Zoloft®

sertraline hydrochloride tablets                  to order (prescription not required)

Description

Zoloft® (sertraline hydrochloride) is an antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C17 H17 N Cl2.HCl is represented by the following structural formula:

Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.

Zoloft® is supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 50 and 100 mg of sertraline and the following inactive ingrediants: dibasic calcium phosphate dihydrate, FD&C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hydroxypropyl methycellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titaium dioxide.

 

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. Invitro studies have shown that sertraline has no significant affinity for andrenergic (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 downregulage brain norepinephrine receptors, as has been observed with other clinically effective antidepressants. 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 concentrators (Cmax) of sertraline occurred between 4.5 to 8.4 hours postdosing. 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 parmacokinetics 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.

The effects of food on the bioavailability of sertraline were studied in subjects administered a single-dose with and without food. AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration decreased from 8 hours post-dosing to 5.5 hours.

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 phamacokinetic parameters between day 1 and day 14.

Protein Binding -- In vitro protein binding studies performed with radiolabelled 3H-sertraline showed that sertraline is highly bound to serum protiens (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.

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. The elimination half-life of sertraline was prolonged in a single dose study of patients with mild, stable cirrhosis, with a mean of 52 hours compared to 22 hours seen in subjects without liver disease. This suggests that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver disease, a lower or less frequent dose should be used.

Renal Disease -- The pharmacokinetics of sertraline in patients with significant renal dysfunction have not been determined.

Indications and Usage

Zoloft® (sertraline hydrochloride) is indicated for the treatment of depression. The efficacy of Zoloft® in the treatment of a major depressive episode was established in six to eight week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of Major depressive disorder.

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.

A study of depressed outpatients who had responded to Zoloft® during an initial eight-week open treatment phase and were then randomized to continuation on Zoloft® or placebo demonstrated a significantly lower relapse rate over the next eight weeks for patients taking Zoloft® compared to those on placebo. However, the effectiveness of Zoloft® in long-term use, that is, for more than 16 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Zoloft® for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Contraindications

None Known

Warnings

Cases of serious reactions have been reported in patients receiving Zoloft® in combination with a monoamine oxidase inhibitor (MAOI). The symptoms have included mental status changes such as memory changes, confusion and irritability, chills, pyrexia and muscle rigidity. In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, it is recommended that Zoloft (sertraline hydrochloride) 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.

 

Precautions
General
Activation of Mania/Hypomania -- During premarketing testing, hypomania or mania occurred in approximately 0.4% of Zoloft® (sertralin hydrochloride) TREATED PATIENTS. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressants.

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 seizure disorder. These patients were excluded from clinical studies during the product's premarket testing. Accordingly, like other antidepressants, Zoloft® should be introduced with care in epileptic patients.

Suicide -- The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high risk patients should accompany initial drug therapy. 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.

Weak Uricosuric Effect -- Zoloft® is associated with a mean decrease in serum uric acide of approximately 7%. The clinical significance of this weak uricosuric effect is unknown, and there have been no reports of acute renal failure with Zoloft® .

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.

Zoloft® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses 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® is extensively metabolized by the liver. In subjects with mild, stable cirrhosis of the liver, the clearance of sertraline was decreased, thus increasing the elimination half-life. A lower or less frequent dose should be used in patients with cirrhosis.

Since Zoloft® is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. However, until the pharmacokinetics of Zoloft® have been studied in patients with renal impairment and until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Zoloft® , it should be used with caution in such patients.

Interference with Cognitive and Motor Performance -- In controlled studies, Zoloft® did not cause sedation and did not interfere with psychomotor performance.

Hyponatremia -- several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when Zoloft® was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

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
Physicians are advised to discuss the following issues with patients for whom they prescribe Zoloft:

 

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.

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 in depressed patients 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.

Laboratory Tests
None.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins -- because sertraline is tightly bound to plasma protein, the administration of Zoloft® (sertraline hydrochloride) to a patient taking another drug which is lightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound Zoloft® by other tightly bound drugs.

In a study compating prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either Zoloft® (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for Zoloft® compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the Zoloft® gorup was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when zoloft therapy is initiated or stopped.

Cimetidine -- In a study assessing disposition of Zoloft® (100mg) on the second of 8 days of cimetidine administration (800mg daily), there were increases in Zoloft mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.

CNS Active Drugs -- In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either Zoloft® (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the Zoloft® group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tmax for desmethyldiazepam in the Zoloft group compared to a 20% decrease in the placebo group (p<0.03). The clinical significance of these changes is unknown.

In a placebo controlled trial in normal volunteers, the administration of two doses of Zoloft® did not significantly alter steady-state lithium levels or the renal clearance of lithium.

Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of Zoloft® therapy with appropriate adjustments to the lithium dose.

The risk of using Zoloft® in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of Zoloft® and such drugs is required.

There is limited controlled experience regarding the optimal timing of switching from other antidepressants to Zoloft® . Care and prudent medical judgement should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.

Hypoglycemic Drugs -- In a placebo controlled trial in normal volunters, administration of Zoloft® for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000mg dose. Zoloft® admnistration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.

Atenolol -- Zoloft (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.

Digoxin -- In a placebo-controlled trial in normal volunteers, administration of Zoloft® for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.

Microsomal Enzyme Induction -- Preclinical studies have shown Zoloft® to induce hepatic microsomal enzymes. In clinical studies, Zoloft® was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.

Electroconvulsive Therapy -- there are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and Zoloft® .

Alcohol -- Although Zoloft® did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of Zoloft® and alcohol in depressed patients is not recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg in mice (10 times, on a mg/kg basis, and the same, on a mg/m^2 basis, as the maximum recommended human dose) and at doses up to 40 mg/kg in rats (10 times, on a mg/kg basis, and 2 times, on a mg/m^2 basis, the maximum recommended human dose). There was a dose-related increase in the incidence of liver adenomas in male mice receiving sertraline at 10-40 mg/kg. No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg; this was not accompanied by thyroid hyperplasta. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10-40 mg/kg compared to placebo controls, this effect was not clearly drug related.

Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutaion assay; mouse lymphoma mutation assay; and tests for cytogenic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (20 times the maximum human dose on a mg/kg basis and 4 times on a mg/m^2 basis).

Pregnancy--Pregnancy Category B
Teratogenic Effects -- Reproduction studies have been performed in rats and rabbits at doses up to approximately 20 times and 10 times the maximum daily human mg/kg dose (4 to 4.5 times the mg/m^2 dose), respectively.

There was no evidence of teratogenicity at any dose level. At doses approximately 2.5-10 times the maximum daily human mg/kg dose, sertraline was associated with delayed ossification in fetuses, probably secondary to effects on the dams.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects -- There was also decreased neonatal survival following maternal administration of sertraline at doses as low as approximately 5 times the maximum human mg/kg dose. The decrease in pup survival was shown to be most probably due to in utero exposure to sertraline. The clinical significance of these effects is unknown.

Labor and Delivery -- The effect of Zoloft® on labor and delivery in humans is unknown.

Nursing Mothers -- It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when zoloft is administered to a nursing woman.

Pediatric Use -- Safety and effectiveness in children have not been established

Geriatric Use -- Several hundred elderly patients have participated in clinical studies with Zoloft® . The pattern of adverse reactions in the elderly was similar to that in younger patients.

 

Adverse Reactions

Commonly Observed -- The most commonly observed adverse events associated with the use of Zoloft® (sertraline hydrochloride) and not seen at an equivalent incidence among placebo treated patients were: gastrointestinal complaints, including nausea, diarrhea/loose stools and dyspepsia; tremor; dizziness; insomnia; somnolence; increased sweating; dry mouth; and male sexual dysfunction (primarily ejaculatory delay).

Associated with Discontinuation of Treatment -- Fifteen percent of 2710 subjects who received Zoloft® in premarketing multiple dose clinical trials discontinued treatment due to an adverse event. The more common events (reported by at least 1% of subjects) associated with discontinuation included agitation, insomnia, male sexual dysfunction (primarily ejaculatory delay), somnolence, dizziness, headache, tremor, anorexia, diarrhea/loose stools, nausea, and fatigue.

Incidence in Controlled Clinical Trials -- The table that follows enumerates adverse events that occurred at a frequency of 1% or more among Zoloft® patients who participated in controlled trials comparing titrated Zoloft® with placebo. Most patients received doses of 50 to 200 mg per day. The prescriber should be aware that these figures 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 which 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. 

Treatement-Emergent Adverse Experience Incidence in Placebo-
               Controlled Clinical Trials (*)

Adverse Experience          (Percent of Patients Reporting)
                                     ZOLOFT         Placebo
                                     (N=861)        (N=853)
Autonomic Nervous System Disorders     
   Mouth Dry                        16.3           9.3
   Sweating Increased             8.4           2.9
Cardiovascular
   Palpitations                        3.5           1.6
   Chest Pain                         1.0           1.6
Centr & Periph Nerv System Disorders
   Headache                         20.3          19.0
   Dizziness                          11.7           6.7
   Tremor                              10.7           2.7
   Paresthesia                        2.0           1.8
   Hypoesthesia                      1.7           0.6
   Twitching                            1.4           0.1
   Hypertonia                          1.3           0.4
Disorders of Skin and Appendages
   Rash                                  2.1           1.5
Gastrointestinal Disorders
   Nausea                              26.1          11.8
   Diarrhea/Loose Stools         17.7           9.3
   Constipation                        8.4           6.3
   Dyspepsia                           6.0           2.8
   Vomiting                             3.8           1.8
   Flatulence                           3.3           2.5
   Anorexia                             2.8           1.6
   Abdominal Pain                   2.4           2.2
   Appetite Increased               1.3           0.9
General 
   Fatigue                               10.6           8.1
   Hot Flashes                          2.2           0.5
   Fever                                   1.6           0.6
   Back Pain                            1.5           0.9
Metabolic and Nutritional Disorders
   Thirst                                   1.4           0.9
Musculoskeletal System Disorders
   Myalgia                                1.7           1.5
Psychiatric Disorders
   Insomnia                            16.4           8.8
   Sexual Dysfunction-Male(1)  15.5           2.2
   Somnolence                        13.4           5.9
   Agitation                              5.6           4.0
   Nervousness                         3.4           1.9
   Anxiety                                2.6           1.3
   Yawning                               1.9            0.2
   Sexual Dysfunction-Female(2) 1.7           0.2
   Concentration Impaired           1.3           0.5
Reproductive
   Menstrual Disorder(2)              1.0          0.5
Respiratory System Disorders
   Rhinitis                                 2.0           1.5
   Pharyngitis                           1.2            0.9
Special Senses
   Vision Abnormal                     4.2           2.1
   Tinnitus                                 1.4           1.1
   Taste Perversion                     1.2           0.7
Urinary System Disorders
   Micturition Frequency              2.0           1.2
   Micturition Disorder                 1.4           0.5

Notes:  (*) Events reported by at least 1% of patients treated with
            Zoloft are included.
        (1) Primary ejaculatory delay; % based on male patients only;
            271 Zoloft and 271 placebo patients.
        (2) % bases on female patients only; 590 Zoloft and 582 placebo
            patients.
Other Events Observed During the Premarketing Evaluation of Zoloft® (sertraline hydrochloride):
During its premarketing assessment, multiple doses of Zoloft® were administered to approximately 2,700 subjects. 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 indications other than depression. 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 approximately 2,700 individuals exposed to multiple doses of Zoloft who experienced an event of the type cited on at least one occasion while receiving Zoloft. All events are included except those already listed in the previous table and those reported in terms so general as to be uninformative. It is important to emphasize that although the events reported occurred during treatment with Zoloft, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo controlled trials appear in this listing; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the Precautions section.

Autonomic Nervous System Disorders -- Infrequent: flushing, mydriasis, increased saliva, cold clammy skin; Rare: pallor.

Cardiovascular -- Infrequent: postural dizziness, hypertension, hypotension, postural hypotension, edema, dependent edema, periorbital edema, peripheral edema, peripheral ischemia, syncope, tachycardia; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, varicose veins.

Central and Peripheral Nervous System Disorders -- Frequent: confusion; Infrequent: ataxia, abnormal coordination, abnormal gait, hyperesthesia, hyperkinesia, hypokinesia, migraine, nystagmus, vertigo; Rare: local anastesia, coma, convulsions, dyskinesia, dysphonia, hyporeflexia, hypotonia, ptosis.

Disorders of Skin and Appendages -- Infrequent: acne, alopecia, pruitus, erythematous rash, maculopapular rash, dry skin; Rare: bullous eruption, dermatitis, erythema multiforme, abnormal hair texture, hypertrichosis, photosensitivity reaction, follicular rash, skin discoloration, abnormal skin odor, urticaria.

Endocrine Disorders -- Rare: exophthalmos, gynecomastia.

Gastrointestinal Disorders -- Infrequent: dysphagia, eructation; Rare: diverticulitis, local incontinence, gastritis, gastroenteritis, glossitis, gum hyperplasia, hemorrhoids, hiccup melana, hemrrhagic peptic ulcer, proctitis, stomatitis, ulcerative stomatitis, tenesmus, tongue edema, tongue ulceration.

General -- Frequent: asthenia; Infrequent: malaise, generalized edema, rigors, weight decrease, weight increase; Rare: enlarged abdomen, halitosis, otitis media, aphthous stomatitis.

Hematopoietic and Lymphatic -- Infrequent: lymphadenopathy, purpura; Rare: anemia, anterior chamber eye hemorrhage.

Metabolic and Nutritional Disorders -- Rare: dehydration, hypercholesterolemia, hypoglycemia.

Musculoskeletal System Disorders -- Infrequent: arthralgia, arthrosis, dystonia, muscle cramps, muscle weakness; Rare: hernia.

Psychiatric Disorders -- Infrequent: abnormal dreams, aggressive reaction, amnesia, apathy, delusion, depersonalization, depression, aggravated depression, emotional lability, euphoria, hallucination, neurosis, paranoid reaction, suicide ideation and attempt, teeth-grinding, abnormal thinking; Rare: hysteria, somnambulism, withdrawal syndrome.

Reproductive -- Infrequent: dysmenorrhea (2), intermenstrual bleeding (2); Rare: amenorrhea (2), balanoposthitis (1), breast enlargement (2), female breast pain (2), leukorrhea (2), menorrhagia (2), atrophic vaginitis (2).

 

(1) -- % based on male subjects only: 1005.

(2) -- % based on female subjects only: 1705.

Respiratory System Disorders -- Infrequent: bronchospasm, coughing, dyspnea, epistaxis; Rare: bradypnea, hyperventilation, sinusitis, stridor.

Special Senses -- Infrequent: abnormal accommodation, conjunctivitis, diplopia, earache, eye pain, xerophthalmia; Rare: abnormal lacrimation, photophobia, visual field defect.

Urinary System Disorders -- Infrequent: dysuria, face edema, nocturia, polyuria, urinary incontinence; Rare: oliguria, renal pain, urinary retention.

Laboratory Tests -- In man, asymptomatic elevations in serum transaminases (SGOT [or AST and SGPT [or ALT) have been reported infrequently (approximately 0,8%) in association with Zoloft administration. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.

Zoloft therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.

Drug Abuse and Dependence

Controlled Substance Class -- Zoloft® (sertraline hydrochloride) is not a controlled substance.

Physical and Psychological Dependence -- Zoloft® has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. However, the premarketing clinical experiance with Zoloft® did not reveal any tendency for a withdrawal syndrome or any drug-seeking behaviour. As with any new CNS active drug, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of Zoloft® misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

 

Overdosage

Human Experience -- As of November, 1992, there were 79 reports of non-fatal acute overdoses involving Zoloft® , of which 28 were overdoses of Zoloft® alone and the remainder involved a combination of other drugs and/or alcohol in addition to Zoloft® . In those cases of overdose involving only Zoloft® , the reported doses ranged from 500mg to 6000mg. In a subset of 18 of these patients in whome Zoloft® blood levels were determined, plasma concentrations ranged from < 5ng/mL to 554ng/mL. Symptoms of overdose with Zoloft® alone included somnolence, nausea, vomiting, tachycardia, ECG changes, anxiety and dilated pupils. Treatment was primarily supportive and included monitoring and use of activated charcoal, gastric lavage or cathartics and hydration. Although there were no reports of death when Zoloft® was taken alone, there were 4 deaths involving overdoses of Zoloft® in combination with other drugs and/or alcohol. Therefore, any overdosage should be treated aggressively.

Management of Overdoses -- Establish and maintain an airway, insure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose.

Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures.

There are no specific antidotes for Zoloft® .

Due to the large volume of distribution of Zoloft® , force diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose.

Dose and Administration

Initial Treatment -- Zoloft® (sertraline hydrochloride) treatment should be initiated with a dose of 50 mg once daily. While a relationship between dose and antidepressant effect has not been established, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the antidepressant effectiveness of Zoloft® . Consequently, patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of Zoloft® , dose changes should not occur at intervals of less than 1 week.

Zoloft® should be administered once daily, either in the morning or evening.

As indicated under Precautions, a lower or less frequent dosage should be used in patients with hepatic impairment. In addition, particular care should be used in patients with renal impairment.

Maintenance/Continuation/Extended Treatment -- There is evidence to suggest that depressed patients responding during an initial 8 week treatment phase will continue to benefit during an additional 8 weeks of treatment. While there are insufficient data regarding any benefits from treatment beyond 16 weeks, it is generally agreed among expert psychopharmacologists that acute episodes of depression require several months or longer of sustained pharmacological therapy. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Store at controlled room temperature, 59 to 86F (15 to 30C).


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