Nursing Drug Guide - Zoloft sertraline

ZOLOFT®
(sertraline hydrochloride)

Tablets and Oral Concentrate

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 Zoloft 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. Zoloft is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)

CLINICAL PHARMACOLOGY

Pharmacodynamics

The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.

Pharmacokinetics

Systemic Bioavailability–In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution.
In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for Cmax which was 126.5%.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to
5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.

Metabolism–Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction,
hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and day 14.

Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol (see PRECAUTIONS).

Pediatric Pharmacokinetics–Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of major depressive disorder or obsessive-compulsive disorder. Patients included both males (N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of 3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of
27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels (see
DOSAGE AND ADMINISTRATION).

Age–Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females.

Liver Disease–As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced,
resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Disease–Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min), moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment (see PRECAUTIONS).

Clinical Trials

Major Depressive Disorder–The efficacy of ZOLOFT as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on ZOLOFT 50-200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on placebo. The mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

Obsessive-Compulsive Disorder (OCD)–The effectiveness of ZOLOFT in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients.
Study 2 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.
Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6-17). Patients receiving ZOLOFT in this study were initiated at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGII of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

Panic Disorder–The effectiveness of ZOLOFT in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores. The difference between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Patients receiving ZOLOFT experienced a significantly greater reduction in panic attack frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose response relationship for effectiveness.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.
In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline. Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued ZOLOFT treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

Posttraumatic Stress Disorder (PTSD)–The effectiveness of ZOLOFT in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.
Studies 1 and 2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical response and toleration. The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that
measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms. ZOLOFT was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans.
As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender interaction is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on ZOLOFT 50-200 mg/day (n=96) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient's condition in the investigator's judgment. Patients receiving continued ZOLOFT treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

Premenstrual Dysphoric Disorder (PMDD) – The effectiveness of ZOLOFT for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown.
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. Other efficacy
assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, ZOLOFT treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
In Study 2, involving n=281 randomized patients, ZOLOFT treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these studies.

Social Anxiety Disorder – The effectiveness of ZOLOFT in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
Study 1 was a 12-week, multicenter, flexible dose study comparing ZOLOFT (50-200 mg/day) to placebo, in which ZOLOFT was initiated at 25 mg/day for the first week. Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). ZOLOFT was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.
Study 2 was a 20-week, multicenter, flexible dose study that compared ZOLOFT (50-200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. ZOLOFT was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I.
Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There was insufficient information to determine the effect of race or age on outcome.
In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on ZOLOFT 50-200 mg/day were randomized to continuation of ZOLOFT or to substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT continuation treatment experienced a statistically significantly lower relapse rate over this 24week study than patients randomized to placebo substitution.

INDICATIONS AND USAGE

Major Depressive Disorder–ZOLOFT (sertraline hydrochloride) is indicated for the treatment of major depressive disorder in adults.
The efficacy of ZOLOFT in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately studied.
The efficacy of ZOLOFT in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving ZOLOFT for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).

Obsessive-Compulsive Disorder–ZOLOFT is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
The efficacy of ZOLOFT was established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.
The efficacy of ZOLOFT in maintaining a response, in patients with OCD who responded during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder–ZOLOFT is indicated for the treatment of panic disorder in adults, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
The efficacy of ZOLOFT was established in three 10-12 week trials in adult panic disorder patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who responded during a 52-week treatment phase while taking ZOLOFT and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Posttraumatic Stress Disorder (PTSD)–ZOLOFT (sertraline hydrochloride) is indicated for the treatment of posttraumatic stress disorder in adults.
The efficacy of ZOLOFT in the treatment of PTSD was established in two 12-week placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
The efficacy of ZOLOFT in maintaining a response in adult patients with PTSD for up to 28 weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Premenstrual Dysphoric Disorder (PMDD) – ZOLOFT is indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the treatment of PMDD was established in 2 placebo-controlled trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-IIIR/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Social Anxiety Disorder – ZOLOFT (sertraline hydrochloride) is indicated for the treatment of social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social anxiety disorder was established in two placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social situation almost always provokes anxiety and feared social or performance situations are avoided or else are endured with intense anxiety or distress. In addition, patients recognize that the fear is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is associated with functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in adult patients with social anxiety disorder for up to 24 weeks following 20 weeks of ZOLOFT treatment was demonstrated in a placebo-controlled trial. Physicians who prescribe ZOLOFT for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated
(see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see
PRECAUTIONS).
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol
content of the concentrate.

WARNINGS

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. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ZOLOFT should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that ZOLOFT is not approved for use in treating bipolar depression.
Cases of serious sometimes fatal reactions have been reported in patients receiving ZOLOFT (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, ZOLOFT should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS – Potential for Interaction with Monoamine Oxidase Inhibitors.)
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Zoloft treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Zoloft with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of Zoloft with serotonin precursors (such as tryptophan) is not recommended.
Treatment with Zoloft and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

PRECAUTIONS

General
Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred in approximately 0.4% of ZOLOFT (sertraline hydrochloride) treated patients.

Weight Loss–Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.

Seizure–ZOLOFT has not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarket testing. No seizures were observed among approximately 3000 patients treated with ZOLOFT in the development program for major depressive disorder. However, 4 patients out of approximately 1800 (220 <18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in patients with a seizure disorder.

Discontinuation of Treatment with Zoloft
During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Zoloft. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).

Abnormal Bleeding
SSRIs and SNRIs, including Zoloft, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Zoloft and NSAIDs, aspirin, or other drugs that affect coagulation.
Weak Uricosuric Effect–ZOLOFT (sertraline hydrochloride) is associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.
Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 774 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate that ZOLOFT is not associated with the development of significant ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization. Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic dysfunction. ZOLOFT treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment (see CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not cause sedation and did not interfere with psychomotor performance. (See Information for Patients.)
Hyponatremia–
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including ZOLOFT. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see GERIATRIC USE). Discontinuation of ZOLOFT should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Platelet Function–There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking ZOLOFT. While there have been reports of abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT had a causative role.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Zoloft and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is available for ZOLOFT. 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 ZOLOFT.
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 a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use
of SNRIs and SSRIs, including Zoloft, and triptans, tramadol, or other serotonergic agents.
Patients should be told that although ZOLOFT has not been shown to impair the ability of
normal subjects to perform tasks requiring complex motor and mental skills in laboratory
experiments, drugs that act upon the central nervous system may affect some individuals
adversely. Therefore, patients should be told that until they learn how they respond to
ZOLOFT they should be careful doing activities when they need to be alert, such as driving a
car or operating machinery.
Patients should be cautioned about the concomitant use of Zoloft and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic
drugs that interfere with serotonin reuptake and these agents has been associated with an
increased risk of bleeding.
Patients should be told that although ZOLOFT has not been shown in experiments with
normal subjects to increase the mental and motor skill impairments caused by alcohol, the
concomitant use of ZOLOFT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOLOFT with over-the-counter
(OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of
any OTC product should be initiated cautiously according to the directions of use given for
the OTC product.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the
alcohol content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the
active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use.
Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze may appear after mixing; this is normal. Note that caution should be exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural rubber.

ADVERSE REACTIONS

During its premarketing assessment, multiple doses of ZOLOFT were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to ZOLOFT varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using 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 untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving ZOLOFT. 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.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.
Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for ZOLOFT and at least twice that for placebo within at least one of the indications) for the treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients treated with ZOLOFT and with incidence greater than placebo who participated in controlled clinical trials comparing ZOLOFT with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.

Nursing Drug Guide - Xanax alprazolam

XANAX® CIV
alprazolam tablets, USP

DESCRIPTION

XANAX Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine
class of central nervous system-active compounds.
The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-Ι] [1,4]
benzodiazepine.

CLINICAL PHARMACOLOGY

Pharmacodynamics

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo
specific receptors at several sites within the central nervous system. Their exact mechanism of
action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system
depressant activity varying from mild impairment of task performance to hypnosis.

Pharmacokinetics

Absorption
Following oral administration, alprazolam is readily absorbed. Peak concentrations in the
plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the
dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were
observed. Using a specific assay methodology, the mean plasma elimination half-life of
alprazolam has been found to be about 11.2 hours (range: 6.3-26.9 hours) in healthy adults.

Distribution
In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts
for the majority of the binding.

Metabolism/Elimination
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4
(CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-
hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans.
Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-
hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration
were always less than 4%. The reported relative potencies in benzodiazepine receptor binding
experiments and in animal models of induced seizure inhibition are 0.20 and 0.66,
respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations
and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they
are unlikely to contribute much to the pharmacological effects of alprazolam. The
benzophenone metabolite is essentially inactive.
Alprazolam and its metabolites are excreted primarily in the urine.

Special Populations
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have
been reported in a variety of disease states including alcoholism, impaired hepatic function
and impaired renal function. Changes have also been demonstrated in geriatric patients. A
mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects
(range: 9.0-26.9 hours, n=16) compared to 11.0 hours (range: 6.3-15.8 hours, n=16) in healthy
adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged
between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9
hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life
of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to
between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes
transplacental passage and that it is excreted in human milk.
Race — Maximal concentrations and half-life of alprazolam are approximately 15% and 25%
higher in Asians compared to Caucasians.

Pediatrics — The pharmacokinetics of alprazolam in pediatric patients have not been studied.
Gender — Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers
compared to non-smokers.

Drug-Drug Interactions
Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most
of the interactions that have been documented with alprazolam are with drugs that inhibit or
induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma
alprazolam concentrations. Drug products that have been studied in vivo, along with their
effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole,
2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS–Drug Interactions).
CYP3A inducers would be expected to decrease alprazolam concentrations and this has been
observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was
increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was
shortened (from 17.1±4.9 to 7.7 ±1.7 h) following administration of 300 mg/day
carbamazepine for 10 days (see PRECAUTIONS–Drug Interactions). However, the
carbamazepine dose used in this study was fairly low compared to the recommended doses
(1000-1200 mg/day); the effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce human hepatic enzyme systems has not yet been
determined. However, this is not a property of benzodiazepines in general. Further, alprazolam
did not affect the prothrombin or plasma warfarin levels in male volunteers administered
sodium warfarin orally.

CLINICAL STUDIES
Anxiety Disorders
XANAX Tablets were compared to placebo in double blind clinical studies (doses up to 4
mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive
symptomatology. XANAX was significantly better than placebo at each of the evaluation
periods of these 4-week studies as judged by the following psychometric instruments:
Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s
Global Impressions and Self-Rating Symptom Scale.
Panic Disorder
Support for the effectiveness of XANAX in the treatment of panic disorder came from three
short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely
corresponding to DSM-III-R criteria for panic disorder.

The average dose of XANAX was 5-6 mg/day in two of the studies, and the doses of XANAX
were fixed at 2 and 6 mg/day in the third study. In all three studies, XANAX was superior to
placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37-
83% met this criterion), as well as on a global improvement score. In two of the three studies,
XANAX was superior to placebo on a variable defined as "change from baseline on the
number of panic attacks per week" (range, 3.3-5.2), and also on a phobia rating scale. A
subgroup of patients who were improved on XANAX during short-term treatment in one of
these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

INDICATIONS AND USAGE

Anxiety Disorders
XANAX Tablets (alprazolam) are indicated for the management of anxiety disorder (a
condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-IIIR]
diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety.
Anxiety or tension associated with the stress of everyday life usually does not require
treatment with an anxiolytic.
Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry
(apprehensive expectation) about two or more life circumstances, for a period of 6 months or
longer, during which the person has been bothered more days than not by these concerns. At
least 6 of the following 18 symptoms are often present in these patients: Motor Tension
(trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy
fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations;
palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or
light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent
urination; trouble swallowing or 'lump in throat’); Vigilance and Scanning (feeling keyed up
or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank’
because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be
secondary to another psychiatric disorder or caused by some organic factor.
Anxiety associated with depression is responsive to XANAX.
Panic Disorder
XANAX is also indicated for the treatment of panic disorder, with or without agoraphobia.
Studies supporting this claim were conducted in patients whose diagnoses corresponded
closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL STUDIES).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization
(feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing
control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or
hot flushes.
Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4
months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however,
patients with panic disorder have been treated on an open basis for up to 8 months without
apparent loss of benefit. The physician should periodically reassess the usefulness of the drug
for the individual patient.

CONTRAINDICATIONS

XANAX Tablets are contraindicated in patients with known sensitivity to this drug or other
benzodiazepines. XANAX may be used in patients with open angle glaucoma who are
receiving appropriate therapy, but is contraindicated in patients with acute narrow angle
glaucoma.
XANAX is contraindicated with ketoconazole and itraconazole, since these medications
significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A)
(see WARNINGS and PRECAUTIONS–Drug Interactions).

WARNINGS

Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence of physical
dependence to XANAX. These include a spectrum of withdrawal symptoms; the most
important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively shortterm
use at the doses recommended for the treatment of transient anxiety and anxiety disorder
(ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system
data suggest that the risk of dependence and its severity appear to be greater in patients treated
with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a
controlled postmarketing discontinuation study of panic disorder patients, the duration of
treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to
zero dose. In contrast, patients treated with doses of XANAX greater than 4 mg/day had more
difficulty tapering to zero dose than those treated with less than 4 mg/day.
The importance of dose and the risks of XANAX as a treatment for panic disorder: Because
the management of panic disorder often requires the use of average daily doses of XANAX
above 4 mg, the risk of dependence among panic disorder patients may be higher than that
among those treated for less severe anxiety. Experience in randomized placebo-controlled
discontinuation studies of patients with panic disorder showed a high rate of rebound and
withdrawal symptoms in patients treated with XANAX compared to placebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic
disorder (primarily panic attacks) to levels approximately equal to those seen at baseline
before active treatment was initiated. Rebound refers to a return of symptoms of panic
disorder to a level substantially greater in frequency, or more severe in intensity than seen at
baseline. Withdrawal symptoms were identified as those which were generally not
characteristic of panic disorder and which occurred for the first time more frequently during
discontinuation than at baseline.
In a controlled clinical trial in which 63 patients were randomized to XANAX and where
withdrawal symptoms were specifically sought, the following were identified as symptoms of
withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded
sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite
decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently
seen during discontinuation, but it could not be determined if they were due to return of
illness, rebound, or withdrawal.
In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue
medication was measured, 71%-93% of patients treated with XANAX tapered completely off
therapy compared to 89%-96% of placebo-treated patients. In a controlled postmarketing
discontinuation study of panic disorder patients, the duration of treatment (3 months compared
to 6 months) had no effect on the ability of patients to taper to zero dose.
Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of
1980 patients with panic disorder or in patients participating in clinical trials where doses of
XANAX greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly
occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg.
Three cases occurred in situations where there was not a clear relationship to abrupt dose
reduction or discontinuation. In one instance, seizure occurred after discontinuation from a
single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other
instances, the relationship to taper is indeterminate; in both of these cases the patients had
been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases
ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients
developing seizures while apparently tapering gradually from XANAX. The risk of seizure
seems to be greatest 24-72 hours after discontinuation (see DOSAGE AND
ADMINISTRATION for recommended tapering and discontinuation schedule).
Status Epilepticus and its Treatment
The medical event voluntary reporting system shows that withdrawal seizures have been
reported in association with the discontinuation of XANAX. In most cases, only a single
seizure was reported; however, multiple seizures and status epilepticus were reported as well.
Interdose Symptoms
Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have
been reported in patients with panic disorder taking prescribed maintenance doses of
XANAX. These symptoms may reflect the development of tolerance or a time interval
between doses which is longer than the duration of clinical action of the administered dose. In
either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels
above those needed to prevent relapse, rebound or withdrawal symptoms over the entire
course of the interdosing interval. In these situations, it is recommended that the same total
daily dose be given divided as more frequent administrations (see DOSAGE AND
ADMINISTRATION).
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes
purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient
is admitted to a hospital). Therefore, the dosage of XANAX should be reduced or
discontinued gradually (see DOSAGE AND ADMINISTRATION).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving XANAX should be cautioned
against engaging in hazardous occupations or activities requiring complete mental alertness
such as operating machinery or driving a motor vehicle. For the same reason, patients should
be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs
during treatment with XANAX.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If
XANAX is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus. Because of experience with
other members of the benzodiazepine class, XANAX is assumed to be capable of causing an
increased risk of congenital abnormalities when administered to a pregnant woman during the
first trimester. Because use of these drugs is rarely a matter of urgency, their use during the
first trimester should almost always be avoided. The possibility that a woman of childbearing
potential may be pregnant at the time of institution of therapy should be considered. Patients
should be advised that if they become pregnant during therapy or intend to become pregnant
they should communicate with their physicians about the desirability of discontinuing the
drug.
Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A
(CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving
very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant
degree, alprazolam should be used only with caution and consideration of appropriate dosage
reduction. For some drugs, an interaction with alprazolam has been quantified with clinical
data; for other drugs, interactions are predicted from in vitro data and/or experience with
similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of alprazolam and/or
related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents— Ketoconazole and itraconazole are potent CYP3A inhibitors and
have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70
fold, respectively. The coadministration of alprazolam with these agents is not recommended.
Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the
coadministration of alprazolam with them is not recommended (see
CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving
alprazolam (caution and consideration of appropriate alprazolam dose reduction are
recommended during coadministration with the following drugs)
Nefazodone—Coadministration of nefazodone increased alprazolam concentration two-fold.
Fluvoxamine—Coadministration of fluvoxamine approximately doubled the maximum
plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%,
and decreased measured psychomotor performance.
Cimetidine—Coadministration of cimetidine increased the maximum plasma concentration of
alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.
Other drugs possibly affecting alprazolam metabolism
Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed
in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions).

PRECAUTIONS

General
Suicide
As with other psychotropic medications, the usual precautions with respect to administration
of the drug and size of the prescription are indicated for severely depressed patients or those in
whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been
associated with primary and secondary major depressive disorders and increased reports of
suicide among untreated patients.
Mania
Episodes of hypomania and mania have been reported in association with the use of XANAX
in patients with depression.
Uricosuric Effect
Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric
effect have been reported to cause acute renal failure, there have been no reported instances of
acute renal failure attributable to therapy with XANAX.
Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose to preclude the
development of ataxia or oversedation which may be a particular problem in elderly or
debilitated patients. (See DOSAGE AND ADMINISTRATION.) The usual precautions in
treating patients with impaired renal, hepatic or pulmonary function should be observed. There
have been rare reports of death in patients with severe pulmonary disease shortly after the
initiation of treatment with XANAX. A decreased systemic alprazolam elimination rate (eg,
increased plasma half-life) has been observed in both alcoholic liver disease patients and
obese patients receiving XANAX (see CLINICAL PHARMACOLOGY).
Information for Patients
For all users of XANAX:
To assure safe and effective use of benzodiazepines, all patients prescribed XANAX should be
provided with the following guidance.
1. Inform your physician about any alcohol consumption and medicine you are taking now,
including medication you may buy without a prescription. Alcohol should generally not be
used during treatment with benzodiazepines.
2. Not recommended for use in pregnancy. Therefore, inform your physician if you are
pregnant, if you are planning to have a child, or if you become pregnant while you are taking
this medication.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate
potentially dangerous machinery, etc.
5. Do not increase the dose even if you think the medication "does not work anymore" without
consulting your physician. Benzodiazepines, even when used as recommended, may produce
emotional and/or physical dependence.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your
physician, since withdrawal symptoms can occur.
Additional advice for panic disorder patients:
The use of XANAX at doses greater than 4 mg/day, often necessary to treat panic disorder, is
accompanied by risks that you need to carefully consider. When used at doses greater than 4
mg/day, which may or may not be required for your treatment, XANAX has the potential to
cause severe emotional and physical dependence in some patients and these patients may find
it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration
where the ability of patients to discontinue medication was measured, 7 to 29% of patients
treated with XANAX did not completely taper off therapy. In a controlled postmarketing
discontinuation study of panic disorder patients, the patients treated with doses of XANAX
greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less
than 4 mg/day. In all cases, it is important that your physician help you discontinue this
medication in a careful and safe manner to avoid overly extended use of XANAX.
In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence
and severity of withdrawal reactions when XANAX is discontinued. These are generally
minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the
medication abruptly. Seizure can be life-threatening.

Nursing Drug Guide - Vicodin acetaminophen and hydrocodone Anexsia, Dolorex Forte, Hycet, Liquicet, Lorcet, Lortab, Maxidone, Norco, Polygesic

VICODINB (Abbott)
(hydrocodone bitartrate and acetaminophen tablets, USP)
5 mg/500 mg
Rx only

DESCRIPTION

Hydrocodone bitartrate and acetaminophen is supplied in tablet form for oral administration.
Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or
as a crystalline powder. It is affected by light. The chemical name is: 4,5(alpha)epoxy-3-
methoxy-17-methy1morphinan-6-oneta rtrate (1 :1 ) hydrate (25).
Each VICODIN tablet contains:
Hydrocodone Bitartrate 5 mg
Acetaminophen 500 mg
In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide,
starch, croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline
cellulose, povidone, and stearic acid.

CLINICAL PHARMACOLOGY

Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple actions
qualitatively similar to those of codeine. Most of these involve the central nervous system and
smooth muscle. The precise mechamism of action of hydrocodone and other opiates is not
known, although it is believed to relate to the existence of opiate receptors in the central nervous
system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental
clouding.
The analgesic action of acetaminophen involves peripheral influences, but the specific
mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalmic heat
regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of
acetaminophen have negligible effects on the cardiovascular or respiratory systems; however,
toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics:
The behavior of the individual components is described below.
Hydrocodone: Following a 1 Omg oral dose of hydrocodone administered to five adult male
subjects, the mean peak concentration was 23.6 f 5.2ng/mL. Maximum serum levels were
achieved at 1.3 f 0.3 hours and the half-life was determined to be 3.8 f 0.3 hours. Hydrocodone
exhibits a complex pattern of metabolism including 0-demethylation, N-demethylation and 6-
keto reduction to the corresponding 6-(alpha)- and 6-(beta)-hydroxymetabolites. See
OVERDOSAGE for toxicity information.
Acetaminophen: Acetaminophen is rapidly absorbed from the gastrointestinal tract and is
distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be
increased by liver damage and following overdosage. Elimination of acetaminophen is
principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites.
Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most
as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. See
OVERDOSAGE for toxicity information.

INDICATIONS AND USAGE

VICODIN tablets are indicated for the relief of moderate to moderately severe pain.

CONTRAINDICATIONS

This product should not be administered to patients who have previously exhibited
hypersensitivity to hydrocodone or acetaminophen.
Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to
hydrocodone.

WARNINGS

Respiratory Depression: At high doses or in sensitive patients, hydrocodone may produce doserelated
respiratory depression by acting directly on the brain stem respiratory center.
Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular
and periodic breathing.
Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of
narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated
in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial
pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical
course of patients with head injuries.
Acute Abdominal Conditions: The administration of narcotics may obscure the diagnosis or
clinical course of patients with acute abdominal conditions.

PRECAUTIONS

General:
Special Risk Patients: As with any narcotic analgesic agent, VICODIN Tablets should be used
with caution in elderly or debilitated patients and those with severe impairment of hepatic or
renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture.
The usual precautions should be observed and the possibility of respiratory depression should be
kept in mind.
Cough Reflex: Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be
exercised when VICODIN Tablets are used postoperatively and in patients with pulmonary
disease.
Information for Patients: Hydrocodone, like all narcotics, may impair the mental and/or
physical abilities required for the performance of potentially hazardous tasks such as driving a
car or operating machinery; patients should be cautioned accordingly.
Alcohol and other CNS depressants may produce an additive CNS depression, when taken with
this combination product, and should be avoided.
Hydrocodone may be habit forming. Patients should take the drug only for as long as it is
prescribed, in the amounts prescribed, and no more frequently than prescribed.

Nursing Drug Guide - Trazodone Desyrel Oleptro Desyrel Dividose

OLEPTRO (trazodone hydrochloride) extended-release tablets Initial U.S. Approval: 1981

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
See full prescribing information for complete boxed warning.
Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders. Oleptro is not approved for use in pediatric patients (5.1).

----------------------------INDICATIONS AND USAGE---------------------------
Oleptro is indicated for the treatment of major depressive disorder (1).
• Efficacy was established in one 8-week trial of Oleptro as well as in trials of trazodone immediate release formulation in patients with major depressive disorder (14).

------------------------DOSAGE AND ADMINISTRATION----------------------
•
Starting dose: 150 mg once daily. May be increased by 75 mg per day every three days. Maximum dose: 375 mg per day (2).
•
Dosing at the same time every day in the late evening, preferably at bedtime, on an empty stomach (2).
•
Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed (2).
•
When discontinued, gradual dose reduction is recommended (2).

-----------------------DOSAGE FORMS AND STRENGTHS--------------------
Bisectable tablets of 150 mg or 300 mg (3).

--------------------------------CONTRAINDICATIONS-----------------------------
None (4).

-------------------------WARNINGS AND PRECAUTIONS----------------------
•
Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1).
•
Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions: Have been reported with antidepressants. Discontinue Oleptro and initiate supportive treatment (5.2).
•
Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania (5.3).
•
QT Prolongation: Increases the QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval (5.4).
•
Use in Patients with Heart Disease: Use with caution in patients with cardiac disease (5.5).
•
Orthostatic Hypotension and Syncope: Have occurred. Warn patients of risk and symptoms of hypotension (5.6).
•
Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk (5.7).
•
Interaction with MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors (5.8).
•
Priapism: Has occurred. Warn male patients of this risk and how/when to seek medical attention (5.9).
•
Hyponatremia: Can occur in association with SIADH (5.10).
•
Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Advise patients to use caution when operating machinery (5.11).
•
Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance. Upon discontinuation, taper Oleptro and monitor for symptoms (5.12).

---------------------------------ADVERSE REACTIONS---------------------------- Most common adverse reactions (incidence ≥5% and twice that of placebo) are: somnolence/sedation, dizziness, constipation, vision blurred (6).
To report SUSPECTED ADVERSE REACTIONS, contact Labopharm at 1-877-345-6177 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

---------------------------------DRUG INTERACTIONS----------------------------
•
Monoamine Oxidase Inhibitors: Should not be used concomitantly with Oleptro (5.8, 7).
•
CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants (7).
•
CYP3A4 Inhibitors: May necessitate lower dose of Oleptro (7).
•
CYP3A4 Inducers (e.g., carbamazepine): May necessitate higher dose of Oleptro (7).
•
Digoxin or Phenytoin: Monitor for increased serum levels (7).
•
Warfarin: Monitor for increased or decreased prothrombin time (7).
•
Serotonergic Medications: Serotonin syndrome has been reported (5.2, 7).
•
NSAIDs, Aspirin or other Anticoagulants: Potential for increased risk of bleeding (5.7, 7).

-------------------------USE IN SPECIFIC POPULATIONS----------------------
•
Pregnancy: Based on animal data, may cause fetal harm (8.1).
•
Nursing Mothers: Use with caution (8.3).
•
Pediatric Patients: Oleptro is not approved in pediatric patients (8.4).
•
Renal or Hepatic Impairment: Use with caution (8.6, 8.7).

Nursing Drug Guide - Tramadol Rybix ODT Ryzolt Ultram ER

ULTRAM ER
(tramadol HCI) Extended-Release Tablets
Clean Proposed Labeling Text

ULTRAM® ER
(tramadol HCI) Extended-Release Tablets
Rx only

Prescribing Information

DESCRIPTION
ULTRAM® ER (tramadol hydrochloride) is a centrally acting synthetic analgesic in an
extended-release formulation. The chemical name is (±) cis-2-[(dimethylamino)methyl]-
1-(3-methoxyphenyl) cyclohexanol hydrochloride.

CLINICAL PHARMACOLOGY

Mechanism of Action
ULTRAM ER is a centrally acting synthetic opioid analgesic. Although its mode of
action is not completely understood, from animal tests, at least two complementary
mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid
receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher
affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal
models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200
times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially
antagonized by the opiate antagonist naloxone in several animal tests. The relative
contribution of both tramadol and M1 to human analgesia is dependent upon the plasma
concentrations of each compound.
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as
have some other opioid analgesics. These mechanisms may contribute independently to
the overall analgesic profile of tramadol. The relationship between exposure of tramadol
and M1 and efficacy has not been evaluated in the ULTRAM ER clinical studies.
Apart from analgesia, tramadol administration may produce a constellation of symptoms
(including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to
that of other opioids. In contrast to morphine, tramadol has not been shown to cause
histamine release. At therapeutic doses, tramadol has no effect on heart rate, leftventricular
function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite.
ULTRAM ER is administered as a racemate and both the [-] and [+] forms of both
tramadol and M1 are detected in the circulation.
The pharmacokinetics of ULTRAM ER are approximately dose-proportional over a
100-400 mg dose range in healthy subjects. The observed tramadol AUC values for the
400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg
dose. The clinical significance of this finding has not been studied and is not known.
Absorption
In healthy subjects, the bioavailability of a ULTRAM ER 200 mg tablet relative to a 50
mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM)
was approximately 85-90%. Consistent with the extended-release nature of the
formulation, there is a lag time in drug absorption following ULTRAM ER
administration. The mean peak plasma concentrations of tramadol and M1 after
tablets to healthy volunteers are attained at about 12 h
and 15 h, respectively, after dosing (see Table 1 and Figure 2). Following administration
of the ULTRAM ER, steady-state plasma concentrations of both tramadol and M1 are
achieved within four days with once daily dosing.

Food Effects
After a single dose administration of 200 mg ULTRAM ER tablet with a high fat meal,
the Cmax and AUC0-∞ of tramadol decreased 28% and 16%, respectively, compared to
fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions
to 17 hr under fed conditions). While ULTRAM ER may be taken without regard to food,
it is recommended that it be taken in a consistent manner.

Distribution
The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female
subjects, respectively, following a 100-mg intravenous dose. The binding of tramadol to
human plasma proteins is approximately 20% and binding also appears to be independent
of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at
concentrations outside the clinically relevant range.
Metabolism
Tramadol is extensively metabolized after oral administration. The major metabolic
pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by
CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite
(O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models.
Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which
may affect the therapeutic response (see PRECAUTIONS - Drug Interactions).
Elimination
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are
eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the
urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The
remainder is excreted either as unidentified or as unextractable metabolites. The mean
terminal plasma elimination half-lives of racemic tramadol and racemic M1 after
administration of ULTRAM ER are approximately 7.9 and 8.8 hours, respectively.

Special Populations

Renal
Impaired renal function results in a decreased rate and extent of excretion of tramadol and
its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with
mild or moderate renal impairment after receiving multiple doses of ULTRAM ER 100
mg. There is no consistent trend observed for tramadol exposure related to renal function
in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal
impairment in comparison to patients with normal renal function. However, exposure of
M1 increased 20-40% with increased severity of the renal impairment (from normal to
mild and moderate). ULTRAM ER has not been studied in patients with severe renal
impairment (CLcr < 30 mL/min). The limited availability of dose strengths of ULTRAM
ER does not permit the dosing flexibility required for safe use in patients with severe
renal impairment. Therefore, ULTRAM ER should not be used in patients with severe
renal impairment (see PRECAUTIONS, Use in Renal and Hepatic Disease and
DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed
during a 4-hour dialysis period is less than 7% of the administered dose.
Hepatic
Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic
impairment after receiving multiple doses of ULTRAM ER 100 mg. The exposure of (+)-
and (-)-tramadol was similar in mild and moderate hepatic impairment patients in
comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-
M1 decreased ~50% with increased severity of the hepatic impairment (from normal to
mild and moderate). The pharmacokinetics of tramadol after the administration of
ULTRAM ER has not been studied in patients with severe hepatic impairment. After the
administration of tramadol immediate-release tablets to patients with advanced cirrhosis
of the liver, tramadol area under the plasma concentration time curve was larger and the
tramadol and M1 half-lives were longer than subjects with normal hepatic function. The
limited availability of dose strengths of ULTRAM ER does not permit the dosing
flexibility required for safe use in patients with severe hepatic impairment. Therefore,
ULTRAM ER should not be used in patients with severe hepatic impairment (see
PRECAUTIONS, Use in Renal and Hepatic Disease and DOSAGE AND
ADMINISTRATION).

Geriatric
The effect of age on the absorption of tramadol from ULTRAM ER in patients over the
age of 65 years has not been studied and is unknown (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).

Gender
Based on pooled multiple-dose pharmacokinetics studies for ULTRAM ER in
166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for
tramadol were somewhat higher in females than in males. There was a considerable
degree of overlap in values between male and female groups. Dosage adjustment based
on gender is not recommended.

Drug Interactions

The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7%
of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450.
Based on a population PK analysis of Phase I studies with immediate-release tablets in
healthy subjects, concentrations of tramadol were approximately 20% higher in "poor
metabolizers" versus "extensive metabolizers," while M1 concentrations were 40%
lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors
of CYP2D6 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the
metabolism of tramadol to various degrees, suggesting that concomitant administration of
these compounds could result in increases in tramadol concentrations and decreased
concentrations of M1. The full pharmacological impact of these alterations in terms of
either efficacy or safety is unknown.
Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such
as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort,
with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol
exposure (see PRECAUTIONS, Drug Interactions).
Quinidine
Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the
effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol
by administering 200 mg quinidine two hours before the administration of ULTRAM ER
100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and
the exposure of M1 decreased 50-60% (see PRECAUTIONS, Drug Interactions). In
vitro drug interaction studies in human liver microsomes indicate that tramadol has no
effect on quinidine metabolism.

Carbamazepine
Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking
carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of
the seizure risk associated with tramadol, concomitant administration of ULTRAM ER
and carbamazepine is not recommended (see PRECAUTIONS, Drug Interactions).
Cimetidine
Concomitant administration of tramadol immediate-release tablets with cimetidine does
not result in clinically significant changes in tramadol pharmacokinetics. No alteration of
the ULTRAM ER dosage regimen with cimetidine is recommended.

INDICATIONS AND USAGE

ULTRAM ER is indicated for the management of moderate to moderately severe chronic
pain in adults who require around-the-clock treatment of their pain for an extended period
of time.

CONTRAINDICATIONS

ULTRAM ER should not be administered to patients who have previously demonstrated
hypersensitivity to tramadol, any other component of this product or opioids. ULTRAM
ER is contraindicated in any situation where opioids are contraindicated, including acute
intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting
analgesics, opioids or psychotropic drugs. ULTRAM ER may worsen central nervous
system and respiratory depression in these patients.

WARNINGS

Seizure Risk
Seizures have been reported in patients receiving tramadol within the recommended
dosage range. Spontaneous post-marketing reports indicate that seizure risk is
increased with doses of tramadol above the recommended range. Concomitant use
of tramadol increases the seizure risk in patients taking:
• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g.,
cyclobenzaprine, promethazine, etc.), or
• Other opioids.
Administration of tramadol may enhance the seizure risk in patients taking:
• MAO inhibitors (see also WARNINGS - Use with MAO Inhibitors),
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history
of seizures, or in patients with a recognized risk for seizure (such as head trauma,
metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol
overdose, naloxone administration may increase the risk of seizure.
Suicide Risk
• Do not prescribe ULTRAM ER for patients who are suicidal or addiction-prone.
• Prescribe ULTRAM ER with caution for patients taking tranquilizers or
antidepressant drugs and patients who use alcohol in excess.
• Tell your patients not to exceed the recommended dose and to limit their intake
of alcohol.

Anaphylactoid Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving
therapy with tramadol. When these events do occur it is often following the first dose.
Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema,
toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of
anaphylactoid reactions to codeine and other opioids may be at increased risk and
therefore should not receive ULTRAM ER (see CONTRAINDICATIONS).
Respiratory Depression
Administer ULTRAM ER cautiously in patients at risk for respiratory depression. In
these patients alternative non-opioid analgesics should be considered. When large doses
of tramadol are administered with anesthetic medications or alcohol, respiratory
depression may result. Respiratory depression should be treated as an overdose. If
naloxone is to be administered, use cautiously because it may precipitate seizures (see
WARNINGS Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) Depressants
ULTRAM ER should be used with caution and in reduced dosages when administered to
patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics,
phenothiazines, tranquilizers or sedative hypnotics. ULTRAM ER increases the risk of
CNS and respiratory depression in these patients.
Increased Intracranial Pressure or Head Trauma
ULTRAM ER should be used with caution in patients with increased intracranial pressure
or head injury. The respiratory depressant effects of opioids include carbon dioxide
retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly
exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol
may obscure the existence, extent, or course of intracranial pathology. Clinicians should
also maintain a high index of suspicion for adverse drug reaction when evaluating altered
mental status in these patients if they are receiving ULTRAM ER. (see WARNINGS -
Respiratory Depression.)
Use in Ambulatory Patients
ULTRAM ER may impair the mental and or physical abilities required for the
performance of potentially hazardous tasks such as driving a car or operating machinery.
The patient using this drug should be cautioned accordingly.
Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors
Use ULTRAM ER with great caution in patients taking monoamine oxidase inhibitors.
Animal studies have shown increased deaths with combined administration. Concomitant
use of ULTRAM ER with MAO inhibitors or SSRIs increases the risk of adverse events,
including seizure and serotonin syndrome.
Withdrawal
Withdrawal symptoms may occur if ULTRAM ER is discontinued abruptly. These
symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors,
diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical
experience suggests that withdrawal symptoms may be reduced by tapering ULTRAM
ER.
Misuse, Abuse and Diversion of Opioids
Tramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug
abusers and people with addiction disorders and are subject to criminal diversion.
Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing ULTRAM ER in situations where
the physician or pharmacist is concerned about an increased risk of misuse, abuse, or
diversion.
ULTRAM ER could be abused by crushing, chewing, snorting, or injecting the dissolved
product. These practices will result in the uncontrolled delivery of the opioid and pose a
significant risk to the abuser that could result in overdose and death (see WARNINGS
and DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction, and diversion should not prevent the proper
management of pain. The development of addiction to opioid analgesics in properly
managed patients with pain has been reported to be rare. However, data are not available
to establish the true incidence of addiction in chronic pain patients.
Healthcare professionals should contact their State Professional Licensing Board, or State
Controlled Substances Authority for information on how to prevent and detect abuse or
diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Tramadol may be expected to have additive effects when used in conjunction with
alcohol, other opioids, or illicit drugs that cause central nervous system depression.
DRUG ABUSE AND ADDICTION
ULTRAM® ER is a mu-agonist opioid. Tramadol, like other opioids used in
analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and
continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing
a multi-disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking
tactics include emergency calls or visits near the end of office hours, refusal to undergo
appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering
with prescriptions and reluctance to provide prior medical records or contact information
for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is
common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance.
Physicians should be aware that addiction may not be accompanied by concurrent
tolerance and symptoms of physical dependence in all addicts. In addition, abuse of
opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical
purposes, often in combination with other psychoactive substances. ULTRAM
ER, like other opioids, may be diverted for non-medical use. Careful record-keeping of
prescribing information, including quantity, frequency, and renewal requests is strongly
advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of
therapy, and proper dispensing and storage are appropriate measures that help to limit
abuse of opioid drugs.
ULTRAM ER is intended for oral use only. The crushed tablet poses a hazard of
overdose and death. This risk is increased with concurrent abuse of alcohol and other
substances. With parenteral abuse, the tablet excipients can be expected to result in local
tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and
valvular heart injury. Parenteral drug abuse is commonly associated with transmission of
infectious diseases such as hepatitis and HIV.
Risk of Overdosage
Serious potential consequences of overdosage with ULTRAM ER are central nervous
system depression, respiratory depression and death. In treating an overdose, primary
attention should be given to maintaining adequate ventilation along with general
supportive treatment (see OVERDOSAGE).

PRECAUTIONS

Acute Abdominal Condition
The administration of ULTRAM ER may complicate the clinical assessment of patients
with acute abdominal conditions.
Use in Renal and Hepatic Disease
Impaired renal function results in a decreased rate and extent of excretion of tramadol and
its active metabolite, M1. ULTRAM ER has not been studied in patients with severe
renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and
once daily dosing of ULTRAM ER do not permit the dosing flexibility required for safe
use in patients with severe renal impairment. Therefore, ULTRAM ER should not be
used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced
in patients with advanced cirrhosis of the liver. The pharmacokinetics of ULTRAM ER
has not been studied in patients with severe hepatic impairment. The limited availability
of dose strengths and once daily dosing of ULTRAM ER do not permit the dosing
flexibility required for safe use in patients with severe hepatic impairment. Therefore,
ULTRAM ER should not be used in patients with severe hepatic impairment (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
• Patients should be informed that ULTRAM ER is for oral use only and should be
swallowed whole. The tablets should not be chewed, crushed, or split.
• Patients should be informed that ULTRAM ER may cause seizures and/or serotonin
syndrome with concomitant use of serotonergic agents (including SRIs, NRIs, and
triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
•Patients should be informed that ULTRAM ER is for oral use only and should be
swallowed whole. The tablets should not be chewed, crushed, or split.
• Patients should be informed that ULTRAM ER may impair mental or physical
abilities required for the performance of potentially hazardous tasks such as driving a
car or operating machinery.
• Patients should be informed that ULTRAM ER should not be taken with alcohol
containing beverages.
• Patients should be informed that ULTRAM ER should be used with caution when
taking medications such as tranquilizers, hypnotics or other opiate containing
analgesics.
• Female patients should be instructed to inform the prescriber if they are pregnant,
think they might become pregnant, or are trying to become pregnant (see
PRECAUTIONS, Labor and Delivery).
• Patients should be educated regarding the single-dose and 24-hour dosing regimen, as
exceeding these recommendations can result in respiratory depression, seizures or
death.
Use in Drug and Alcohol Addiction
ULTRAM ER is an opioid with no approved use in the management of addictive
disorders. Its proper usage in individuals with drug or alcohol dependence, either active
or in remission, is for the management of pain requiring opioid analgesia.
Drug Interactions
CYP2D6 and CYP3A4 inhibitors: Concomitant administration of CYP2D6 and/or
CYP3A4 inhibitors (See CLINICAL PHARMACOLOGY—Pharmacokinetics), such as
quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and
ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance
of tramadol increasing the risk for serious adverse events including seizures and
serotonin syndrome.
Serotonergic Drugs: There have been postmarketing reports of serotonin syndrome
with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers.
Caution is advised when ULTRAM ER is coadministered with other drugs that may
affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans,
linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St.
John’s Wort. If concomitant treatment of ULTRAM ER with a drug affecting the
serotonergic neurotransmitter system is clinically warranted, careful observation of the
patient is advised, particularly during treatment initiation and dose increases (see
WARNINGS – Serotonin Syndrome).
Triptans: Based on the mechanism of action of tramadol and the potential for serotonin
syndrome, caution is advised when ULTRAM ER is coadministered with a triptan. If
concomitant treatment of ULTRAM ER with a triptan is clinically warranted, careful
observation of the patient is advised, particularly during treatment initiation and dose
increases (see WARNINGS - Serotonin Syndrome ).
Use With Carbamazepine
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced
analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and
because of the seizure risk associated with tramadol, concomitant administration of
ULTRAM ER and carbamazepine is not recommended.
Use With Quinidine
Coadministration of quinidine with ULTRAM ER resulted in a 50-60% increase in
tramadol exposure and a 50-60% decrease in M1 exposure (see CLINICAL
PHARMACOLOGY, Drug Interactions). The clinical consequences of these findings
are unknown.
Use With Digoxin and Warfarin
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and
alteration of warfarin effect, including elevation of prothrombin times.
Potential for Other Drugs to Affect Tramadol
In vitro drug interaction studies in human liver microsomes indicate that concomitant
administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and
amitriptyline could result in some inhibition of the metabolism of tramadol.
Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or
inducers, such as rifampin and St. John’s Wort, with ULTRAM ER may affect the
metabolism of tramadol leading to altered tramadol exposure.
Potential for Tramadol to Affect Other Drugs
In vitro drug interaction studies in human liver microsomes indicate that tramadol has no
effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to
inhibit the CYP3A4-mediated metabolism of other drugs when administered
concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug
metabolism pathways measured in animals
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral
doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD]
of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in
rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females
(approximately 2-fold MDHD) for two years. However, the excessive decrease in body
weight gain observed in the rat study might have reduced their sensitivity to any potential
carcinogenic effect of the drug.
Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay
using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic
activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in
the presence of metabolic activation in the mouse lymphoma assay. Overall, the weight
of evidence from these tests indicates that tramadol does not pose a genotoxic risk to
humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day
in male and female rats (approximately equivalent to MDHD).
Pregnancy
Teratogenic Effects: Pregnancy Category C
Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately
equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits
during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and
skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic
dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold
MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD).
Non-teratogenic Effects
Tramadol caused a reduction in neonatal body weight and survival at an oral dose of 80
mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation
throughout lactation period.
There are no adequate and well-controlled studies in pregnant women. ULTRAM ER
should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth
have been reported during post-marketing reports with tramadol HCl immediate-release
products.
Labor and Delivery
ULTRAM ER should not be used in pregnant women prior to or during labor unless the
potential benefits outweigh the risks. Safe use in pregnancy has not been established.
Chronic use during pregnancy may lead to physical dependence and post-partum
withdrawal symptoms in the newborn (see DRUG ABUSE AND ADDICTION).
Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the
umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol
HCl during labor.
The effect of ULTRAM ER, if any, on the later growth, development, and functional
maturation of the child is unknown.
Nursing Mothers
ULTRAM ER is not recommended for obstetrical preoperative medication or for postdelivery
analgesia in nursing mothers because its safety in infants and newborns has not
been studied. Following a single IV 100-mg dose of tramadol, the cumulative excretion
in breast milk within sixteen hours postdose was 100 μg of tramadol (0.1% of the
maternal dose) and 27 μg of M1.
Pediatric Use
The safety and efficacy of ULTRAM ER in patients under 18 years of age have not been
established. The use of ULTRAM ER in the pediatric population is not recommended.
Geriatric Use
Nine-hundred-one elderly (65 years of age or older) subjects were exposed to ULTRAM
ER in clinical trials. Of those subjects, 156 were 75 years of age and older. In general,
higher incidence rates of adverse events were observed for patients older than 65 years of
age compared with patients 65 years and younger, particularly for the following adverse
events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this
reason, ULTRAM ER should be used with great caution in patients older than 75 years of
age (see CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).

DOSAGE AND ADMINISTRATION

ULTRAM ER should not be used in patients with:
• creatinine clearance less than 30 mL/min,
• severe hepatic impairment (Child-Pugh Class C)
(See PRECAUTIONS, Use in Renal and Hepatic Disease).
ULTRAM ER must be swallowed whole and must not be chewed, crushed, or split (see
WARNINGS, Misuse, Abuse and Diversion of Opioids and DRUG ABUSE AND
ADDICTION).
Adults (18 years of age and over)
Patients Not Currently on Tramadol Immediate-Release Products
For patients not currently treated with tramadol immediate-release (IR) products,
ULTRAM ER should be initiated at a dose of 100 mg once daily and titrated up as
necessary by 100-mg increments every five days to relief of pain and depending upon
tolerability. ULTRAM ER should not be administered at a dose exceeding 300 mg per
day.
Patients Currently on Tramadol Immediate-Release Products
For patients maintained on tramadol IR products, calculate the 24-hour tramadol IR dose
and initiate a total daily dose of ULTRAM ER rounded down to the next lowest 100 mg
increment. The dose may subsequently be individualized according to patient need. Due
to limitations in flexibility of dose selection with ULTRAM ER, some patients
maintained on tramadol IR products may not be able to convert to ULTRAM ER. Ultram
ER should not be administered at a dose exceeding 300 mg per day. The concomitant
use of ULTRAM ER with other tramadol products is not recommended (see
WARNINGS).
Individualization of Dose
Good pain management practice dictates that the dose be individualized according to
patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate
upward as tolerated to achieve an adequate effect. Clinical studies of ULTRAM ER have
not demonstrated a clinical benefit at a total daily dose exceeding 300 mg.
In general, dosing of an elderly patient (over 65 years of age) should be initiated
cautiously, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal or cardiac function and of concomitant disease or
other drug therapy. ULTRAM ER should be administered with even greater caution in
patients over 75 years, due to the greater frequency of adverse events seen in this
population.