Contents
ZOLOFT Pfizer
Sertraline HCI
Use:
SSRI. Depression: Patients > 18 years of age: Initially, 50 mg once daily; increase dosage gradually, if needed, at 1-week intervals. Maximum: 200 mg/day. Maintenance: lowest effective dose.
Panic disorder: 25 mg once daily and increase, if necessary, by 50 mg increments at intervals of no less than 1 week, to a maximum of 200 mg/day.
Obsessive-compulsive disorder (OCD): Initially, 50 mg/day. Thereafter, increase the dosage, if necessary, by 50 mg increments, over several weeks or months, to a maximum of 200 mg/day.
Zolofts effectiveness for more than 12 weeks of therapy in panic disorder and OCD not yet established.
Contraindications:
Not to be use with an MAOI or within 14 days of starting or discontinuing MAOI therapy. Concomitant use with pimozide.
Precautions:
Pregnancy, lactation, patients< 18 years of age. Seizure disorders, a history of drug abuse, renal or hepatic impairment. Activation of mania/hypomania, suicidal tendency, concomitant illnesses that could affect metabolism or hemodynamic responses. Rare reports of altered platelet function; hyponatremia, possibly due to the syndrome of inappropriate antidiuretic hormone secretion.
Side effects:
Nausea, diarrhea/loose stools, dyspepsia, male sexual dysfunction (primarily ejaculatory delay), insomnia, somnolence, tremor, increased sweating, dry mouth, dizziness.
Interactions:
See Contraindications. Use cautiously with CNS-active drugs; serotonergic drugs, such as fenfluramine, should not be used with sertraline. Hypoglycemic agents, drugs highly bound to plasma proteins, cimetidine (may decrease clearance of sertraline). Warfarin (monitor PT). St. Johns Wort (increase in undesirable effects).
Patient tips:
Full therapeutic effect may be delayed until 4 or more weeks of treatment. Take capsules with food once daily, preferably with evening meal or breakfast. May cause dizziness (NB driving). Restrict alcohol intake.
Supplied:
25 mg, 50 mg, 100mg capsules.
to top
Antidepressant
The antidepressant effect of sertraline is presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets.
Like most clinically effective antidepressants, sertraline downregulates brain norepinephrine and serotonin receptors in animals. In receptor binding studies, sertraline has no significant affinity for adrenergic (alpha(1), alpha(2) and beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2) or benzodiazepine binding sites.
In placebo-controlled studies in normal volunteers, sertraline did not cause sedation and did not interfere with psychomotor performance.
Pharmacokinetics:
Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (C(max)) of sertraline is 0.19 mcg/mL occurring between 6 to 8 hours post-dose. The area under the plasma concentration time is 2.8 mg hr/L. For desmethylsertraline, C(max) is 0.14 mcg/mL, the half-life 65 hours and the area under the curve 2.3 mg hr/L. Following single or multiple oral once-daily doses of 50 to 400 mg/day the average terminal elimination half-life is approximately 26 hours. Linear dose proportionality has been demonstrated over the clinical dose range of 50 to 200 mg/day.
Food appears to increase the bioavailability by about 40%: it is recommended that sertraline be administered with meals.
Sertraline is extensively metabolized to N-desmethylsertraline, which shows negligible pharmacological activity. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation and glucuronide conjugation. Biliary excretion of metabolites is significant.
Approximately 98% of sertraline is plasma protein bound. The interactions between sertraline and other highly protein bound drugs have not been fully evaluated (see Precautions).
The pharmacokinetics of sertraline itself appear to be similar in young and elderly subjects. Plasma levels of N-desmethylsertraline show a 3-fold elevation in the elderly following multiple dosing, however, the clinical significance of this observation is not known.
Liver and Renal Disease:
The pharmacokinetics of sertraline in patients with significant hepatic or renal dysfunction have not been determined.
to top
For the symptomatic relief of depressive illness. However, the antidepressant action of sertraline in hospitalized depressed patients has not been adequately studied.
A placebo-controlled European study carried out over 44 weeks, in patients who were responders to sertraline has indicated that sertraline may be useful in continuation treatment, suppressing reemergence of depressive symptoms.
However, because of methodological limitations, these findings on continuation treatment have to be considered tentative at this time.
to top
Patients with known hypersensitivity to the drug.
No clinical data are available on the effects of the combined use of sertraline and MAO inhibitors; therefore, sertraline should not be administered together with MAO inhibitors. At least 14 days should elapse between the discontinuation of an MAO inhibitor and the initiation of treatment with sertraline, as well as between the discontinuation of sertraline and the initiation of treatment with an MAO inhibitor. Administration at shorter intervals may increase the risk of serious events.
to top
None.
to top
Activation of Mania/Hypomania:
During clinical testing in depressed patients, hypomania or mania occurred in approximately 0.6% of sertraline-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.
Seizure:
Sertraline has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the products premarket testing. Accordingly, sertraline 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. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for sertraline should be written for the smallest quantity of drug consistent with good patient management.
Occupational Hazards:
Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that the drug treatment does not affect them adversely.
Patients with Concomitant Illness:
General:
Clinical experience with sertraline in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using sertraline in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Cardiac Disease:
Sertraline has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.
The electrocardiograms of 598 patients who received sertraline were compared in a blinded fashion to the electrocardiograms of 244 placebo patients and 206 amitriptyline patients. The data indicate that sertraline is not associated with the development of significant ECG abnormalities.
Effect on Blood Pressure:
The frequency of clinically noticeable changes (+/-15 to 20 mm Hg) in blood pressure in placebo controlled studies was similar for patients being treated with sertraline or placebo (see Table I).
---------------------------------------------------------------------- Table I Percentage of Patients with Noticeable Changes in Blood Pressure ---------------------------------------------------------------------- Change Numbers and % of Patients Relative to Numbers Tested with Specified Change Parameter Baseline Sertraline Placebo Sertraline Placebo ---------------------------------------------------------------------- Standing increase 703 358 13 1.8% 3 0.8% Systolic BP decrease 31 4.4% 16 4.5% Standing increase 703 358 20 2.8% 13 3.6% Diastolic BP decrease 28 4.0% 12 3.4% Supine increase 706 362 15 2.1% 6 1.7% Systolic BP decrease 19 2.7% 7 1.9% Supine increase 706 362 16 2.3% 7 1.9% Diastolic BP decrease 18 2.5% 4 1.1% ----------------------------------------------------------------------
Hepatic Dysfunction:
Sertraline is extensively metabolized by the liver. The pharmacokinetics and therapeutic efficacy of sertraline have not been studied in patients with significant hepatic dysfunction. Accordingly, it should be used with caution in such patients.
Renal Dysfunction:
Sertraline is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. The pharmacokinetics of sertraline have not been studied in patients with renal impairment and, until adequate numbers of patients with mild, moderate or severe renal impairment have been evaluated during chronic treatment with sertraline, it should be used with caution in such patients.
Carcinogenesis:
In carcinogenicity studies in CD-1 mice, sertraline at doses up to 40 mg/kg produces a dose related increase in the incidence of liver adenomas in male mice. Liver adenomas have a very variable rate of spontaneous occurrence in the CD-1 mouse. The clinical significance of these findings is unknown.
Pregnancy and Lactation:
The safety of sertraline during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.
Labor and Delivery:
The effect of sertraline on labor and delivery in humans is unknown.
Children:
The safety and effectiveness of sertraline in children below the age of 18 have not been established.
Geriatrics:
462 elderly patients (>=65 years) have participated in multiple dose therapeutic studies with sertraline. The pattern of adverse reactions in the elderly was comparable to that in younger patients.
Drug Interactions:
Co-Administration of Drugs Highly Bound to Plasma Proteins:
Because sertraline is highly bound to plasma proteins, the co-administration of other highly bound drugs such as warfarin or digitoxin may cause a shift in plasma concentrations potentially resulting in adverse effects. At this time, the effect of sertraline on the anticoagulant activity of warfarin is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or discontinued. Conversely, adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs.
CNS Active Drugs:
The risk of using sertraline in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline and such drugs is required.
Co-administration with tryptophan may lead to a high incidence of serotonin-associated side effects. There is no experience with the concomitant use of sertraline and tryptophan in depressed patients.
In placebo-controlled trials in normal volunteers, the combined administration of lithium and sertraline did not alter the pharmacokinetics of sertraline. There is, however, no clinical experience with sertraline in lithium treated patients. Therefore, it is recommended that plasma lithium levels be monitored following initiation of sertraline therapy, so that appropriate adjustments to the lithium dose may be made if necessary. Co-administration with lithium may lead to a high incidence of serotonin-associated side effects.
Electroconvulsive Therapy:
There are no clinical studies with the combined use of electroconvulsive therapy (ECT) and sertraline.
Alcohol:
Although sertraline did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline and alcohol in depressed patients has not been studied and is not recommended.
Hypoglycemic Drugs:
There are no controlled clinical trials with sertraline in diabetic patients treated with insulin or oral hypoglycemic drugs.
In a placebo-controlled trial in normal volunteers, the administration of sertraline for 22 days (dose was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an i.v. dose of 1000 mg.
Hypoglycemia requiring dextrose infusion was observed in one patient treated with sertraline, glibenclamide, haloperidol, bisacodyl, ASA and flucloxacillin. The causal relationship to sertraline treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with sertraline and oral hypoglycemic drugs or insulin is recommended.
Beta Blockers:
There is no experience with the use of sertraline in hypertensive patients controlled by beta-blockers. In a placebo-controlled crossover study in normal volunteers, the effect of sertraline on the beta-adrenergic blocking activity of atenolol was assessed. The mean CD25s (the doses of isoproterenol required to increase heart rate by 25 bpm, the chronotropic dose 25 or CD25) and the average decreases in heart rate seen with atenolol during exercise test were not statistically different in the sertraline versus the placebo group. These data suggest that sertraline does not alter the beta-blocking action of atenolol.
Cimetidine:
In a placebo-controlled crossover study in normal volunteers, the potential of cimetidine to alter the disposition of a single 100 mg dose of sertraline was assessed. The mean sertraline C(max) and AUC were significantly higher in the cimetidine-treated group, as were the mean desmethylsertraline T(max) and AUC. These data suggest that concomitant administration of cimetidine may inhibit the metabolism of sertraline and its metabolite, desmethylsertraline, and may result in a decrease in the clearance and first pass metabolism of sertraline, with a possible increase in drug-related side effects.
Microsomal Enzyme Induction:
Sertraline was shown to induce hepatic enzymes as determined by the decrease of the antipyrine half-life. This degree of induction reflects a clinically insignificant change in hepatic metabolism.
to top
In clinical development programs, sertraline has been evaluated in 1902 subjects with depression. The most commonly observed adverse events associated with the use of sertraline were: gastrointestinal complaints, including nausea, diarrhea/loose stools and dyspepsia; male sexual dysfunction (primarily ejaculatory delay); insomnia and somnolence; tremor; increased sweating and dry mouth; and dizziness. In the fixed dose placebo controlled study, the overall incidence of side effects was dose related with a majority occurring in the patients treated with 200 mg dose.
The discontinuation rate due to adverse events was 15% in 2710 subjects who received sertraline in premarketing multiple dose clinical trials. 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:
Table II enumerates adverse events that occurred at a frequency of 1% or more among sertraline patients who participated in controlled trials comparing titrated sertraline with placebo.
----------------------------------------------------------------- Table II Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials* ----------------------------------------------------------------- Percent of Patients Reporting Zoloft Placebo Difference Adverse Experience (N=861) (N=853) Percentage Autonomic Nervous System Disorders Mouth Dry 16.3 9.3 7.0 Sweating Increased 8.4 2.9 5.5 Cardiovascular Palpitations 3.5 1.6 1.9 Chest Pain 1.0 1.6 -0.6 Central and Peripheral Nervous System Disorders Headache 20.3 19.0 1.3 Dizziness 11.7 6.7 5.0 Tremor 10.7 2.7 8.0 Paresthesia 2.0 1.8 0.2 Hypoesthesia 1.7 0.6 1.1 Twitching 1.4 0.1 1.3 Hypertonia 1.3 0.4 0.9 Disorders of Skin and Appendages Rash 2.1 1.5 0.6 Gastrointestinal Disorders Nausea 26.1 11.8 14.3 Diarrhea/Loose Stools 17.7 9.3 8.4 Constipation 8.4 6.3 2.1 Dyspepsia 6.0 2.8 3.2 Vomiting 3.8 1.8 2.0 Flatulence 3.3 2.5 0.8 Anorexia 2.8 1.6 1.2 Abdominal Pain 2.4 2.2 0.2 Appetite Increased 1.3 0.9 0.4 General Fatigue 10.6 8.1 2.5 Hot Flushes 2.2 0.5 1.7 Fever 1.6 0.6 1.0 Back Pain 1.5 0.9 0.6 Metabolic and Nutritional Disorders Thirst 1.4 0.9 0.5 Musculo-Skeletal System Disorders Myalgia 1.7 1.5 0.2 Psychiatric Disorders Insomnia 16.4 8.8 7.6 Sexual Dysfunction- Male (1) 15.5 2.2 13.3 Somnolence 13.4 5.9 7.5 Agitation 5.6 4.0 1.6 Nervousness 3.4 1.9 1.5 Anxiety 2.6 1.3 1.3 Yawning 1.9 0.2 1.7 Sexual Dysfunction- Female (2) 1.7 0.2 1.5 Concentration Impaired 1.3 0.5 0.8 Reproduction Menstrual Disorder (2) 1.0 0.5 0.5 Respiratory System Disorders Rhinitis 2.0 1.5 0.5 Pharyngitis 1.2 0.9 0.3 pecial Senses Vision Abnormal 4.2 2.1 2.1 Tinnitus 1.4 1.1 0.3 Taste Perversion 1.2 0.7 0.5 Urinary System Disorders Micturition Frequency 2.0 1.2 0.8 Micturition Disorder 1.4 0.5 0.9 ----------------------------------------------------------------- *Events reported by at least 1% of patients treated with Zoloft are included. (1)% based on male patients only: 271 Zoloft and 271 placebo patients. Male sexual dysfunction can be broken down into the categories of decreased libido, impotence and ejaculatory delay. In this data set, the percentages of males in the Zoloft group with these complaints are 4.8%, 4.8% and 8.9%, respectively. It should be noted that since some Zoloft patients reported more than one category of male sexual dysfunction, the incidence of each category of male sexual dysfunction combined is larger than the incidence for the general category of male sexual dysfunction, in which each patient is counted only once. (2)% based on female patient only: 590 Zoloft and 582 placebo patients. -----------------------------------------------------------------
Other events observed during the premarketing evaluation of sertraline:
During its premarketing assessment, multiple doses of sertraline were administered to 2710 subjects. The conditions and duration of exposure to sertraline 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.
All events are included except those already listed in Table II or in the Precautions section, 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 sertraline, they were not necessarily caused by it.
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 anesthesia, coma, convulsions, dyskinesia, dysphonia, hyporeflexia, hypotonia, ptosis.
Disorders of Skin and Appendages:
Infrequent: Acne, alopecia, pruritus, 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, fecal incontinence, gastritis, gastroenteritis, glossitis, gum hyperplasia, hemorrhoids, hiccup, melena, hemorrhagic 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.
Musculo-Skeletal 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 attempt (including suicidal ideation), 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 hepatic transaminases [AST (SGOT) and ALT (SGPT)] to a value >=3 times the upper limit of normal have been reported infrequently (approximately 0.6% and 1.1%, respectively) in association with sertraline administration. The proportion of patients having these elevations was greater in the sertraline group than in the placebo group. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.
Sertraline 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.
to top
Symptoms and Treatment:
Human Experience:
There have been 3 cases of sertraline overdosage (approximately 4 to 10 times the maximum recommended daily dose). These 3 patients recovered completely without the need for specific therapy.
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 are recommended along with general symptomatic and supportive measures.
There are no specific antidotes for sertraline.
Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.
In managing overdose, the possibility of multiple drug involvement must be considered.
to top
The administration should be initiated at 50 mg daily and increased gradually if needed, noting carefully the clinical response and any evidence of intolerance. It should be kept in mind that there may be a lag in therapeutic response. Increasing the dosage rapidly does not normally shorten this latent period and may increase the incidence of side effects.
Initial Treatment:
As no clear dose-response relationship has been demonstrated, a dose of 50 mg/day is recommended as the initial dose. A gradual increase in dosage may be considered if no clinical improvement is observed. Based on pharmacokinetic parameters, steady-state sertraline plasma levels are achieved after approximately 1 week of once daily dosing; accordingly, dose changes, if necessary, should be made at intervals of at least 1 week. Doses should not exceed a maximum of 200 mg/day.
As with other antidepressants, the full antidepressant effect may be delayed until 4 weeks of treatment or longer.
Sertraline should be administered with food once daily preferably with the evening meal, or, if administration in the morining is desired, with breakfast.
As with many other medications, sertraline should be used with caution in patients with renal and/or hepatic impairment (see Precautions).
Maintenance:
When a satisfactory clinical response has been obtained, the dosage should be reduced (within the 50 to 200 mg range) to the minimum that will maintain relief of symptoms.
to top
