Consumer medicine information

APO-Sertraline Tablets

Sertraline

BRAND INFORMATION

Brand name

APO-Sertraline

Active ingredient

Sertraline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Sertraline Tablets.

SUMMARY CMI

APO-SERTRALINE TABLETS

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using APO-Sertraline?

APO-Sertraline contains the active ingredient sertraline hydrochloride. APO-Sertraline is used to treat obsessive compulsive disorder (OCD) in children over the age of 6 and depression, OCD, panic disorder, social anxiety disorder and pre-menstrual dysphoric disorder (PMDD) in adults. For more information, see Section 1. Why am I using APO-Sertraline? in the full CMI.

2. What should I know before I use APO-Sertraline?

Do not use if you have ever had an allergic reaction to sertraline or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use APO-Sertraline? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-Sertraline and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APO-Sertraline?

Obsessive Compulsive DisorderStarting dose is 25 mg a day (half a 50 mg tablet) for children and 50 mg tablet per day for adults and adolescents.
DepressionStarting dose is one 50 mg tablet per day.
Panic disorder and Social PhobiaStarting dose is 25 mg per day (half a 50 mg tablet).
PMDDStarting dose is one 50 mg tablet each day, either throughout the menstrual cycle (to a maximum of 150 mg daily) or for the last 14 days before the start of your period (to a maximum of 100 mg daily).

More instructions can be found in Section 4. How do I use APO-Sertraline? in the full CMI.

5. What should I know while using APO-Sertraline?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-Sertraline.
  • If you become pregnant while taking this medicine, tell your doctor immediately.
  • Call your doctor straight away if you have any suicidal thoughts or other mental/mood changes.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not take sertraline if you are taking any other medicines for depression or monoamine oxidase inhibitors (MAOIs) or have been taking them within the last 14 days.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how sertraline affects you.
  • This medicine may cause dizziness, drowsiness or impaired concentration in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your medicine below 25°C
  • Keep your medicine in its original packaging until it is time to take it.

For more information, see Section 5. What should I know while using APO-Sertraline? in the full CMI.

6. Are there any side effects?

Some of the very serious side effects include convulsions, coma, breathing problems, a sudden increase in body temperature, very high blood pressure, hallucinations, thoughts of suicide. You may need urgent medical attention or hospitalization.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APO-SERTRALINE TABLETS

Active ingredient(s): Sertraline (as sertraline hydrochloride)


Consumer Medicine Information (CMI)

This leaflet provides important information about using sertraline hydrochloride. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using sertraline hydrochloride.

Where to find information in this leaflet:

1. Why am I using APO-Sertraline?
2. What should I know before I use APO-Sertraline?
3. What if I am taking other medicines?
4. How do I use APO-Sertraline?
5. What should I know while using APO-Sertraline?
6. Are there any side effects?
7. Product details

1. Why am I using APO-Sertraline?

APO-Sertraline contains the active ingredient sertraline hydrochloride. APO-Sertraline belongs to a group of medicines called Selective Serotonin Re-uptake Inhibitors (SSRIs). Serotonin is one of the chemicals in your brain that helps control your mood. Sertraline and other SSRIs are thought to help by increasing the amount of serotonin in your brain.

APO-Sertraline is used to treat:

  • depression
  • obsessive compulsive disorder (OCD)
  • panic disorder
  • social anxiety disorder or social phobia
  • Pre-Menstrual Dysphoric Disorder (PMDD)

Depression is longer lasting and/or more severe than the "low moods" everyone has from time to time due to the stress of everyday life.

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

This medicine 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 this medicine for the treatment of medical conditions (other than OCD) in this age group has not been satisfactorily established.

For the treatment of OCD, this medicine 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.

2. What should I know before I use APO-Sertraline?

Warnings

Do not use APO-Sertraline if:

  • You are allergic to sertraline hydrochloride, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • You have epilepsy not properly controlled by medication.
  • You are pregnant, plan to become pregnant or are breastfeeding
  • You are taking pimozide, used to treat disorders which affect the way you think, feel or act.
  • You are taking a medicine known as a Monoamine Oxidase Inhibitors (MAOIs) or have been taking it within the last 14 days.
    Taking sertraline with MAOIs may cause a serious reaction with signs such as a sudden increase in body temperature, very high blood pressure, rigid muscles, nausea or vomiting and/or fits (convulsions). Do not take sertraline until 14 days after stopping any MAOI, and do not take MAOIs until 14 days after stopping sertraline.
  • You are taking phentermine (a weight loss medicine), tryptophan (contained in protein-based foods or dietary supplements), methadone (used to treat pain or drug addiction), triptans (medicines used to treat migraine), dextromethorphan (used as a cough suppressant in cold and flu medicines), and medicines used for pain management (such as fentanyl, tapentadol, tramadol, and penthidine).
    These medicines can cause an exaggerated response to sertraline.
  • It has expired or if the packaging is torn or shows signs of tampering.

Do not give APO-Sertraline:

  • To children or adolescents under the age of 18 unless the doctor has prescribed it for the treatment of OCD.
  • To children under the age of 6 for the treatment of OCD.

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

  • any mental illness (such as mania, hypomania or bipolar disorder)
  • epilepsy or convulsions, fits or seizures - you should avoid taking sertraline if your epilepsy is not properly controlled; if it is properly controlled your doctor will wish to watch you carefully if you take sertraline
  • heart problems causing irregular heartbeats
  • liver problems
  • kidney problems
  • problems with blood clotting or abnormal bleeding
  • diabetes mellitus
  • glaucoma (an eye condition)
  • thoughts or actions relating to self-harm or suicide

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Sertraline may affect your developing baby if you take it during pregnancy. There have been reports that babies exposed to sertraline and other antidepressants during the third trimester of pregnancy may develop complications immediately after birth e.g. you may experience heavy vaginal bleeding shortly after birth (postpartum haemorrhage). Your doctor will discuss with you the risks and benefits involved.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Sertraline passes into breast milk and may affect your baby. Your doctor will discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with APO-Sertraline and affect how it works.

The following medicines must not be taken with sertraline as it may increase the risk of serious side effects and are potentially life-threatening:

  • monoamine oxidase inhibitors (MAOIs), such as moclobemide, phenelzine, tranylcypromine, selegiline and linezolid
  • pimozide, used to treat disorders which affect the way you think, feel or act.

The following medicines may be affected by sertraline or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

  • phentermine, a weight loss medicine
  • tryptophan, contained in some protein-based foods and herbal preparations
  • medicines for strong pain management such as fentanyl, tapentadol, tramadol or pethidine
  • triptans, used for treating migraines e.g. sumatriptan, naratriptan and zolmitriptan
  • St John's Wort (Hypericum perforatum), a herbal remedy for mood disorders
  • other SSRIs e.g. fluoxetine, citalopram, paroxetine and fluvoxamine
  • other medicines for depression, mood disorders or social anxiety disorder e.g. dothiepin, desipramine, amitriptyline, lithium and venlafaxine
  • dextromethorphan, used in cold and flu medicines to suppress cough
  • antipsychotics, used to treat psychoses, schizophrenia and other conditions which affect the way you think, feel or act
  • prochlorperazine, used to prevent or treat severe nausea and vomiting
  • phenytoin, used to control epilepsy or fits
  • medicines used to treat heart conditions, such as flecainide and propafenone
  • medicines known to prolong bleeding, such as aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs) and anti-coagulants (such as warfarin)
  • cimetidine, used to treat stomach ulcers or reflux
  • methadone, used to treat drug addiction
  • diazepam, used to treat anxiety disorders
  • medicines called diuretics, used to get rid of excess fluid from the body, and to treat high blood pressure
  • dexamphetamine and lisdexamphetamine, medicines used to treat Attention Deficit Hyperactivity Disorder (ADHD)
  • some antibiotics

Other medicines not listed above may also interact with sertraline.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-Sertraline.

4. How do I use APO-Sertraline?

How much to take

  • Depression in 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 in
    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.
    Adults and Adolescents (13-18 Years)
    The usual starting dose is one 50 mg tablet each day.
  • Panic Disorder in 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) in adults
    The usual starting dose is 25 mg per day (half a 50 mg tablet), increasing to 50 mg per day after one week.
  • Pre-Menstrual Dysphoric Disorder (PMDD)
    The usual starting dose is one 50 mg tablet each day, either throughout the menstrual cycle (to a maximum of 150 mg daily) or for the last 14 days before the start of your period (to a maximum of 100 mg daily).

Follow the instructions provided and use APO-Sertraline until your doctor tells you to stop.

When to take

  • Take APO-Sertraline at about the same time each day in the morning.
    It does not matter if you take this medicine before or after food.

How to take

  • Swallow the tablets with a full glass of water.

How long to take it for

  • Continue taking your medicine for as long as your doctor tells you.

Most antidepressants take time to work, so don't be discouraged if you don't feel better right away.

Some of your symptoms may improve in 1 or 2 weeks, but it can take up to 4 to 6 weeks to feel any real improvement.

Even when you feel well, you will usually have to take sertraline for several months or even longer to make sure the benefits will last.

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, 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 APO-Sertraline

APO-Sertraline should be used regularly at the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If you miss your dose at the usual time, if it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of you experiencing side effects.

If you use too much APO-Sertraline

If you think that you have used too much APO-Sertraline, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much sertraline, you may experience sedation, nausea, diarrhoea, vomiting, fast heartbeat, tremor, agitation, dizziness and unconsciousness.

5. What should I know while using APO-Sertraline?

Things you should do

If you become pregnant while taking this medicine, tell your doctor immediately. If you are a woman of child-bearing age, you should avoid becoming pregnant while taking sertraline.

When taken during pregnancy, particularly in the last 3 months of pregnancy, sertraline may increase the risk of a serious condition in babies called persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and appear bluish. These symptoms usually begin during the first 24 hours after the baby is born. If this happens to your baby, you should contact your midwife and/or doctor immediately.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

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

If you are about to have any urine or blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor will monitor you to make sure the medicine is working and to prevent side effects.

Tell your doctor if you get a headache or start to feel dizzy, confused, forgetful, weak, unsteady or unable to concentrate.

Some people (especially older people or those taking diuretics/water tablets) may experience a lack of sodium in the blood when taking this medicine.

Call your doctor straight away if:

  • You have any suicidal thoughts or other mental/mood changes.
    Depressive symptoms, including thoughts of suicide or self-harm, may worsen during the first one to two months of taking sertraline or after your dose changes. These symptoms should stop when the full effect of sertraline takes place.
    This is more likely to occur if you are a young adult under 24 years of age, and you have not used antidepressant medicines before.
  • You or someone you know demonstrates any of the following warning signs of suicide-related behaviour while taking sertraline:
    - 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 mentions of suicide or violence must be taken seriously.

Remind any doctor, dentist or pharmacist you visit that you are using APO-Sertraline.

Things you should not do

  • Do not take this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
    If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.
    Your doctor may decide that you should continue to take it for some time, even when you have overcome your problem. For the best effect, this medicine must be taken regularly.
  • When you stop treatment with this medicine, you may experience unwanted side effects such as headache, feeling dizzy, sick, irritable, agitated, lethargic or anxious, sweating, pins and needles or electric shock feelings, changing moods or emotions, or disturbed sleep if sertraline is stopped, particularly if stopped suddenly. You should wait at least 14 days after stopping sertraline before starting any other medicines for depression or MAOIs.

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

When your doctor decides that you should stop taking this medicine, the dose may be reduced slowly or the time between the doses increased over 1 to 2 weeks.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-Sertraline affects you.

This medicine may cause dizziness, drowsiness or impaired concentration in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may worsen the dizziness, drowsiness, or impaired concentration.

Although drinking moderate amounts of alcohol is unlikely to affect your response to this medicine, your doctor may suggest avoiding alcohol while you are being treated with this medicine.

Looking after your medicine

  • Keep your medicine in its original packaging until it is time to take it.
    If you take your medicine out of its original packaging it may not keep well.
  • Keep your medicine below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

If you are over 65 years of age you may have an increased chance of getting side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • feeling tired and weak (fatigued), hot flushes, fever, feeling unwell, shaking or tremors, headache or dizziness
  • muscle pain, stiffness, weakness or cramps, decrease or loss of touch or other senses
  • dry mouth, increased sweating, feeling of being sick, diarrhoea or loose bowel motions, constipation, indigestion or stomach pain
  • tiredness, sleepiness or sleeping difficulties
  • weight increase or decrease
  • increase or decrease appetite
  • sleeping difficulties, sexual problems or painful erection
  • sexual dysfunction (including impaired sexual function in males) that may continue even after stopping sertraline
  • frightening dreams, yawning, teeth grinding, increased or decreased appetite
  • impaired concentration
  • excessive and/or abnormal movements
  • increased muscle tension or muscle twitching
  • vision disturbance, dilated pupils or eye pain
  • menstrual irregularities, unusual vaginal bleeding
  • loss of bladder control
  • unusual hair loss or thinning
  • tingling or numbness of the hands or feet
  • breast enlargement in men or unusual secretion of breast milk in men or women
  • increased sensitivity of the skin to sun
  • mild rash or itchy skin
  • ringing or other persistent noise in the ears
  • migraine
  • inflammation of the colon (causing diarrhoea)
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • headache, dizzy, confused, forgetful, weak, unsteady or unable to concentrate (may be a sign of reduced sodium in the blood)
  • agitation, nervousness, anxiety or worsening of depression
  • abnormal or suspicious thinking
  • general swelling or swollen hands, ankles, feet or face or eye area due to fluid build-up
  • severe stomach or abdominal pain
  • symptoms of hyperglycaemia (high blood sugar) such as feeling hungry, thirsty and/or frequent or excessive urination
  • uncontrollable muscle spasms affecting the eyes, head, neck and body, temporary paralysis or weakness of muscles
  • lockjaw
  • painful or swollen joints
  • uncontrollable movements of the body, shuffling walk or unusual weakness
  • agitation, anxiety, dizziness, feeling tense and restless, tired, drowsy, lack of energy, irritable, problems sleeping, headache, nausea and tingling or numbness of the hands and feet after stopping sertraline
  • difficulty in breathing, wheezing or coughing
  • palpitations, fainting or chest pain
  • irregular heartbeats
  • abnormal bleeding including vaginal bleeding
  • sudden onset of severe headache
  • rapid onset of shortness of breath, cough, fatigue, night sweats and weight loss.
Tell your doctor as soon as possible if you notice any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
  • convulsions (fits or seizures)
  • coma (unconsciousness)
  • a collection of symptoms including weight gain (despite loss of appetite), feeling and being sick, muscle weakness and irritability
  • severe rash, with blisters and/ or excessive peeling of skin
  • skin rash combined with inflamed blood vessels
  • a sudden increase in body temperature, very high blood pressure, rigid muscles, nausea/vomiting and/or fits (convulsions) - these symptoms may be signs of a rare condition called Serotonin Syndrome* (SS). SS is caused by medications which build up high levels of serotonin in the body.
  • Neuroleptic Malignant Syndrome* (NMS) - a serious reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsions. NMS is a life threatening emergency associated with the use of antipsychotic medicines.
  • lack of body co-ordination
  • nausea, vomiting, diarrhoea
  • fast, slow or irregular heartbeat, or high blood pressure
  • palpitations, fainting or chest pain
  • abnormal bleeding
  • difficulty in passing urine or blood in the urine
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • fever, sore throat, swollen glands, mouth ulcers, unusual bleeding or bruising under the skin
  • mood of excitement, over-activity and uninhibited behaviour or aggression
  • hearing, seeing or feeling things that are not there (hallucinations)
  • thoughts of suicide or attempting suicide or self-harm
  • breathing problems
  • jaundice (yellowing of the skin and/or eyes), with or without other signs of hepatitis or liver failure (loss of appetite, tiredness, feeling or being sick, dark urine, stomach pain or swelling, confusion, unconsciousness)
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

*The risk of SS and NMS with SSRI's is increased with combined use of other SSRIs, MAOIs and other antipsychotic medicines.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some of these side effects, such as changes to your blood count, can only be found when your doctor does tests from time to time to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What APO-Sertraline contains

Active ingredient
(main ingredient)
Sertraline hydrochloride 50 mg or 100 mg
Other ingredients
(inactive ingredients)
  • Calcium hydrogen phosphate
  • Microcrystalline cellulose
  • Hyprolose
  • Sodium starch glycollate type A
  • Magnesium stearate
  • Hypromellose
  • Titanium dioxide
  • Macrogol 400
  • Polysorbate 80

Do not take this medicine if you are allergic to any of these ingredients.

This medicine does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

What APO-Sertraline looks like

50 mg tablets:

White to off white, capsule shaped, biconvex, film coated tablets with breakline on one side and '50' and 'BL' debossed on either side of the breakline (Aust R 213177).

Blister packs of 30.

100 mg tablets:

White to off white, capsule shaped, biconvex, film coated tablets with '100' and 'BL' debossed on one side (Aust R 213180).

Blister packs of 30.

Who distributes APO-Sertraline

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in January 2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

APO-Sertraline

Active ingredient

Sertraline

Schedule

S4

 

1 Name of Medicine

Sertraline hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 50 mg or 100 mg sertraline (as sertraline hydrochloride).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

50 mg tablets.

White to off white, capsule shaped, biconvex, film coated tablets with breakline on one side and '50' and 'BL' debossed on either side of the breakline.

100 mg tablets.

White to off white, capsule shaped, biconvex, film coated tablets with '100' and 'BL' debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Children and adolescents.

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

Adults.

Sertraline hydrochloride is indicated for the treatment of:
Major depression, obsessive compulsive disorder (OCD) and panic disorder.
Social phobia (social anxiety disorder) and the prevention of its relapse.
Pre-menstrual dysphoric disorder (PMDD) as defined by DSM-IV criteria.

4.2 Dose and Method of Administration

APO-Sertraline tablets are intended for oral administration.

Children and adolescents (6-18 years).

Obsessive compulsive disorder.

The administration of sertraline hydrochloride 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 hydrochloride 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.

Sertraline 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 sertraline.
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 sertraline, 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 hydrochloride has been associated with sustained efficacy, safety and tolerability in up to 2 years of treatment of OCD. If no effect is apparent after 6 to 8 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 sertraline 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, increasing to 50 mg/day after one week.
Pre-menstrual dysphoric disorder. Sertraline 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.
Sertraline should be administered once daily, either in the morning or evening. Sertraline may be administered with or without food.
As indicated under Section 4.4 Special Warnings and Precautions for Use, particular care should be taken in patients with hepatic impairment.
Use in the elderly requires no special precautions. The usual adult dosage is recommended.

4.3 Contraindications

Sertraline 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 (MAOI).

Cases of serious reactions, sometimes fatal, have been reported in patients receiving sertraline in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI, selegiline, and the reversible MAOI (reversible inhibitor of monoamine oxidase - RIMA), moclobemide and MAOI drugs, e.g. linezolid (an antibiotic which is a reversible non-selective 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. Sertraline 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 sertraline before starting a MAOI.

4.4 Special Warnings and Precautions for Use

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS).

The development of potentially life-threatening syndromes like serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) has been reported with 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 opioids (e.g. fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, pentazocine)], with drugs which 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. hyperreflexia, 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.

Co-administration 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 or 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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

Switching from other antidepressants or antiobsessional drugs.

There is limited controlled experience regarding the optimal timing of switching from other antidepressants or anti-obsessional drugs to sertraline. 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 torsades de pointes (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 Pharmacodynamic Properties, Clinical trials).

Activation of mania/ hypomania.

During pre-marketing testing, hypomania or mania occurred in approximately 0.4% of sertraline treated patients. Activation of mania/ hypomania has also been reported in a small proportion of patients with major affective disorder treated with other 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 6-12 year old patients and 3/39 (7.7%) versus 0/41 (0%) of 13-17 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 sertraline 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 1,801 patients (0.2%) exposed to sertraline experienced seizures. In the paediatric OCD trial programme, the incidence of seizures in the adolescent (13-17 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 to sertraline therapy was uncertain. Since sertraline has not been evaluated in patients with a seizure disorder it should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. Sertraline 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 co-existence of depression in patients with other psychiatric disorders, such as OCD, panic disorder social phobia (social anxiety disorder) and PMDD and depression, 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 sertraline 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.

Sertraline 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 sertraline.

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. Sertraline 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.

Postpartum haemorrhage.

SSRI/SNRIs may increase the risk of postpartum haemorrhage (see Section 4.6 Fertility, Pregnancy and Lactation; Section 4.8 Adverse Effects (Undesirable Effects)).

Hyponatraemia.

Hyponatraemia may occur as a result of treatment with SSRIs (selective serotonin reuptake inhibitors) or SNRIs (serotonin and noradrenaline reuptake inhibitors) 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 which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

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 sertraline. 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 predisposed. 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 sertraline in patients with diseases or conditions that could affect metabolism or haemodynamic responses. Sertraline has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 774 patients who received sertraline in double blind trials were evaluated and the data indicate that sertraline is not associated with the development of significant ECG abnormalities.

Symptoms associated with discontinuation.

During marketing of sertraline 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 sertraline. 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 the 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 sertraline 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 sertraline.

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 three-fold greater AUC and Cmax for sertraline and a two-fold 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, sertraline 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 sertraline. 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 sertraline hydrochloride in these paediatric studies is comparable to that observed in the adult OCD studies.
Long-term safety on cognitive, emotional, physical, and pubertal maturation in children and adolescents aged 6 to 16 years was evaluated in a long-term observational study for up to 3 years (see Section 5.1 Pharmacodynamic Properties).
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 co-administration. Co-administration 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 which 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 Pharmacodynamic Properties, Clinical trials).

CNS depressants and alcohol.

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

Co-administration of drugs with serotonergic action.

Sumatriptan.

There have been rare post-marketing reports describing patients with weakness, hyperreflexia, incoordination, confusion, anxiety and agitation following the use of sertraline and sumatriptan. If concomitant treatment with sertraline and sumatriptan is clinically warranted, appropriate observation of the patient is advised (see Section 4.4 Special Warnings and Precautions for Use).

Other serotonergic drugs.

(See Section 4.3 Contraindications, Monoamine oxidase inhibitors (MAOI); Section 4.4 Special Warnings and Precautions for Use, Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS), 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 re-uptake 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 sertraline.

Potential effects of co-administration of drugs highly bound to plasma proteins.

Because sertraline is tightly bound to plasma protein, the administration of sertraline 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 Warfarin and Other drug interactions).

Warfarin.

Co-administration 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 sertraline 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. Co-administering 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, co-administration 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 the inhibition and the therapeutic index of the co-administered drug. Consequently, concomitant use of a drug metabolised by CYP2D6 with sertraline may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from co-therapy, an increased dose of the co-administered 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.
Coadministration of sertraline with metamizole, which is an inducer of metabolising enzymes including CYP 2B6 and CYP 3A4 may cause a reduction in plasma concentrations of sertraline with potential decrease in clinical efficacy, therefore, caution is advised when metamizole and sertraline are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

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 Other drug interactions, Phenytoin, 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 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.

Co-administration 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.

Co-administration 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 co-administration with other SSRIs, isolated cases of increased clozapine levels have been reported.

Microsomal enzyme induction.

Preclinical studies have shown sertraline to induce hepatic microsomal enzymes. In clinical studies, sertraline 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 sertraline, other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, 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, hyperreflexia, 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 foetuses, probably secondary to effects on the dams.

Non-teratogenic effects.

Observational studies have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to SSRIs, including sertraline, especially within the month prior to birth.
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. Animal reproduction studies are not always predictive of human response, sertraline should not be used during pregnancy unless in the judgement of the physician, the expected benefit justifies the risk to the foetus. 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 sertraline.
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 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 six-fold 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 1997-2005 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 sertraline on labour and delivery in humans is unknown.
Only limited data concerning sertraline levels in breast milk are available. However, in breastfed infants whose mothers were taking sertraline, there have been reports of adverse effects. Because sertraline is excreted in human milk, breastfeeding while on sertraline is not recommended. If sertraline 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 sertraline.

4.7 Effects on Ability to Drive and Use Machines

In controlled studies, sertraline 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.

4.8 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 sertraline 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 sertraline treatment.

Metabolism and nutrition disorders.

Common: decreased appetite.

Autonomic nervous system.

Common: increased sweating.

General disorders and administration site conditions.

Very common: fatigue.
Common: malaise, pyrexia.

Investigations.

Common: weight increased, weight decreased.

Vascular disorders.

Common: hot flush.

Cardiac disorders.

Common: palpitations.

Nervous system disorders.

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

Gastrointestinal disorders.

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

Psychiatric disorders.

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

Respiratory, thoracic and mediastinal disorders.

Common: yawning.

Reproductive system and breast disorders.

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

Skin and subcutaneous tissue disorders.

Common: rash, hyperhidrosis, urticaria.

Renal and urinary disorders.

Common: urinary retention.

Eye disorders.

Common: visual impairment.
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 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 sertraline, as adverse events are also reported in the context of post-marketing exposure, when the relationship of these adverse events to sertraline may not be differentiated clearly from effects of concomitant medications or disease states for which sertraline was prescribed.

Reproductive system and breast disorders.

Rare: priapism, galactorrhoea, gynaecomastia.
Unknown: postpartum haemorrhage.*
* This event has been reported for the therapeutic class of SSRIs/SNRIs (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).

Blood and lymphatic system disorders.

Rare: thrombocytopenia, leukopenia.

Immune system disorders.

Uncommon: hypersensitivity.
Rare: anaphylactoid reaction.

Cardiac disorders.

Common: chest pain.
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.
Rare: cerebrovascular vasoconstriction (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis.

Nervous system disorders.

Very common: headache.
Common: hypertonia, paraesthesia.
Uncommon: syncope, muscle contractions involuntary, migraine.
Rare: coma, neuroleptic malignant syndrome.
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.

Endocrine disorders.

Rare: hyperprolactinaemia, hypothyroidism, syndrome of inappropriate ADH secretion (SIADH).

Gastrointestinal disorders.

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

Ear and labyrinth disorders.

Common: tinnitus.

Injury, poisoning and procedural complications.

Rare: bone fracture.

Investigations.

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

Hepatobiliary disorders.

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

Metabolism and nutrition disorders.

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

Musculoskeletal and connective tissue disorders.

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

Psychiatric disorders.

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

Respiratory, thoracic and mediastinal disorders.

Uncommon: bronchospasm.
Rare: eosinophilic pneumonia.
Unknown: dyspnoea.

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.

Renal and urinary disorders.

Uncommon: haematuria, urinary incontinence.
Rare: enuresis.

Eye disorders.

Uncommon: mydriasis, periorbital oedema, eye pain.
Rare: visual field defect.

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).

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 and contact Arrotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

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.

Symptoms.

Symptoms of overdose include serotonin mediated side effects such as electrocardiogram QT prolonged, torsades de pointes (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 Pharmacodynamic Properties, 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.
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.

Treatment.

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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Sertraline hydrochloride is a selective serotonin re-uptake inhibitor (SSRI) antidepressant for oral administration. It 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 humans 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 re-uptake. 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 non-selective 5HT reuptake inhibitor clomipramine. Tricyclic antidepressants without SRI effects have no efficacy in OCD.

Clinical trials.

Major depression.

Adults.

The efficacy of sertraline in the treatment of a major depressive episode in adults was established in controlled trials of 6-8 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 sertraline in hospitalised depressed patients has not been adequately studied. A study of depressed outpatients who had responded to sertraline during an initial 8-week open treatment phase and were then randomised to continuation on sertraline or placebo demonstrated a significantly lower relapse rate over the next eight weeks for patients taking sertraline compared to those on placebo. Therefore, the physician who elects to use sertraline 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 sertraline hydrochloride 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 sertraline hydrochloride 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. Sertraline hydrochloride 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 sertraline hydrochloride 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 sertraline hydrochloride in the treatment of OCD were established in three eight to twelve week controlled trials of non-depressed 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 ego-dystonic. 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 sertraline hydrochloride 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 sertraline hydrochloride 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 sertraline hydrochloride 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 sertraline hydrochloride and placebo groups, respectively. The proportion of patients having no panic attacks at the final evaluation was 69% in the sertraline hydrochloride 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-IIIR 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 sertraline 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 sertraline (50 mg/day to 200 mg/day) to placebo, in which sertraline 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). Sertraline was significantly more effective than placebo as measured by the LSAS and the percentage of responders.
A 20-week, multicentre, flexible dose study compared sertraline (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. Sertraline 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 sertraline during the 20 week placebo controlled trial were randomised to continuation of sertraline or to substitution of placebo for up to 24 weeks of observation for relapse. Patients receiving sertraline 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 sertraline 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, sertraline 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, sertraline 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.
Sertraline 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 humans, 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 post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once daily dosing. Linear dose proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 mg to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose of sertraline, with repeated dosing over a 50 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 post-dosing 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. 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. 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.

Excretion.

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.

Children and adolescents.

The pharmacokinetics of sertraline hydrochloride 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 body weights (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 sertraline 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 sertraline 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 10-40 mg/kg compared to placebo controls, this effect was not clearly drug related.

6 Pharmaceutical Particulars

6.1 List of Excipients

Calcium hydrogen phosphate; microcrystalline cellulose; hyprolose; sodium starch glycollate type A; magnesium stearate; hypromellose; titanium dioxide; macrogol 400; polysorbate 80.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 25°C.

6.5 Nature and Contents of Container

50 mg tablets.

Blister pack PVC/ Aluminium blisters of 30 tablets (AUST R 213177).

100 mg tablets.

Blister pack PVC/ Aluminium blisters of 30 tablets (AUST R 213180).
Not all strengths may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Sertraline hydrochloride is a white to off-white crystalline powder that is slightly soluble in water and isopropyl alcohol and sparingly soluble in ethanol and dimethylformamide.
Sertraline hydrochloride is a selective serotonin re-uptake inhibitor (SSRI) antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.
Sertraline is a disubstituted tetrahydronaphthalene with two asymmetric centres and can exist as four enantiomeric forms in either the trans- or cis-configuration. The cis-(1S,4S) sertraline enantiomer is used.

Chemical structure.

Structural formula:
Chemical name: (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.
Molecular formula: C17H17Cl2N.HCl.
Molecular weight: 342.7.

CAS number.

79559-97-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes