

In a second continuous dosing double-blind, cross-over study, patients (N = 19) were treated with fluoxetine 20 to 60 mg/day (mean dose = 27 mg/day) and placebo daily throughout the menstrual cycle for a period of 3 months each. Fluoxetine was significantly more effective than placebo as measured by within cycle follicular to luteal phase changes in the VAS total score (mood, physical, and social impairment symptoms). The average VAS total score (follicular to luteal phase increase) was 3.8 times higher during placebo treatment than what was observed during fluoxetine treatment.

In another continuous dosing double-blind, parallel group study, patients with LLPDD (N = 42) were treated daily with fluoxetine 20 mg/day, bupropion 300 mg/day, or placebo for 2 months. Neither fluoxetine nor bupropion was shown to be superior to placebo on the primary endpoint, i.e., response rate [defined as a rating of 1 (very much improved) or 2 (much improved) on the CGI], possibly due to sample size.

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