ZOLOFT
Sertraline hydrochloride
50 mg, 100 mg tablets
Registered trademark of Pfizer Inc
Presentation
White film-coated tablets containing sertraline
hydrochloride equivalent to 50 mg sertraline, with the Pfizer logo on one side
and code ZLT-50 on the other. Approximate tooling dimensions are 1.03cm x 0.42cm
x 0.36cm.
White film-coated tablets containing sertraline
hydrochloride equivalent to 100 mg sertraline, with the Pfizer logo on one side
and code ZLT-100 on the other. Approximate tooling dimensions are 1.31cm x
0.52cm x 0.44cm.
Zoloft tablets include the following inert
ingredients: Calcium hydrogen phosphate, microcrystalline cellulose,
hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate, white
opadry, clear opadry.
Uses
Actions
Sertraline is a potent and specific inhibitor of
neuronal serotonin (5-HT) uptake in vitro, which results in the
potentiation of the effects of 5-HT in animals. It has only very weak effects on
noradrenaline and dopamine neuronal reuptake. At clinical doses, sertraline
blocks the uptake of serotonin into human platelets. It is devoid of stimulant,
sedative or anticholinergic activity, or cardiotoxicity in animals. In
controlled studies in normal volunteers, sertraline did not cause sedation and
did not interfere with psychomotor performance. In accord with its selective
inhibition of 5-HT uptake, sertraline does not enhance catecholaminergic
activity. Sertraline has no affinity for muscarinic (cholinergic), serotonergic,
dopaminergic, adrenergic, histaminergic, GABA or benzodiazepine receptors. The
chronic administration of sertraline in animals was associated with
downregulation of brain noradrenaline receptors as observed with other
clinically effective antidepressants and antiobsessional drugs.
Sertraline has not demonstrated potential for
abuse. In a placebo-controlled, double blind, randomised study of the
comparative abuse liability of sertraline, alprazolam and d-amphetamine in
humans, sertraline did not produce positive subjective effects indicative of
abuse potential. In contrast, subjects rated both alprazolam and d-amphetamine
significantly greater than placebo on measures of drug liking, euphoria and
abuse potential. Sertraline did not produce either the stimulation and anxiety
associated with d-amphetamine or the sedation and psychomotor impairment
associated with alprazolam. Sertraline does not function as a positive
reinforcer in rhesus monkeys trained to self-administer cocaine, nor does it
substitute as a discriminative stimulus for either d-amphetamine or
pentobarbital in rhesus monkeys.
Pharmacokinetics
Sertraline exhibits dose proportional
pharmacokinetics over the range of 50 to 200 mg. In man, following oral once
daily dosing over the range of 50 to 200 mg for 14 days, peak plasma
concentrations (Cmax) of sertraline occur at about 4.5 to 8.4 hours
post dosing. The pharmacokinetic profile in either adolescents or the elderly is
not significantly different from that in adults between 18 and 65 years. The
mean half life of sertraline for young and elderly men and women ranges from
22-36 hours. Consistent with the terminal elimination half-life, there is an
approximately two-fold accumulation up to steady state concentrations, which are
achieved after one week of once daily dosing. Approximately 98% of the
circulating drug is bound to plasma proteins. Animal studies indicate that
sertraline has a large apparent volume of distribution. The pharmacokinetics of
sertraline in paediatric OCD patients have been shown to be comparable with
adults (although paediatric patients metabolise sertraline with slightly greater
efficiency). However, lower doses may be advisable for paediatric patients given
their lower body weights (especially 6-12 years), in order to avoid excessive
plasma levels.
Sertraline undergoes extensive first pass hepatic
metabolism. The principal metabolite in plasma, N-desmethylsertraline, is
substantially less active (about 20 times than sertraline) in vitro,
and there is no evidence of activity in in vivo models of depression.
The half-life of N-desmethylsertraline is in the range of 62-104 hours.
Sertraline and N-desmethylsertraline are both extensively metabolised in man and
the resultant metabolites excreted in faeces and urine in equal amounts. Only a
small amount (<0.2%) of unchanged sertraline is excreted in the
urine.
Food does not significantly change the
bioavailability of sertraline tablets.
Indications
ZOLOFT is indicated for the treatment of symptoms
of depression, including depression accompanied by symptoms of anxiety, in
patients with or without a history of mania. Following satisfactory response,
continuation with ZOLOFT therapy is effective in preventing relapse of the
initial episode of depression or recurrence of further depressive
episodes.
Zoloft is indicated for the treatment of obsessive
compulsive disorder (OCD). Following initial response, sertraline has been
associated with sustained efficacy, safety and tolerability in up 2 years of
treatment of OCD.
Zoloft is indicated for the treatment of paediatric
patients with OCD.
Zoloft is indicated for the treatment of panic
disorder, with or without agoraphobia.
Dosage and Administration
ZOLOFT should be administered once daily, either in
the morning or evening.
ZOLOFT tablets can be administered with or without
food.
Initial Treatment
Depression and OCD -
Sertraline treatment should be administered at a dose of 50
mg/day.
Panic Disorder - Therapy for
panic disorder should be initiated at 25 mg/day. After one week, the dose should
be increased to 50 mg once daily. This dosage regimen has been shown to reduce
the frequency of early treatment emergent side effects characteristic of panic
disorder.
Titration
Depression, OCD and Panic Disorder
- Patients not responding to a 50 mg dose may benefit from dose
increases. Dose changes should be made at intervals of at least one week, up to
a maximum of 200 mg/day.
The onset of therapeutic effect may be seen within
7 days. However, longer periods are usually necessary to demonstrate therapeutic
response, especially in OCD.
Maintenance - Dosage during
long-term therapy should be kept at the lowest effective level, with subsequent
adjustment depending on therapeutic response.
Use in Children - The safety
and efficacy of sertraline has been established in paediatric OCD patients aged
6 to 17. The administration of sertraline to paediatric OCD patients (aged 13 to
17) should commence at 50 mg/day. Therapy for paediatric OCD patients (aged 6 to
12) should commence at 25 mg/day, increasing to 50 mg/day after one week.
Subsequent doses may be increased in case of lack of response in 50 mg/day
increments, up to 200 mg/day, as needed. In a clinical trial in patients aged 6
to 17 years with depression or OCD, sertraline appeared to have a similar
pharmacokinetic profile to that found in adults. However, the generally lower
body weights of children compared to those of adults should be taken into
consideration in advancing the dose from 50 mg, in order to avoid excessive
dosing.
Titration in Children and Adolescents
- Sertraline has an elimination half-life of approximately one day;
dose changes should not occur at intervals of less than one
week.
Use in the Elderly - The
same dose range as in younger patients may be used in the elderly. Over 700
elderly patients (>65 years) have participated in clinical studies which
demonstrated the efficacy of sertraline in this patient population. The pattern
and incidence of adverse reactions in the elderly was similar to that in younger
patients.
Use in Hepatic Insufficiency
- The use of sertraline in patients with hepatic disease should be
approached with caution. A lower or less frequent dose should be used in
patients with hepatic impairment (see WARNINGS AND
PRECAUTIONS).
Use in Renal Insufficiency -
Sertraline is extensively metabolised. Excretion of unchanged drug in urine is a
minor route of elimination. As expected from the low renal excretion of
sertraline, sertraline dosing does not have to be adjusted based on the degree
of renal impairment (see WARNINGS AND PRECAUTIONS).
Use in Children
More than 250 paediatric OCD patients have been
exposed to sertraline in completed and ongoing studies. The safety profile of
sertraline in these paediatric studies is comparable to that observed in adult
OCD studies. The efficacy of sertraline in paediatric patients with depression
or panic has not been demonstrated in controlled trials. Safety and
effectiveness in paediatric patients below the age of 6 have not been
established.
Contraindications
ZOLOFT is contraindicated in patients with a known
hypersensitivity to sertraline.
Concomitant use in patients taking monoamine
oxidase inhibitors (MAOIs) is contraindicated (see Warnings and
Precautions ).
Warnings and Precautions
Monoamine Oxidase Inhibitors:
Cases of serious reactions, sometimes fatal, have been reported in
patients receiving sertraline in combination with a monoamine oxidase inhibitor
(MAOI), including the selective MAOI, selegiline and the reversible MAOI,
moclobemide. Some cases presented with features resembling serotonin syndrome
the symptoms of which 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. Therefore, sertraline 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 elapse after discontinuing sertraline
treatment before starting an MAOI (see Contraindications
).
Other Serotonergic Drugs -
Coadministration of sertraline with other drugs which enhance the effects of
serotonergic neurotransmission, such as tryptophan or fenfluramine or 5-HT
agonists, should be undertaken with caution and avoided whenever possible due to
the potential for pharmacodynamic interaction (see Interactions
).
Switching from Selective Serotonin
Reuptake Inhibitors (SSRIs), Antidepressants or Antiobsessional Drugs -
There is limited controlled experience regarding the optimal timing of switching
from SSRIs, antidepressants or antiobsessional drugs to sertraline. Care and
prudent medical judgment should be exercised when switching, particularly from
long-acting agents such as fluoxetine. The duration of washout period which
should intervene before switching from one SSRI to another has not been
established.
Activation of Mania/Hypomania
- During premarketing testing, hypomania or mania occurred in
approximately 0.4% 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 antidepressant and antiobsessional
drugs.
Seizures - Seizures are a
potential risk with antidepressant and antiobsessional drugs. Seizures were
reported in approximately 0.08% of patients treated with sertraline in the
development program for depression. No seizures were reported in patients
treated with sertraline in the development program for panic. During the
development program for OCD, four out of approximately 1,800 patients exposed to
sertraline experienced seizures (approximately 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. In all
these cases, the relationship to sertraline therapy was uncertain. Since
sertraline has not been evaluated in patients with a seizure disorder, it should
be avoided in patients with unstable epilepsy and patients with controlled
epilepsy should be carefully monitored. Sertraline should be discontinued in any
patient who develops seizures.
Suicide - Since the
possibility of a suicide attempt is inherent in depression and may persist until
significant remission occurs, patients should be closely supervised during the
early course of therapy.
Withdrawal - Withdrawal
effects may occur and dosage may need to be tapered when discontinuing
treatment, particularly for those on higher doses.
Use in Hepatic Insufficiency
- Sertraline is extensively metabolised by the liver. A multiple dose
pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a
prolonged elimination half-life and approximately three-fold greater AUC and
Cmax in comparison to normal subjects. There were no significant
differences in plasma protein binding observed between the two groups. The use
of sertraline in patients with hepatic disease should be approached with
caution. A lower or less frequent dose should be used in patients with hepatic
impairment.
Use in Renal Insufficiency -
Sertraline is extensively metabolised. Excretion of unchanged drug in urine is a
minor route of elimination. In studies of patients with mild to moderate renal
impairment (creatinine clearance 30-60 mL/min) or moderate to severe renal
impairment (creatinine clearance 10-29 mL/min), multiple dose pharmacokinetic
parameters (AUC0-24 or Cmax) were not significantly
different compared with controls. Half-lives were similar and there were no
differences in plasma protein binding in all groups studied. This study
indicates that, as expected from the low renal excretion of sertraline,
sertraline dosing does not have to be adjusted based on the degree of renal
impairment.
Driving/Use of Machinery -
Clinical pharmacology studies have shown that sertraline has no effect on
psychomotor performance. However, as psychotropic drugs may impair the mental or
physical ability required for the performance of potentially hazardous tasks
such as driving a car or operating machinery, the patient should be cautioned
accordingly.
Use in Pregnancy and Lactation
Reproduction studies have been performed in rats
and rabbits at doses up to approximately 20 and 10 times the maximum daily human
mg/kg dose respectively. There was no evidence of teratogenicity at any dose
level. At the dose level corresponding to approximately 2.5 to 10 times the
maximum daily human mg/kg dose, however, sertraline was associated with delayed
ossification processes in foetuses, probably secondary to effects on the
dams.
There was decreased neonatal survival following
maternal administration of sertraline at doses of approximately 5 times the
maximum human mg/kg dose. Similar effects on neonatal survival have been
described for other antidepressant drugs. The clinical significance of these
effects is unknown.
There are no adequate and well controlled studies
in pregnant women. Because animal reproduction studies are not always predictive
of human response, sertraline should be used during pregnancy only if the
perceived benefits outweigh the risks.
Limited data concerning sertraline levels in breast
milk are available. Isolated studies in very small numbers of nursing mothers
and their infants indicated negligible or undetectable levels of sertraline in
infant serum, although levels in breast milk were more concentrated than in
maternal serum. Use in nursing mothers is not recommended unless, in the
judgment of the physician, the benefit outweighs the risk.
If sertraline is used during pregnancy and/or
lactation, the physician should be aware that symptoms, including those
compatible with withdrawal reactions, have been reported in some neonates whose
mothers had been on SSRI antidepressants, including sertraline.
Women of childbearing potential should employ an
adequate method of contraception if taking sertraline.
Adverse Effects
Clinical Trial
Data:
Side effects that occurred significantly more
frequently with sertraline than with placebo in multiple dose studies for
depression and OCD were:
Autonomic Nervous System:
Dry mouth and increased sweating.
Central and Peripheral Nervous
System: Dizziness and tremor.
Gastrointestinal:
Diarrhoea/loose stools, dyspepsia and nausea.
Psychiatric: Anorexia,
insomnia and somnolence.
Reproductive: Sexual
dysfunction (principally ejaculatory delay in males).
The side effect profile commonly observed in
double-blind, placebo-controlled studies in patients with OCD and panic disorder
was similar to that observed in clinical trials in patients with
depression.
Unlike tricyclic antidepressants, no weight gain is
observed in controlled clinical trials with sertraline treatment for depression
or OCD; some patients may experience a reduction in body weight with
sertraline.
Post-Marketing Data
Voluntary reports of adverse events in patients
receiving sertraline since market introduction have been received. They include
the following:
Autonomic Nervous System:
Mydriasis and priapism.
Body as a Whole: Allergic
reaction, allergy, asthenia, fatigue, fever and hot flushes.
Cardiovascular: Chest pain,
hypertension, palpitations, periorbital oedema, syncope and
tachycardia.
Central and Peripheral Nervous
System: Coma, convulsions, headache, migraine, movement disorders
(including extrapyramidal symptoms such as hyperkinesia, hypertonia, teeth
grinding or gait abnormalities), paresthesia and hypoesthesia. Also reported
were signs and symptoms associated with serotonin syndrome: In some cases
associated with concomitant use of serotonergic drugs, that included agitation,
confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and
tachycardia.
Endocrinological:
Galactorrhea, hyperprolactinemia and hypothyroidism.
Gastrointestinal: Abdominal
pain, pancreatitis and vomiting.
Haematopoietic: Altered
platelet function, abnormal bleeding (such as epistaxis, gastrointestinal
bleeding or hematuria), leucopoenia, purpura and
thrombocytopenia.
Laboratory Changes: Abnormal
clinical laboratory results.
Liver/Biliary: Serious liver
events (including hepatitis, jaundice and liver failure) and asymptomatic
elevations in serum transaminases (SGOT and SGPT).
Metabolic/Nutritional:
Hyponatremia and increased serum cholesterol.
Psychiatric: Agitation,
aggressive reaction, anxiety, depressive symptoms, hallucination and
psychosis.
Reproductive: Menstrual
irregularities.
Respiratory:
Bronchospasm.
Skin: Alopecia, angiooedema
and rash (including rare reports of serious exfoliative skin
disorders).
Urinary: Face oedema and
urinary retention.
Other: Symptoms following
the discontinuation of sertraline have been reported and included agitation,
anxiety, dizziness, headache, nausea and paresthesia.
Interactions
Monoamine Oxidase Inhibitors
- See Contraindications and Warnings and
Precautions.
CNS Depressants and Alcohol
- The co-administration of sertraline 200mg daily did not potentiate
the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive
and psychomotor performance in healthy subjects; however, the concomitant use of
sertraline and alcohol is not recommended.
Lithium - In
placebo-controlled trials in normal volunteers, the co-administration of
sertraline with lithium did not significantly alter lithium pharmacokinetics,
but did result in an increase in tremor relative to placebo, indicating a
possible pharmacodynamic interaction. When co-administering sertraline with
medications, such as lithium, which may act via serotonergic mechanisms,
patients should be appropriately monitored.
Phenytoin - A
placebo-controlled trial in normal volunteers suggests that chronic
administration of sertraline 200 mg/day does not produce clinically important
inhibition of phenytoin metabolism. Nonetheless, it is recommended that plasma
phenytoin concentrations be monitored following initiation of sertraline
therapy, with appropriate adjustments to the phenytoin dose.
Sumatriptan - There have
been rare post-marketing reports describing patients with weakness,
hyperreflexia, incoordination, confusion, anxiety and agitation following the
use of sertraline and sumatriptan. If concomitant treatment with sertraline and
sumatriptan is clinically warranted, appropriate observation of the patient is
advised (see Warnings and Precautions ).
Serotonergic Drugs - (see
Warnings and Precautions )
Protein Bound Drugs - Since
sertraline is bound to plasma proteins, the potential of sertraline to interact
with other plasma protein bound drugs should be borne in mind. However, in three
formal interaction studies with diazepam, tolbutamide, and warfarin,
respectively, sertraline was not shown to have significant effects on the
protein binding of the substrate ( see subsections Warfarin, CNS Active
Drugs and Hypoglycaemic Drugs ).
Warfarin - Co-administration
of sertraline 200 mg daily with warfarin resulted in a small but statistically
significant increase in prothrombin time, the clinical significance of which is
unknown. Accordingly, prothrombin time should be carefully monitored when
sertraline therapy is initiated or stopped ( see subsection CYP 2C9
).
Cimetidine -
Co-administration of sertraline with cimetidine caused a substantial decrease in
sertraline clearance. The clinical significance of this change is
unknown.
CNS active drugs -
Co-administration of sertraline 200mg daily with diazepam resulted in small,
statistically significant changes in some pharmacokinetic parameters. The
clinical significance of these changes is unknown.
Hypoglycaemic drugs -
Co-administration of sertraline 200mg daily with tolbutamide resulted in small,
statistically significant changes in some pharmacokinetic parameters. The
clinical significance of these changes is unknown.
Sertraline 200mg daily did not affect the
pharmacokinetics of glibenclamide.
Patients receiving biguanides should monitor their
blood glucose carefully when sertraline is introduced.
Atenolol - Sertraline had no
effect on the beta-adrenergic blocking ability of atenolol.
Digoxin - Sertraline 200mg
daily did not change serum digoxin levels or digoxin renal
clearance.
Electroconvulsive Therapy
(ECT) - There are no clinical studies establishing the risks or
benefits of the combined use of ECT and sertraline.
Drugs Metabolised by Cytochrome P450
(CYP) 2D6 - There is variability among antidepressants in the extent to
which they inhibit the activity of isozyme cytochrome CYP 2D6 The clinical
significance of this depends on the extent of the inhibition and the therapeutic
index of the co-administered drug. CYP 2D6 substrates with a narrow therapeutic
index include TCAs and class 1C antiarrhythmics such as propafenone and
flecainide. In formal interaction studies, chronic dosing with sertraline 50mg
daily showed minimal elevation (mean 23-37%) of steady state desipramine plasma
levels (a marker of CYP 2D6 isoenzyme activity).
Drugs Metabolised by Other CYP
Enzymes (CYP 3A3/4, CYP 2C9, CYP 2C19, CYP 1A2) -CYP 3A3/4 :
In vivo interaction studies have demonstrated that chronic
administration of sertraline 200 mg daily does not inhibit the CYP 3A3/4
mediated 6-b hydroxylation of endogenous cortisol or the metabolism of
carbamazepine or terfenadine. In addition, the chronic administration of
sertraline 50 mg daily does not inhibit the CYP 3A3/4 mediated metabolism of
alprazolam. The results of these studies suggest that sertraline is not a
clinically relevant inhibitor of CYP 3A/34.
CYP 2C9 - The apparent lack
of clinically significant effects of the chronic administration of sertraline
200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin
suggests that sertraline is not a clinically relevant inhibitor of CYP
2C9.
CYP 2C19 - The apparent lack
of clinically significant effects of the chronic administration of sertraline
200 mg daily on plasma concentrations of diazepam suggests that sertraline is
not a clinically relevant inhibitor of CYP 2C19.
CYP 1A2 - In vitro
studies indicate that sertraline has little or no potential to inhibit CYP
1A2.
Overdosage
On the evidence available, sertraline has a wide
margin of safety in overdose. An overdose of sertraline alone of up to 13.5g has
been reported. Deaths have been reported involving overdoses of sertraline,
primarily in combination with other drugs and/or alcohol. Therefore, any
overdosage should be treated aggressively. Symptoms of overdose include
serotonin-mediated side effects such as somnolence, gastrointestinal
disturbances (such as nausea and vomiting), tachycardia, tremor, agitation and
dizziness. Less frequently reported was coma.
There are no specific antidotes to sertraline.
Establish and maintain an airway and ensure adequate oxygenation and
ventilation, if necessary. Activated charcoal, which may be used with a
cathartic, may be as or more effective than lavage, and should be considered in
treating overdose. Induction of emesis is not recommended. Cardiac and vital
sign monitoring is recommended along with general symptomatic and supportive
measures. Due to the large volume of distribution of sertraline, forced
diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be
of benefit.
Pharmaceutical Precautions
Store below 30°C
Medicine Classification
Prescription Medicine
Package Quantities
Tablets :
50 mg x 28
100 mg x 28
Further Information
Sertraline hydrochloride is a naphthylamine
derivative, having the following chemical name: (1S, cis
)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride. It has a molecular weight of 342.7.
Preclinical Safety Data
