Consumer medicine information

Zoloft

Sertraline

BRAND INFORMATION

Brand name

Zoloft

Active ingredient

Sertraline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zoloft.

What is in this leaflet

This leaflet answers some common questions about Zoloft.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits.

Your doctor has weighed the risks of you taking Zoloft against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ZOLOFT is used for

Zoloft is used to treat depression and conditions called obsessive compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder) and premenstrual dysphoric disorder (PMDD).

PMDD affects some women in the days before their period. PMDD is different from premenstrual syndrome (PMS). The mood symptoms (anger, sadness, tension, etc) in PMDD are more severe than in PMS and affect the woman's daily activities and relationships with others.

Zoloft belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). They are thought to work by blocking the uptake of a chemical called serotonin into nerve cells in the brain. Serotonin and other chemicals called amines are involved in controlling mood.

Your doctor, however, may prescribe Zoloft for another purpose.

Ask your doctor if you have any questions about why Zoloft has been prescribed for you.

Zoloft should not be used in children and adolescents under the age of 18 years for the treatment of any medical condition other than obsessive compulsive disorder (OCD). The safety and efficacy of Zoloft for the treatment of medical conditions (other than OCD) in this age group has not been satisfactorily established.

For the treatment of OCD, Zoloft is not recommended for use in children under the age of 6, as the safety and efficacy in children of this age group has not been established.

This medicine is only available with a doctor's prescription.

There is no evidence that Zoloft is addictive.

Before you take ZOLOFT

When you must not take it

Do not take Zoloft if you have an allergy to:

  • any medicine containing sertraline
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Zoloft if you have epilepsy not properly controlled by medication.

Do not take Zoloft if you are taking another medicine for depression called a monoamine oxidase inhibitor (MAOI) or have been taking it within the last 14 days. Taking Zoloft with a MAOI (e.g. Aurorix, Eldepryl, Nardil, Parnate) may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and convulsions (fits).

Do not take Zoloft if you are taking phentermine (used to help weight loss), tryptophan (contained in protein-based foods or dietary proteins), methadone (used to treat drug addiction), medicines used to treat migraine, e.g. sumatriptan (Imigran), dextromethorphan (used as a cough suppressant in cold and 'flu medications), medicines used for pain management such as fentanyl, tapentadol (Palexia), tramadol or pethidine. These medicines can cause an exaggerated response to Zoloft.

Do not take Zoloft if you are taking pimozide (used to treat disturbances in thinking, feeling and behaviour).

Ask your doctor or pharmacist if you are not sure if you have been taking one of these medicines.

Do not give Zoloft to children or adolescents under the age of 18 unless the doctor has prescribed it for the treatment of OCD. Do not give Zoloft to children under the age of 6 for the treatment of OCD.

If you are not sure whether you should be taking Zoloft, talk to your doctor.

Do not take Zoloft if:

  • the expiry date marked on the packaging has passed, even though the tablets may look alright
  • the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have any allergies to any foods, dyes, preservatives or any other medicines.

Tell your doctor if you have or have had any of the following medical conditions:

  • any other mental illness
  • epilepsy or seizures
  • liver or kidney problems
  • heart conditions causing irregular heartbeats
  • a tendency to bleed more than normal
  • diabetes mellitus
  • glaucoma, an eye condition.

Tell your doctor if you are pregnant or intend to become pregnant. There have been reports that babies exposed to Zoloft and other antidepressants during the third trimester of pregnancy may develop complications immediately after birth.

Tell your doctor if you are breastfeeding or wish to breastfeed. Zoloft passes into breast milk and may affect your baby.

Your doctor will discuss the risks and benefits of taking Zoloft when pregnant or breastfeeding.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by Zoloft or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • other medicines for the treatment of depression called monoamine oxidase inhibitors (MAOIs).

Taking Zoloft with, or within 14 days of stopping a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and convulsions.

  • other MAOI drugs such as linezolid, an antibiotic used to treat pneumonia and certain skin infections
  • other medicines for depression, panic disorder, social anxiety disorder or obsessive illnesses (e.g. Prothiaden, Prozac, Aropax, Luvox, Cipramil, Efexor XR, Xydep)
  • lithium (e.g. Lithicarb), a medicine used to treat mood swings
  • other medicines for PMDD (e.g. Prozac, Lovan, Xydep)
  • tryptophan (contained in protein-based foods or dietary proteins)
  • phentermine (weight-reducing medicines)
  • dextromethorphan (used in cold and 'flu medicines to suppress cough)
  • medicines for strong pain management such as fentanyl, tapentadol (Palexia), tramadol or pethidine
  • methadone (used to treat drug addiction)
  • other medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis (e.g. aspirin or NSAIDs such as ibuprofen or diclofenac)
  • pimozide (used to treat disturbances in thinking, feeling and behaviour)
  • St John's wort, a herbal remedy used to treat mood disorders
  • medicines for treating psychotic illness such as clozapine (e.g. Clozaril) which is used to treat schizophrenia
  • medicines for irregular heartbeats (e.g. Tambocor)
  • warfarin (e.g. Marevan, Coumadin) or other medicines that stop the blood from clotting
  • phenytoin (e.g. Dilantin), a medicine used to treat epilepsy
  • sumatriptan (e.g. Imigran), a medicine used to treat migraine
  • diazepam or other medicines that act on the brain or nervous system (e.g. Serepax, Valium)
  • cimetidine (e.g. Tagamet), a medicine used to treat reflux and ulcers
  • Medicines used to treat Attention Deficit Hyperactivity Disorder (ADHD) such as dexamphetamine and lisdexamphetamine
  • antibiotics.

Not all brand names are given for the medicines listed above. Your doctor or pharmacist has more information on these medicines or other medicines to be careful with or avoid while taking Zoloft.

If you have not told your doctor or pharmacist about these things, tell them before you start taking Zoloft.

Some combinations of medicines may increase the risk of serious side effects and are potentially life-threatening.

How to take ZOLOFT

Follow all directions given to you by your doctor. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you need to take each day. This may depend on your age, your condition and whether or not you are taking any other medicines.

Depression - Adults
The usual starting dose is one 50 mg tablet each day. The dose can be increased gradually up to 200 mg a day if necessary.

Obsessive Compulsive Disorder - Children (6-12 Years)
The usual starting dose is 25 mg a day which is half a 50 mg tablet. Increase to one 50 mg tablet a day after one week.

Obsessive Compulsive Disorder - Adults and Adolescents (13-18 Years)
The usual starting dose is one 50 mg tablet each day.

Panic Disorder - Adults
The usual starting dose is 25 mg day which is half a 50 mg tablet. Increase to one 50 mg tablet a day after one week.

Social Phobia (Social Anxiety Disorder) - Adults
The usual starting dose is 25 mg a day which is half a 50 mg tablet. Increase to one 50 mg a day after one week.

Do not take more than 200 mg a day for the conditions listed above.

Premenstrual Dysphoric Disorder (PMDD)

If taking throughout the menstrual cycle
The usual starting dose is one 50 mg tablet a day. This may be increased to a maximum of 150 mg a day if needed. Increase the dose in a step wise fashion. If you are unclear how to do this ask your pharmacist or doctor for advice.

If taking in the last 14 days of the menstrual cycle
The usual starting dose is one 50 mg tablet a day. This may be increased to a maximum of 100 mg a day.

Do not take more than the maximum doses recommended above for PMDD.

How to take ZOLOFT

Swallow the tablets with a glass of water.

Try to take your tablet at the same time each day, either morning or evening. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take ZOLOFT for

Most medicines for depression and obsessive illnesses take time to work so do not be discouraged if you do not feel better straight away.

It may take 2 to 4 weeks or even longer to feel the full benefit of Zoloft.

Continue taking Zoloft until your doctor tells you to stop.

Even when you feel well, you may need to take Zoloft for several months or longer.

If you have PMDD, your doctor may ask you to take this medicine only at certain times of the month.

Do not stop taking Zoloft, or change the dose, without first checking with your doctor.

Occasionally the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide. It is possible that these symptoms may continue or increase until the full anti-depressant effect of your medicine becomes apparent (i.e. one to two months).

You or anyone close to you or caring for you should watch for these symptoms and tell your doctor immediately or go to the nearest hospital if you have any distressing thoughts or experiences during this initial period or at any other time.

Contact your doctor if you experience any worsening of your depression or other symptoms at any time during your treatment.

If you forget to take ZOLOFT

Do not take a double dose to make up for the dose that you missed. Wait until the next day and take your normal dose then.

If you are not sure what to do in this situation, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much ZOLOFT (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have taken too much Zoloft.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include:

  • feeling drowsy
  • nausea, diarrhoea, vomiting
  • fast or irregular heartbeats
  • tremors
  • feeling agitated or dizzy.

While you are taking ZOLOFT

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking Zoloft.

Tell your doctor or pharmacist that you are taking Zoloft if you are about to be started on any new medicines.

Tell your doctor if you become pregnant while taking Zoloft.

If you are a woman of child-bearing age, you should avoid becoming pregnant while taking Zoloft.

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes. A worsening of depressive symptoms including thoughts of suicide or self-harm may occur in the first one or two months of you taking Zoloft or when the doctor changes your dose. These symptoms should subside when the full effect of Zoloft takes place.

Children, adolescents or young adults under 24 years of age are more likely to experience these effects during the first few months of treatment.

Patients and caregivers should be alert and monitor for these effects.

Signs and symptoms of suicide include:

  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts of suicide or self-harm
  • increase in aggressive behaviour, irritability or agitation
  • worsening of depression.

All mention of suicide or violence must be taken seriously.

If you or someone you know is demonstrating these warning signs of suicide while taking Zoloft, contact your doctor or a mental health professional right away.

Children should have regular check-ups with the doctor to monitor growth and development.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may interact with other medicines used during surgery and cause unwanted side effects.

If you are about to have any urine tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Things you must not do

Do not stop taking Zoloft, or change the dose, without first checking with your doctor.

Do not let yourself run out of tablets over the weekend or on holidays.

Suddenly stopping Zoloft may cause dizziness, light headedness, numbness, unusual tingling feelings or shakiness.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not take Zoloft to treat any other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how Zoloft affects you. Some medicines for depression may affect your ability to drive or operate machinery or do things that could be dangerous if you are not alert.

Although drinking moderate amounts of alcohol is unlikely to affect your response to Zoloft, your doctor may suggest avoiding alcohol while you are taking Zoloft.

If you are feeling drowsy or are uncoordinated, be careful that you do not fall over. Zoloft, like other medicines in this class, may increase your risk of bone fracture.

You should wait at least 14 days after stopping Zoloft before starting any other medicines for depression or obsessive illnesses from the MAOI group, such as Aurorix, Eldepryl, Nardil, and Parnate.

All of the above precautions are important even after you have stopped taking Zoloft.

The effects of Zoloft may last for some days after you have stopped taking it.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Zoloft.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking Zoloft, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

Do not be alarmed by the list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if...

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache, dizziness, shaking or tremors, unusually overactive, muscle stiffness or weakness, decrease or loss of touch or other senses, sleepiness, drowsiness, impaired concentration
  • dry mouth, nausea, feeling sick, diarrhoea, indigestion, vomiting, stomach pain, constipation
  • increased sweating, rash and hives
  • tiredness, , fever, feeling unwell
  • hot flush, high blood pressure
  • weight increase or loss
  • increased or decreased appetite
  • sleeping difficulties, sexual problems,
  • vision disturbance
  • menstrual irregularities, sexual dysfunction including impaired sexual function in males, difficulty in passing urine, or increased frequency
  • persistent noise in the ears
  • tingling and numbness of hands and feet

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any of the following:

  • agitation, nervousness, anxiety, frightening dreams, yawning, abnormal thinking, teeth grinding, symptoms of agitation, anxiety dizziness, headache, nausea and tingling or numbness of the hands and feet after stopping Zoloft
  • uncontrollable muscle spasms affecting the eyes, head, neck and body, temporary paralysis or weakness of muscles
  • lockjaw
  • painful, swollen joints
  • difficulty in breathing, wheezing or coughing
  • uncontrollable movements of the body, shuffling walk, unusual weakness
  • palpitations, fainting or chest pain
  • irregular heartbeats
  • abnormal bleeding including vaginal bleeding
  • sudden onset of severe headache.

Go to hospital if...

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • fits or seizures
  • signs of allergy such as rash or hives, swelling of the face, lips or tongue, wheezing or difficulty breathing
  • symptoms of sudden fever with sweating, fast heartbeat and muscle stiffness, which may lead to loss of consciousness
  • thoughts of suicide or attempting suicide or self-harm.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some of these side effects (e.g., changes in thyroid function, liver function or glucose control) can only be found when your doctor does tests from time to time to check your progress.

After taking ZOLOFT

Storage

Keep your tablets where young children cannot reach them. A locked cupboard at least 1and a half metres above the ground is a good place to store medicines.

Keep Zoloft in a cool, dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your tablets in their blister pack until it is time to take them.

Disposal

If your doctor tells you to stop taking Zoloft, or the tablets have passed their expiry date, ask your pharmacist what to do with any left over.

Product description

What it looks like

Zoloft tablets come in two strengths:

  • Zoloft 50 mg - white, capsule-shaped scored tablets embossed with ZLT 50 on one side and the Pfizer logo on the other.
  • Zoloft 100 mg - white, capsule-shaped tablets embossed with ZLT 100 on one side and the Pfizer logo on the other.

A box contains 30 tablets.

Ingredients

Zoloft contains 50 mg or 100 mg of sertraline as the active ingredient.

It also contains:

  • microcrystalline cellulose
  • calcium hydrogen phosphate dihydrate
  • hyprolose
  • sodium starch glycollate
  • magnesium stearate
  • White Opadry
  • Clear Opadry

Zoloft does not contain gluten, lactose or sugar.

Supplier

Zoloft is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number:
1800 675 229
www.pfizer.com.au

Australian registration numbers:

Zoloft 50 mg - AUST R 42979, 321601

Zoloft 100 mg - AUST R 42950, 321602

This leaflet was prepared in March 2020.

® Registered Trademark

© Pfizer Australia Pty Ltd 2020.

pfczolot10320

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Zoloft

Active ingredient

Sertraline

Schedule

S4

 

1 Name of Medicine

Sertraline hydrochloride.

6.7 Physicochemical Properties

Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol and sparingly soluble in ethanol.
Chemical name: (1S,4S)-4-(3,4- dichlorophenyl)-1,2,3,4- tetrahydro-N- methyl-1- naphthalenamine hydrochloride.
Molecular formula: C17H17NCl2.HCl.
Molecular weight: 342.7.

Chemical structure.


CAS number.

79559-97-0.

2 Qualitative and Quantitative Composition

Zoloft 50 mg tablets contain 50 mg sertraline (as hydrochloride).
Zoloft 100 mg tablets contain 100 mg sertraline (as hydrochloride).

Excipient(s) with known effect.

None.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zoloft 50 mg capsule-shaped tablets: white film coated tablets embossed with the Pfizer logo on one side, and "ZLT" scoreline "50" on the other side.
Zoloft capsule-shaped 100 mg tablets: white film coated tablets embossed with the Pfizer logo on one side, and "ZLT 100" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Zoloft is an antidepressant, the active ingredient sertraline hydrochloride is chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.
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 noradrenaline and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity to adrenergic (alpha1, alpha2, beta), cholinergic, gamma-aminobutyric acid (GABA), dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2) or benzodiazepine receptors; antagonism of such receptors has been hypothesised 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 noradrenaline receptors as has been observed with other clinically effective antidepressant and anti-obsessional drugs. Sertraline does not inhibit monoamine oxidase.
Drugs known to influence serotonin receptors in animals and isolated cell preparations have been used to investigate possible 5HT receptor abnormalities in patients with obsessive compulsive disorder (OCD). No clear picture has emerged but OCD symptoms were worsened by meta-chlorophenylpiperazine (mCPP), a mixed agonist at serotonin receptors, in untreated OCD patients in comparison to healthy controls, but not after patients had been treated with the nonselective 5HT reuptake inhibitor clomipramine. Tricyclic antidepressants without SRI effects have no efficacy in OCD.

Clinical trials.

Major depression.

Adults.

The efficacy of Zoloft in the treatment of a major depressive episode in adults was established in controlled trials of six to eight weeks in outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder. Efficacy and safety have been established in studies up to 24 weeks.
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 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 hospitalised 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 randomised 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. 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.

Obsessive compulsive disorder (OCD).

Children and adolescents.

The effectiveness of Zoloft for the treatment of OCD was first demonstrated in a 12 week, multicentre, parallel group study in a paediatric outpatient population (children and adolescents, ages 6-17). Patients 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, if 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 points on the CYBOCS total score which was significantly greater than the mean 3 point 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.
The safety of Zoloft use in children and adolescents, ages 6-18, for 52 weeks, was established in a flexible dose, open extension study of 137 patients who had completed the initial 12 week, double blind, placebo controlled study. Zoloft was administered at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In this 52 week study Zoloft was well tolerated with an adverse event profile generally similar to that observed in the acute 12 week paediatric study. In the 12 week study, a marginally greater number of sertraline treated patients (90%) experienced one or more adverse events (irrespective of causality), when compared to placebo (73%). The majority of adverse events in the sertraline group were classified as mild to moderate in severity.

Adults.

The efficacy and safety of Zoloft in the treatment of OCD were established in three eight to twelve week controlled trials of nondepressed adult outpatients with mild, moderate or severe OCD, diagnosed on the basis of DSM-III or DSM-III-R criteria. Efficacy and safety were maintained in a 40 week continuation of the 12 week fixed dose, placebo controlled study. In patients with OCD, the obsessions or compulsions must cause marked distress, be time consuming, or significantly interfere with social or occupational functioning in order to meet the DSM-III-R diagnosis of OCD.
Obsessions are recurrent, persistent ideas, thoughts, images or impulses that are egodystonic. Compulsions are repetitive, purposeful and intentional behaviours performed in response to an obsession or in a stereotyped fashion, and are recognised by the person as excessive or unreasonable. In three double blind, multicentre, parallel group, placebo controlled trials, both clinically relevant and statistically significant improvements in response rates (40%) were noted in sertraline treatment groups.
In a 12 week double blind fixed dose placebo controlled study in OCD, 26% of patients receiving placebo were regarded as responders to therapy, whereas 40% of patients receiving sertraline were regarded as responders.

Long-term treatment.

In an open extension study of the 40 week continuation study mentioned above, 38 patients treated with sertraline received 2 full years of sertraline treatment. Sertraline responders treated for more than one year continued improvement during a second year of open treatment.
In addition, to assess the efficacy of sertraline in preventing relapse in patients who had achieved a sustained response during 52 weeks of single blind sertraline therapy, a 28 week double blind, placebo controlled extension study of 223 patients demonstrated continued significant improvement in OCD symptoms when compared to placebo, with completion rates in the sertraline and placebo groups of 70% and 48%, respectively.

Panic disorder.

Adults.

The efficacy and safety of Zoloft in the treatment of panic disorder in adults has been evaluated in four double blind, placebo controlled clinical trials for up to 12 weeks: two flexible dose studies and two fixed dose studies. At the last week of treatment (week 10 or 12), both flexible dose studies and one of the fixed dose studies showed statistically significant differences from placebo in favour of Zoloft in terms of mean change from baseline in the total number of DSM-III-R defined panic attacks (last observation carried forward analysis). As the flexible dose studies were of identical protocol, data for these investigations can be pooled. The mean number of full panic attacks at baseline was 6.2/week (n = 167) in the Zoloft group and 5.4/week in the placebo group (n = 175). At week 10 (last observation carried forward analysis), the mean changes from baseline were 4.9/week and 2.5/week for the Zoloft and placebo groups, respectively. The proportion of patients having no panic attacks at the final evaluation was 69% in the Zoloft group and 57% in the placebo group. The mean daily dose administered at the last week of treatment was approximately 120 mg (range: 25-200 mg) in the flexible dose studies. All patients entered into clinical trials had a DSM-III-R diagnosis of panic disorder with or without agoraphobia. It was found in the flexible dose studies that initiating treatment at 25 mg/day for one week led to a lower incidence of early discontinuations.
The primary efficacy measure was the number of DSM-III-R defined panic attacks occurring each week. Secondary efficacy variables measured included the Sheehan Panic and Anticipatory Anxiety Scale (PAAS), Hamilton Anxiety (HAM-A) Scale and the Clinical Global Impressions (CGI) rating of severity of Illness and Improvement.
The statistically significant superiority of sertraline over placebo in the treatment of panic disorder was demonstrated by the reduction in the number of panic attacks per week at study endpoint. Analyses of the secondary efficacy variables confirmed that the reduction in panic attack frequency was associated with significant improvement in a broad range of disease symptoms. No clear dose dependency has been demonstrated over the 50 mg/day to 200 mg/day dose range investigated in the fixed dose studies. Efficacy beyond 12 weeks has not been assessed.

Social phobia (social anxiety disorder).

Adults.

The effectiveness of Zoloft in the treatment of social phobia (social anxiety disorder) was established in two multicentre placebo controlled studies of adult outpatients who met DSM-IV criteria for social phobia (social anxiety disorder). These criteria involve a marked and persistent fear or anxiety of behaving in an embarrassing or humiliating manner while under the gaze of other people in one or more social or performance situations. Exposure to the social or performance situation almost invariably provokes an immediate anxiety response. The patient recognises that the fear is excessive or unreasonable. The avoidance, anxious anticipation, or distress in the feared social or performance situation(s) interferes significantly with the patient's normal routine, occupational (academic) functioning, or social activities, or relationships, or there is marked distress about having the phobia. Performance anxiety, stage fright and shyness in social situations involving unfamiliar people should not be diagnosed as social phobia (social anxiety disorder) unless the anxiety or avoidance leads to clinically significant impairment or marked distress.
A 12 week, multicentre, flexible dose study compared Zoloft (50 mg/day to 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), 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 significantly more effective than placebo as measured by the LSAS and the percentage of responders.
A 20 week, multicentre, flexible dose study compared Zoloft (50 mg/day to 200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), and (c) the CGI-I responder criterion of ≤ 2. Zoloft was shown to be 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.
In a 24 week extension study of the 20 week study, patients meeting DSM-IV criteria for social phobia (social anxiety disorder) who had responded to Zoloft during the 20 week placebo controlled trial were randomised to continuation of Zoloft or to substitution of placebo for up to 24 weeks of observation for relapse. Patients receiving Zoloft continuation treatment experienced a significantly lower relapse rate than patients randomised to placebo substitution.

Cardiac electrophysiology.

In a dedicated thorough QTc study, conducted at steady-state at supratherapeutic exposures in healthy volunteers (treated with 400 mg/day, twice the maximum recommended daily dose), the upper bound of the 2-sided 90% CI for the time matched Least Square mean difference of QTcF between sertraline and placebo (11.666 msec) was greater than the predefined threshold of 10 msec at the 4-hour postdose time point. Exposure-response analysis indicated a slightly positive relationship between QTcF and sertraline plasma concentrations [0.036 msec/(nanogram/mL); p < 0.0001]. Based on the exposure-response model, the threshold for clinically significant prolongation of the QTcF (i.e. for predicted 90% CI to exceed 10 msec) is at least 2.6-fold greater than the average Cmax (86 nanogram/mL) following the highest recommended dose of sertraline (200 mg/day) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

Premenstrual dysphoric disorder (PMDD).

Adults.

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 three 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 PMDD in DSM-IV. Patients in study 2 met DSM-IV criteria for PMDD. The DSM-IV criteria include markedly depressed mood, anxiety or tension, affective lability and persistent anger or irritability. Other features include decreased interest in usual 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 by prospective daily ratings during at least two consecutive symptomatic cycles. Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient rated instrument that 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 randomised 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 tolerance.
In study 2, involving n = 281 randomised 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 tolerance. 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.
Zoloft administered continuously (study 1) or intermittently (study 2) was significantly more effective than placebo on all primary efficacy parameters as shown in Table 1.

5.2 Pharmacokinetic Properties

Absorption.

In man, following oral once daily dosing over the range of 50 mg to 200 mg for 14 days, mean peak plasma concentrations (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 pharmacokinetics was 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 mg to 200 mg. Consistent with the terminal elimination half-life, there is an approximately twofold accumulation, compared to a single dose of sertraline, with repeated dosing over a 50 mg 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 postdosing to 5.5 hours. These changes were not considered clinically significant. Animal studies indicate that sertraline has a large apparent volume of distribution.

Distribution.

In vitro protein binding studies performed with radiolabelled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 nanogram/mL. However, at up to 300 and 200 nanogram/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 Section 4.4 Special Warnings and Precautions for Use).

Metabolism.

Sertraline undergoes extensive first-pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation.

Excretion.

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 radiolabelled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40 to 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 to 45% of the administered radioactivity was accounted for in faeces, including 12 to 14% unchanged sertraline. Desmethylsertraline exhibits time related, dose dependent increases in AUC(0-24 hour), Cmax and Cmin with about a 5 to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.

Special populations.

Children and adolescents.

The pharmacokinetics of sertraline in paediatric OCD patients have been shown to be comparable to adults (although paediatric patients metabolise sertraline with slightly greater efficiency). However, lower doses may be advisable for paediatric patients, given their lower bodyweights (especially those patients aged 6 to 12 years), in order to avoid excessive plasma levels.

Adults.

Sertraline plasma clearance were compared in male and female young subjects (18 to 45 years) and elderly subjects (≥ 65 years) in an open label, multiple dose study. Eleven subjects in each group received sertraline once daily for 30 days according to a titrated regimen up to 200 mg/day. No significant differences in Cmax, AUC or elimination half-life were found for the young women or the elderly of either sex. In comparison, Cmax and AUC were lower and half-life shorter in young men. Thus, the elimination of sertraline appears to be slightly more rapid in young males. Although these differences are statistically significant, they are unlikely to be clinically significant. The ratios of sertraline clearance to desmethylsertraline clearance of the four groups were similar.

Hepatic impairment.

Sertraline is extensively metabolised by the liver. A multiple dose pharmacokinetic study in subjects with mild, stable cirrhosis administered sertraline 50 mg/day for 21 days demonstrated a prolonged elimination half-life and approximately a threefold greater AUC and Cmax for sertraline and a twofold greater AUC and Cmax for the metabolite in comparison to normal subjects. Patients with moderate and severe hepatic impairment have not been studied. If Zoloft is administered to patients with hepatic impairment a lower or less frequent dose should be considered (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Renal impairment.

In patients with mild to moderate renal impairment (creatinine clearance 30 mL/min to 60 mL/min) or moderate to severe renal impairment (creatinine clearance 10 mL/min to 29 mL/min) administered sertraline 50 mg/day for 21 days multiple dose pharmacokinetic parameters (AUC0-24 or Cmax) were not statistically significantly different compared with controls. This indicates that Zoloft dosing does not have to be adjusted based on degree of renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

The carcinogenic potential of sertraline has not been fully elucidated. Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats (at doses up to 40 mg/kg), giving rise to plasma drug exposure levels similar to or slightly higher than that achieved following the maximum recommended human dose of 200 mg. There was a dose related increase in the incidence of liver adenomas in male mice receiving sertraline at 10 mg/kg to 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 hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10 mg/kg to 40 mg/kg compared to placebo controls, this effect was not clearly drug related.

4 Clinical Particulars

4.1 Therapeutic Indications

Children and adolescents.

Zoloft (sertraline hydrochloride) is indicated for the treatment of children (aged 6 years of age and older) and adolescents with OCD.

Adults.

Zoloft (sertraline hydrochloride) is indicated for the treatment of major depression, obsessive compulsive disorder (OCD) and panic disorder.
Zoloft (sertraline hydrochloride) is indicated for the treatment of social phobia (social anxiety disorder) and the prevention of its relapse.
Zoloft (sertraline hydrochloride) is indicated for the treatment of premenstrual dysphoric disorder (PMDD) as defined by DSM-IV criteria.

4.3 Contraindications

Zoloft is contraindicated in patients with known hypersensitivity to sertraline.
Concomitant use in patients taking pimozide is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Monoamine oxidase inhibitors.

Cases of serious reactions, sometimes fatal, have been reported in patients receiving Zoloft in combination with a monoamine oxidase inhibitor (MAOI) including the selective MAOI selegiline, the reversible MAOI (reversible inhibitor of monoamine oxidase (RIMA)) moclobemide, and MAOI drugs, e.g. linezolid (an antibiotic that is a reversible nonselective MAOI) and methylene blue. Some cases presented with features resembling the serotonin syndrome. Similar cases, sometimes fatal, including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma have been reported with other antidepressants during combined treatment with a MAOI and in patients who have recently discontinued an antidepressant or an anti-obsessional drug and have been started on a MAOI. Zoloft should not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should be allowed after stopping Zoloft before starting a MAOI.

4.4 Special Warnings and Precautions for Use

Serotonin syndrome or neuroleptic malignant syndrome.

The development of potentially life threatening syndromes like serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) has been reported with selective serotonin reuptake inhibitors (SSRIs), including treatment with sertraline. The risk of SS or NMS with SSRIs is increased with concomitant use of serotonergic drugs (including amphetamines, triptans and fentanyl), with drugs that impair metabolism of serotonin (including MAOIs), antipsychotics and other dopamine antagonists. SS symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyper-reflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Some signs of SS, including hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes resemble NMS. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see Section 4.3 Contraindications).

Other serotonergic drugs.

Coadministration of SSRIs such as sertraline with other drugs that enhance the effects of serotonergic neurotransmission, such as amphetamines, tryptophan, phentermine, fentanyl and its analogues, tramadol, 5-HT agonists, dextromethorphan, tapentadol, pethidine or methadone should be undertaken only with caution and avoided whenever possible due to the potential for pharmacodynamic interaction.

St John's wort.

Concomitant use of the herbal remedy St John's wort (Hypericum perforatum) in patients receiving SSRIs should be avoided since there is a possibility of serotonergic potentiation.

Switching from other antidepressants or anti-obsessional drugs.

There is limited controlled experience regarding the optimal timing of switching from other antidepressants or anti-obsessional drugs to Zoloft. Care and prudent medical judgement should be exercised when switching, particularly from long acting agents. The duration of a washout period for switching from one SSRI to another has not been established.

QTc prolongation/ torsades de pointes (TdP).

Cases of QTc prolongation and TdP have been reported during post-marketing use of sertraline. The majority of reports occurred in patients with other risk factors for QTc prolongation/TdP. Therefore sertraline should be used with caution in patients with risk factors for QTc prolongation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1, Clinical trials.

Activation of mania/ hypomania.

During premarketing testing, hypomania or mania occurred in approximately 0.4% of Zoloft treated patients. Activation of mania/ hypomania has also been reported in a small proportion of patients with major affective disorder treated with other antidepressant and anti-obsessional drugs.
Hyperkinesia has been noted in paediatric patients treated with sertraline for OCD, with an incidence of 8/53 (15.1%) for sertraline versus 3/54 (5.6%) for placebo in 6 to 12 year olds, and 0/39 (0%) for sertraline versus 1/41 (2.4%) for placebo in 13 to 17 year olds.

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 0.5 to 1 kg weight loss, versus smaller changes on placebo. Only rarely (< 0.1%) have sertraline patients been discontinued for weight loss. In paediatric patients, weight loss was seen in 2/53 (3.8%) versus 0/54 (0%) of 6 to 12 year old patients and 3/39 (7.7%) versus 0/41 (0%) of 13 to 17 year olds treated with sertraline versus placebo. It is recommended that paediatric patients receiving long-term treatment should be monitored for weight and growth, consistent with good medical care.

Seizures.

Seizures are a potential risk with antidepressant and anti-obsessional drugs. Seizures were reported in three out of 4000 patients (0.08%) treated with Zoloft in the development programme for depression. No seizures were reported in patients treated with sertraline in the development programme for panic. During the development programme for OCD, four out of 1801 patients (0.2%) exposed to Zoloft experienced seizures. In the paediatric OCD trial programme, the incidence of seizures in the adolescent (13 to 17 years old) population was 3/163 (1.8%) on sertraline compared with 0/41 (0%) on placebo. Seizures/ convulsions were not noted in 6 to 12 year old patients. In all these cases, the relationship with sertraline therapy was uncertain. Since Zoloft has not been evaluated in patients with a seizure disorder it should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. Zoloft should be discontinued in any patient who develops seizures.

Clinical worsening and suicide risk.

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk of suicide must be considered in all depressed patients.
Because of the coexistence of depression in patients with other psychiatric disorders, such as OCD, panic disorder, social phobia (social anxiety disorder) and PMDD, the same precautions should be observed when treating patients with these disorders as when treating patients with depression.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the initial treatment period (generally the first one to two months) in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients treated with placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
A further pooled analysis of short-term placebo controlled trials of antidepressant medicines (SSRIs and others) showed the increased risk of suicidal thinking and behaviour (suicidality) during the initial treatment period (generally the first one to two months) extends to young adults (aged 18 to 24 years) with major depressive disorder (MDD) and other psychiatric disorders. These 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.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non psychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or non psychiatric), should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
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 acid 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.

Sexual dysfunction.

SSRIs may cause symptoms of sexual dysfunction (see Section 4.8 Adverse Effects (Undesirable Effects)). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.

Abnormal bleeding/ haemorrhage.

Bleeding abnormalities have been reported with the use of SSRIs (including purpura, haematoma, epistaxis, vaginal bleeding, ecchymoses, gastrointestinal bleeding and life threatening haemorrhage). This risk may be potentiated by concurrent use of atypical antipsychotics and phenothiazines, most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin or other medicines that affect coagulation. Zoloft should, therefore, be used with caution in patients concomitantly treated with medicines that increase the risk of bleeding or in patients with a past history of abnormal bleeding or those with predisposing conditions. Pharmacological gastroprotection should be considered for high risk patients.

Hyponatraemia.

Hyponatraemia may occur as a result of treatment with SSRIs or serotonin and noradrenaline reuptake inhibitors (SNRIs) including sertraline. In many cases, hyponatraemia appears to be the result of a syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatraemia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly). Discontinuation of sertraline should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatraemia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness that 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.

Bone fractures.

Epidemiological studies show an increased risk of bone fractures in patients receiving serotonin reuptake inhibitors (SRIs) including sertraline. The mechanism leading to this risk is not fully understood.

Diabetes/ loss of glycaemic control.

Cases of new onset diabetes mellitus have been reported in patients receiving SSRIs including Zoloft. Loss of glycaemic control including both hyperglycaemia and hypoglycaemia has also been reported in patients with and without pre-existing diabetes. Patients should therefore be monitored for signs and symptoms of glucose fluctuations. Diabetic patients especially should have their glycaemic control carefully monitored since their dosage of insulin and/or concomitant oral hypoglycaemic drug may need to be adjusted.

Angle closure glaucoma.

SSRIs including sertraline may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle, resulting in increased intraocular pressure and angle closure glaucoma, especially in patients pre-disposed. Sertraline should therefore be used with caution in patients with angle closure glaucoma or history of glaucoma.

Use in patients with concomitant illness.

Caution is advisable in using Zoloft in patients with diseases or conditions that could affect metabolism or haemodynamic 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 (ECG) 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.

Symptoms associated with discontinuation.

During marketing of Zoloft and other SSRIs and SNRIs (serotonin and noradrenaline 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. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, some have been reported to be severe.
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 Section 4.8 Adverse Effects (Undesirable Effects); Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation; Section 4.2 Dose and Method of Administration).

Drug abuse and dependence.

In human studies, sertraline has not demonstrated potential for abuse. In a placebo controlled, double blind, randomised study of comparative abuse liability of sertraline, alprazolam and d-amphetamine in humans, sertraline did not produce positive subjective effects indicative of abuse potential, such as euphoria or drug liking. As with any CNS active drug, however, 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 behaviour).

Electroconvulsive therapy.

There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and Zoloft.

Use in hepatic impairment.

Sertraline is extensively metabolised by the liver. A multiple dose pharmacokinetic study in subjects with mild, stable cirrhosis administered sertraline 50 mg/day for 21 days demonstrated a prolonged elimination half-life and approximately a threefold greater AUC and Cmax for sertraline and a twofold greater AUC and Cmax for the metabolite 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. Patients with moderate and severe hepatic impairment have not been studied. A lower or less frequent dose should be used in patients with hepatic impairment.

Use in renal impairment.

Sertraline is extensively metabolised. Excretion of unchanged drug in urine is a minor route of elimination. In a study of patients with mild to moderate renal impairment (creatinine clearance 30 mL/min to 60 mL/min) or moderate to severe renal impairment (creatinine clearance 10 mL/min to 29 mL/min) administered sertraline 50 mg/day for 21 days multiple dose pharmacokinetic parameters (AUC0-24 or Cmax) were not statistically significantly different compared to controls. Half-lives were similar and there were no differences in plasma protein binding of all the groups studied. This study indicates that, as expected from the low renal excretion of sertraline, Zoloft dosing does not have to be adjusted based on degree of renal impairment.

Use in the elderly.

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.

Paediatric use.

A total of 225 paediatric patients have completed OCD trials with sertraline. The safety profile of Zoloft in these paediatric studies is comparable to that observed in the adult OCD studies.
Only limited clinical evidence is available concerning long-term safety data in children and adolescents, including effects on growth, sexual maturation and cognitive and behavioural developments. Physicians must monitor paediatric patients on long-term treatment for abnormalities in growth and development.
Safety and effectiveness in paediatric patients below the age of 6 years have not been established.
Sertraline should not be used in children and adolescents below the age of 18 years for the treatment of major depressive disorder. The efficacy and safety of sertraline has not been satisfactorily established for the treatment of major depressive disorder in this age group.

Effects on laboratory tests.

False positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/ mass spectrometry, will distinguish sertraline from benzodiazepines.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Monoamine oxidase inhibitors.

See Section 4.3 Contraindications.

Pimozide.

Increased pimozide levels have been demonstrated in a study of single low dose pimozide (2 mg) with sertraline coadministration. Coadministration of pimozide and sertraline increased pimozide Cmax and AUC by 35% and 37%, respectively. These increased levels did not significantly increase the QTc interval. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant administration of sertraline and pimozide is contraindicated. There are no data with pimozide at doses greater than 2 mg (see Section 4.3 Contraindications).

Drugs that prolong the QTc interval.

The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) is increased with concomitant use of other drugs that prolong the QTc interval (e.g. some antipsychotics and antibiotics) (see Section 4.4 Special Warnings and Precautions for Use, QTc prolongation/ torsades de pointes (TdP); Section 5.1, Clinical trials).

CNS depressants and 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.

Coadministration of drugs with serotonergic action.

Sumatriptan.

There have been rare postmarketing reports describing patients with weakness, hyper-reflexia, 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 Section 4.4 Special Warnings and Precautions for Use).

Other serotonergic drugs.

(See Section 4.3 Contraindications, Monoamine oxidase inhibitors; Section 4.4 Special Warnings and Precautions for Use, Serotonin syndrome or neuroleptic malignant syndrome, Other serotonergic drugs).

St John's wort.

See Section 4.4 Special Warnings and Precautions for Use.

Medicines that interfere with haemostasis (NSAIDs, aspirin, warfarin, etc.).

Serotonin release by platelets plays an important role in haemostasis. There is an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of abnormal bleeding. Concurrent use of an NSAID, aspirin or warfarin potentiates the risk. Thus, patients should be cautioned about using such medicines concurrently with Zoloft.

Potential effects of coadministration of drugs highly bound to plasma proteins.

Because sertraline is tightly bound to plasma protein, the administration of Zoloft to a patient taking another drug which is bound to protein may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline by other protein bound drugs. However, in three formal interaction studies with diazepam, tolbutamide and warfarin respectively, sertraline was not shown to have any significant effects on the protein binding of the substrate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Warfarin).

Warfarin.

Coadministration of sertraline 200 mg daily with warfarin resulted in an 8% delay in normalisation of prothrombin time compared to placebo (p < 0.02). The clinical significance of this is unknown. Accordingly, prothrombin time should be carefully monitored when Zoloft therapy is initiated or stopped.

Lithium.

In placebo controlled trials in normal volunteers, the coadministration of sertraline with lithium did not significantly alter the lithium pharmacokinetics, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. Coadministering sertraline with medications such as lithium, which may act via serotonergic mechanisms, should be undertaken with caution in patients and appropriately monitored.

Phenytoin.

A placebo controlled trial in healthy volunteers given sertraline 200 mg and phenytoin 100 mg for 10 days did not produce statistically significant differences in phenytoin pharmacokinetic parameters between the sertraline and placebo groups. Nonetheless, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline therapy, with appropriate adjustments to the phenytoin dose. In addition, coadministration of phenytoin may cause a reduction of sertraline plasma levels.

Drugs metabolised by cytochrome P450 2D6.

There is variability among antidepressants in the extent to which they inhibit the activity of isozyme cytochrome P450 (CYP) 2D6, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. The clinical significance of this depends on the extent of inhibition and the therapeutic index of the coadministered drug. Consequently, concomitant use of a drug metabolised by CYP2D6 with Zoloft may require lower doses than usually prescribed for the other drug. Furthermore, whenever Zoloft is withdrawn from cotherapy, an increased dose of the coadministered drug may be required. CYP2D6 substrates with a narrow therapeutic index include tricyclic antidepressants (TCAs), class 1C antiarrhythmics, such as propafenone and flecainide, and methadone. In formal interaction studies, sertraline 50 mg daily produced increases (p < 0.001) in desipramine Cmax (44%) and AUC (mean 23% to 37%).

Drugs metabolised by other CYP enzymes (CYP3A3/4, CYP2C9, CYP2C19, CYP1A2).

CYP3A3/4.

In vivo interaction studies have demonstrated that administration of sertraline for 17-21 days at the high dose of 200 mg daily did not statistically significantly inhibit the CYP3A3/4 metabolism of carbamazepine or terfenadine. In addition, the administration of sertraline 50 mg daily for 14 days did not statistically significantly inhibit the CYP3A3/4 mediated metabolism of alprazolam. The results of these studies suggest that sertraline is not likely to be a clinically important inhibitor of CYP3A3/4.

CYP2C9.

The apparent lack of clinically significant effects of the chronic administration of sertraline at the high dose of 200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin suggests that sertraline is not a clinically important inhibitor of CYP2C9 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Phenytoin and Warfarin).

CYP2C19.

The apparent lack of clinically significant effects of the chronic administration of sertraline at the high dose of 200 mg daily on plasma concentrations of diazepam suggests that sertraline is not a clinically important inhibitor of CYP2C19 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Other drug interactions).

CYP1A2.

An in vitro study indicates that sertraline is a weak inhibitor of CYP1A2.

Other drug interactions.

Formal drug interaction studies have been performed with sertraline. Changes in drug levels as a result of interactions have been demonstrated. The precise clinical significance of these changes is unknown.

Cimetidine.

Coadministration of cimetidine caused a statistically significant increase in sertraline mean AUC by 50% and Cmax by 24% and t1/2 by 26%.

Atenolol/ digoxin.

Sertraline had no effect on the beta-adrenergic blocking activity of atenolol. No interaction was observed with digoxin.

Diazepam.

Coadministration of diazepam showed a statistically significant decrease in diazepam clearance of 32% from baseline compared to a 19% decrease with placebo. Tmax for desmethyldiazepam was also statistically significantly prolonged by 23% in the sertraline group versus a decrease in the placebo group.

Glibenclamide.

No interaction was observed with glibenclamide.

Clozapine.

As in the coadministration with other SSRIs, isolated cases of increased clozapine levels have been reported.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (giving rise to plasma drug exposure levels similar to or slightly higher than that achieved following the maximum recommended human dose of 200 mg).
(Category C)
This category is defined as drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
Neonates exposed to Zoloft, other SSRIs, or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalisation, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hyper-reflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.

Teratogenic effects.

Reproduction studies have been performed in rats and rabbits at doses up to 80 and 40 mg/kg, respectively, giving rise to plasma drug exposure levels similar to or slightly higher than that achieved following the maximum recommended human dose of 200 mg.
There was no evidence of teratogenicity at any dose level. However, sertraline was associated with delayed ossification in fetuses, probably secondary to effects on the dams.

Non-teratogenic effects.

There was also decreased neonatal survival following maternal administration of sertraline at doses giving rise to plasma drug exposure levels similar to or slightly higher than that achieved following the maximum recommended human dose of 200 mg. 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. Similar effects have been described with other antidepressants.
There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zoloft should not be used during pregnancy unless in the judgement of the physician, the expected benefit justifies the risk to the fetus. The use of SSRIs in the third trimester may result in a withdrawal state in the newborn infant.
Women of childbearing potential should avoid becoming pregnant if taking Zoloft.
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately sixfold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997 to 2005 found a PPHN risk ratio of 2.4 (95%, CI: 1.2 to 4.3) associated with patient reported maternal use of SSRIs in early pregnancy and a PPHN risk ratio of 3.6 (95%, CI: 1.2 to 8.3) associated with a combination of patient reported maternal use of SSRIs in early pregnancy and an antenatal SSRI prescription in later pregnancy.

Labour and delivery.

The effect of Zoloft on labour and delivery in humans is unknown.
Only limited data concerning sertraline levels in breast milk are available. However, in breast-fed infants whose mothers were taking sertraline, there have been reports of adverse effects. Because sertraline is excreted in human milk, breastfeeding while on Zoloft is not recommended. If Zoloft is used during lactation, the physician should be aware that withdrawal reactions have been reported in some neonates whose mothers had been on SSRI antidepressants, including Zoloft.

4.8 Adverse Effects (Undesirable Effects)

Adverse events are listed within body system and categorised by frequency according to the following definitions: very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%. Unknown: cannot be estimated from available data.

Placebo-controlled clinical trial data.

The following adverse events occurred at a frequency of 1% or more among Zoloft patients and at least twice the frequency seen in placebo patients who participated in placebo controlled clinical trials (adults: depression, OCD; paediatric OCD: children and adolescents). In these clinical trials most patients received doses of 50 to 200 mg/day. These events are not necessarily related to Zoloft treatment.

Metabolism and nutrition disorders.

Common: decreased appetite.

Psychiatric disorders.

Very common: insomnia. Common: agitation, anxiety, bruxism, libido decreased, nervousness, nightmare, thinking abnormal.

Nervous system disorders.

Very common: tremor, somnolence, dizziness. Common: convulsion (including myoclonus), hypoaesthesia, hyperkinesia, hypertonia, disturbance in attention.

Eye disorders.

Common: visual impairment.

Cardiac disorders.

Common: palpitations.

Vascular disorders.

Common: hot flush.

Respiratory, thoracic and mediastinal disorders.

Common: yawning.

Gastrointestinal disorders.

Very common: diarrhoea, nausea. Common: vomiting, dry mouth, dyspepsia.

Skin and subcutaneous tissue disorders.

Common: rash, hyperhidrosis, urticaria.

Renal and urinary disorders.

Common: urinary retention.

Reproductive system and breast disorders.

Common: ejaculation disorder, sexual dysfunction (see Section 4.4 Special Warnings and Precautions for Use), vaginal haemorrhage, menstruation irregular.

General disorders and administration site conditions.

Very common: fatigue. Common: malaise, pyrexia.

Investigations.

Common: weight increased, weight decreased.
Other adverse events reported (incidence > 10%) and not meeting the above criteria were dry mouth, dizziness, diarrhoea/ loose stools, headache and abdominal pain (paediatric OCD patients only).
In a 12 week placebo controlled study in paediatric patients with OCD, adverse events of at least 5% incidence that were seen with a statistically significantly increased level for sertraline compared with placebo were headache, insomnia and agitation in 6-12 year olds. For 13-17 year olds, the comparable categories were insomnia, decreased appetite and tremor. Most of the effects seen were mild to moderate in severity. In these clinical trials, sexual dysfunction was not specifically reported. However, in common with all other SSRIs, sexual dysfunction in males and, to a lesser extent, females have been reported in adult studies.
The side effect profile commonly observed in double blind, placebo controlled studies in patients with panic disorder, social phobia (social anxiety disorder) and PMDD was similar to that observed in clinical trials patients with depression.

Adverse effects from clinical trials in paediatric MDD.

In clinical trials in children and adolescents aged 6 to 17 years with major depressive disorder the following adverse events were reported at a frequency of at least 2% of subjects and occurred at a rate of at least twice that of placebo: diarrhoea (9.5% vs 1.6%), agitation (6.3% vs 1.1%), decreased appetite (5.3% vs 1.1%), vomiting (4.2% vs 1.1%), hyperkinesia (2.6% vs 0.5%), dry mouth (2.1% vs 0.5%), tremor (2.1% vs 0%) and urinary incontinence (2.1% vs 0%). The incidence of discontinuation due to adverse events was 9% (n = 17) with sertraline and 2.1 (n = 4) with placebo. The most common reasons for discontinuation due to adverse events, whether or not related to sertraline, were aggression (1.6%), agitation (1.6%), suicidal ideation (1.6%), hyperkinesia (1.1%), suicide attempt (1.1%) and aggravated depression (1.1%).
In the safety analysis, suicide attempt was reported in the same number of patients in sertraline (2/189, 1.1%) and placebo (2/184, 1.1%) with an incidence of suicide attempts in sertraline treated subjects of 1.1% (2 attempts in 2/189 subjects) versus 1.6% in placebo treated subjects (3 attempts in 2/184 subjects). Suicidal ideation was reported by 3 sertraline treated patients (1.6%) and no placebo treated patients. This difference is not statistically significant. Note that sertraline should not be used in children and adolescents to treat MDD (see Section 4.4 Special Warnings and Precautions for Use).

Post-marketing experience.

In addition to the adverse events reported from the clinical trials above, the following adverse events, which are not necessarily related to Zoloft, as adverse events are also reported in the context of post-marketing exposure, when the relationship of these adverse events to Zoloft may not be differentiated clearly from effects of concomitant medications or disease states for which Zoloft was prescribed.

Blood and lymphatic system disorders.

Rare: thrombocytopenia, leukopenia.

Immune system disorders.

Uncommon: hypersensitivity. Rare: anaphylactoid reaction.

Endocrine disorders.

Rare: inappropriate antidiuretic hormone secretion, hyperprolactinaemia, hypothyroidism.

Metabolism and nutrition disorders.

Common: increased appetite. Rare: diabetes mellitus, hyponatraemia, hypoglycaemia, hyperglycaemia.

Psychiatric disorders.

Uncommon: hallucination, aggression, confusional state, depressive symptoms, euphoric mood. Rare: psychotic disorder, mania.

Nervous system disorders.

Very common: headache. Common: hypertonia, paraesthesia. Uncommon: syncope, muscle contractions involuntary, migraine. Rare: coma, neuroleptic malignant syndrome, visual field defect. Unknown: amnesia. Also reported were signs and symptoms associated with serotonin syndrome, in some cases associated with concomitant use of serotonergic drugs, that included agitation, confusional state, hyperhidrosis, diarrhoea, pyrexia, hypertension, muscle rigidity and tachycardia.

Eye disorders.

Uncommon: mydriasis, periorbital oedema, eye pain.

Ear and labyrinth disorders.

Common: tinnitus.

Cardiac disorders.

Uncommon: tachycardia. Rare: atrial arrhythmia, bradycardia, atrioventricular block, QTc prolongation and torsades de pointes, electrocardiogram QT prolonged, blood cholesterol increased.

Vascular disorders.

Common: hypertension. Uncommon: haemorrhage, predominantly of the skin and mucous membranes, including purpura, epistaxis, haematomas, vaginal haemorrhage and gastrointestinal haemorrhage. Rare: cerebrovascular vasoconstriction (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis.

Respiratory, thoracic and mediastinal disorders.

Uncommon: bronchospasm. Unknown: dyspnoea.

Gastrointestinal disorders.

Common: constipation, abdominal pain. Uncommon: gastrointestinal haemorrhage. Rare: pancreatitis.

Hepatobiliary disorders.

Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased. Rare: serious liver injury (including hepatitis, jaundice and hepatic failure).

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, alopecia. Rare: serious exfoliative skin disorders (e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis), angioedema, photosensitivity skin reaction.

Musculoskeletal and connective tissue disorders.

Common: arthralgia. Uncommon: muscle spasms. Rare: rhabdomyolysis, trismus.

Renal and urinary disorders.

Uncommon: haematuria, urinary incontinence. Rare: enuresis.

Reproductive system and breast disorders.

Rare: priapism, galactorrhoea, gynaecomastia.

General disorders and administration site conditions.

Common: movement disorders (including extrapyramidal symptoms such as akathisia, dystonia and gait disturbance), chest pain, asthenia. Uncommon: gait disturbance, oedema peripheral. Rare: face oedema, drug withdrawal syndrome (symptoms following the discontinuation of sertraline have been reported and included agitation, anxiety, dizziness, headache, nausea and paraesthesia).

Investigations.

Rare: platelet function test abnormal, increased coagulation times, laboratory test abnormal.

Injury, poisoning and procedural complications.

Rare: fracture.

Discontinuation symptoms.

Rare: symptoms following the discontinuation of sertraline have been reported and included agitation, anxiety, dizziness, headache, nausea and paraesthesia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Children and adolescents (6-18 years).

Obsessive compulsive disorder.

The administration of Zoloft in children with OCD (ages 6-12 years) is recommended to commence at 25 mg/day (half a 50 mg tablet) for the first week and then increasing to 50 mg/day. Adolescents (ages 13-18 years) may commence at 50 mg/day. Clinical effects may be noted after 2 weeks of treatment but clinical responses should be monitored for 6 weeks before any increase in dose. In children, a dose of 200 mg/day should not be exceeded. Sertraline has an elimination half-life of approximately 26 hours; a once daily dose in the morning is recommended.

Adults (18 years and older).

Major depression/ obsessive compulsive disorder.

Initial treatment.

Zoloft (sertraline hydrochloride) treatment should be initiated with a dose of 50 mg once daily. The usual therapeutic dose for depression and OCD is 50 mg/day. While a relationship between dose and antidepressant and anti-obsessive effect has not been established, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the antidepressive and anti-obsessive effectiveness of Zoloft. Consequently, patients not responding to a 50 mg/day 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. The onset of therapeutic effect may be seen within 7 days; however for full activity 2 to 4 weeks are usually necessary for depression, and possibly even longer for OCD.
Following initial response, sertraline has been associated with sustained efficacy, safety and tolerability in up to 2 years of treatment of OCD. If no effect is apparent after six to eight weeks, discontinuation of treatment should be considered. Studies of efficacy did not examine the role of psychotherapy.

Panic disorder.

Initial treatment.

Therapy for panic disorder should commence at 25 mg/day (half a 50 mg tablet), increasing to 50 mg/day after one week. This dosage regimen has been demonstrated to reduce the frequency of early treatment emergent side effects commonly experienced on initiation of treatment of panic disorder. The long-term efficacy of Zoloft in panic disorder has not been established.

Social phobia (social anxiety disorder).

Initial treatment.

Therapy for social phobia (social anxiety disorder) should commence at 25 mg/day (half a 50 mg tablet), increasing to 50 mg/day after one week.

Premenstrual dysphoric disorder.

Zoloft treatment should be initiated with a dose of 50 mg/day either continuously (every day of the menstrual cycle) or intermittently (by starting 14 days prior to the anticipated onset of menstruation through to the first full day of menses and repeating with each cycle), depending on physician assessment.
Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/ menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.
Dosage adjustments, which may include changes between dosage regimens (e.g. daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

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 16 weeks of treatment. While there are insufficient data regarding benefits from treatment beyond 24 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.
Discontinuation should be accomplished by a gradual reduction in dosage.

General.

The daily dose for all indications may be increased in 50 mg increments over a period of weeks. However, dose titrations in 50 mg increments will depend on tolerability and clinical response. The interval between dose increments should be at least one week. The maximum recommended dose of sertraline is 200 mg/day.
The onset of therapeutic effect may be seen after a week, however, most responders can be expected to show a good response within 2-4 weeks.
During prolonged maintenance therapy for any indication, dosage should be kept at the lowest effective level.
Zoloft should be administered once daily, either in the morning or evening. Zoloft may be administered with or without food.
As indicated, see Section 4.4 Special Warnings and Precautions for Use, particular care should be taken in patients with hepatic impairment.

Method of administration.

Oral administration.

4.7 Effects on Ability to Drive and Use Machines

In controlled studies, Zoloft did not cause sedation and did not interfere with psychomotor performance. However, as psychotropic drugs may impair the mental or physical attributes required for the performance of potentially hazardous tasks such as driving a car or using machinery the patient should be cautioned accordingly.

4.9 Overdose

On the evidence available, sertraline has a wide margin of safety in overdose. Overdoses in adults of 700 to 2100 mg have not resulted in serious symptoms. Ingestion of 4000 mg resulted in seizures in an adolescent. The largest known ingestion is 13.5 g with recovery reported. Another overdose of 2.5 g of sertraline alone resulted in death. Overdosage of 400 and 500 mg in two children have resulted in serotonin syndrome.

Signs and symptoms.

Symptoms of overdose include serotonin mediated side effects, such as electrocardiogram QT prolonged, TdP (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1, Clinical trials), somnolence, gastrointestinal disturbances (such as nausea, diarrhoea and vomiting), tachycardia, tremor, agitation and dizziness. Other important adverse events reported with sertraline overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT interval prolongation, stupor and syncope. Hyperthermia, increased respirations and cutaneous vasodilation have also been reported. Minor ECG abnormalities, palpitations, prolonged tachycardia and increased pulse rate have also been reported following paediatric overdose. Seizures have been reported rarely. Serotonin syndrome may result following significant overdose and onset may be delayed. A death due to asthma exacerbation has been reported following sertraline overdose.
Deaths have been reported involving overdoses of sertraline, primarily in combination with other drugs and/or alcohol. Therefore, any overdosage should be treated aggressively.
Elevated liver enzymes and elevated creatine phosphokinase levels have been noted following acute overdose. Hyponatraemia secondary to SIADH has been reported following overdose and has been severe enough to cause seizures.

Treatment of overdosage.

In managing overdosage, consider the possibility of multiple drug involvement. Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Establish and maintain an airway, ensure adequate oxygenation and ventilation if necessary. Patients should be monitored for potential cardiovascular, gastrointestinal or hepatic abnormalities. Also monitor for signs/ symptoms of serotonin syndrome (mental status changes, hyperthermia, myoclonus, autonomic instability, high CK levels) and possible seizures.
There are no specific antidotes for sertraline. Activated charcoal should be considered in treating overdose and is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Routine use of a cathartic with activated charcoal is not recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects, such as nausea, vomiting, abdominal cramps, electrolyte imbalances and, occasionally, hypotension.
Induction of emesis is not recommended because of the potential for CNS depression and seizures. Due to the large volume of distribution of sertraline, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.
Contact the Poisons Information Centre on 131126 for advice on the management of an overdose.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Zoloft tablet contains the following inactive ingredients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, hyprolose, sodium starch glycollate, magnesium stearate, Opadry complete film coating system YS-1-7003 White and Opadry complete film coating system YS-1-7006 Clear.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Zoloft 50 mg capsule-shaped tablets are packaged in PVC/Al blister packs of 7, 28 or 30 tablets.
Zoloft 100 mg capsule-shaped tablets are packaged in PVC/Al blister packs of 28 or 30 tablets.
Not all presentations are available in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes