Consumer medicine information

Setrona

Sertraline

BRAND INFORMATION

Brand name

Setrona

Active ingredient

Sertraline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Setrona.

SUMMARY CMI

SETRONA

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 SETRONA?

SETRONA contains the active ingredient sertraline hydrochloride. SETRONA is used to treat depression and conditions called obsessive compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder) and premenstrual dysphoric disorder (PMDD).

For more information, see Section 1. Why am I using SETRONA? in the full CMI.

2. What should I know before I use SETRONA?

Do not use if you have ever had an allergic reaction to SETRONA 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 SETRONA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SETRONA 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 SETRONA?

  • SETRONA is to be taken by mouth, every morning or evening with or without food. Swallow the tablet whole with a full glass of water.
  • Take SETRONA exactly as your doctor has prescribed.

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

5. What should I know while using SETRONA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SETRONA.
  • Take SETRONA exactly as your doctor tells you to.
  • Visit your doctor regularly for check ups.
Things you should not do
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not use SETRONA tablets to treat any other complaints unless your doctor tells you to.
  • Do not stop taking SETRONA tablets, or lower the dose, without first checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how SETRONA affects you.
  • SETRONA tablets may affect your ability to drive a car or operate machinery.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Although drinking moderate amounts of alcohol is unlikely to affect your response to SETRONA, your doctor may suggest avoiding alcohol while you are taking SETRONA.
Looking after your medicine
  • Keep your SETRONA in a cool, dry place where it stays below 25°C.

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

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.

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

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

SETRONA

Active ingredient(s): sertraline hydrochloride


Consumer Medicine Information (CMI)

This leaflet provides important information about using SETRONA. 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 SETRONA.

Where to find information in this leaflet:

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

1. Why am I using SETRONA?

SETRONA contains the active ingredient sertraline hydrochloride. SETRONA belongs to a group of medicines known as selective serotonin reuptake inhibitors (SSRIs). These medicines are thought to work by increasing the activity of the chemical serotonin in the brain.

SETRONA is used to treat depression and conditions called obsessive compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder) and premenstrual 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. It is thought to be caused by a chemical imbalance in parts of the brain. This imbalance affects your whole body and can cause emotional and physical symptoms such as feeling low in spirit, loss of interest in activities, being unable to enjoy life, poor appetite or overeating, disturbed sleep, often waking up early, loss of sex drive, lack of energy and feeling guilty over nothing. SETRONA corrects this chemical imbalance and may help relieve the symptoms of depression.

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

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.

Your doctor, however, may have prescribed SETRONA for another purpose. Ask your doctor if you have any questions about why SETRONA tablets have been prescribed for you.

SETRONA is only available with a doctor's prescription

There is no evidence that SETRONA is addictive.

2. What should I know before I use SETRONA?

Warnings

Do not use SETRONA if:

  • You are taking another medicine for depression called a monoamine oxidase inhibitor (MAOI) or have been taking it within the last 14 days. Taking SETRONA with a MAOI (eg seligeline, phenelzine, tranylcypromine, moclobemide) may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and convulsions (fits).
  • You have epilepsy not properly controlled by medication
  • You are pregnant, plan to become pregnant or are breastfeeding
  • You are taking pimozide (medicines used for treating mental illness).
  • 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
  • You are allergic to sertraline, or any of the ingredients listed at the end of this leaflet.
  • Some of the symptoms of an allergic reaction to SETRONA may include a skin rash, itchiness, difficulty breathing and swelling of the face.
  • Always check the ingredients to make sure you can use this medicine.
  • Do not take SETRONA tablets after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well.
  • Do not take SETRONA if the tablets do not look quite right.
  • Do not take SETRONA tablets if the packaging is torn or shows signs of tampering.

Do not give SETRONA:

  • 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 any other medical conditions especially the following:
    - Liver or kidney problems
    - History of a heart attack or have heart problems
    - Epilepsy or seizures
    - History of bleeding disorders or a tendency to bleed more than normal
    - Bipolar disorder (manic depression)
    - Syndrome of Inappropriate Antidiuretic Hormone Secretion
    - Mental illness, family history of suicide or depression
    - Pregnant or intend to become pregnant
    - take any medicines for any other condition
    - have any allergies to any other medicines and any other substances, such as foods, preservatives or dyes

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.

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

Your doctor will discuss the risk and benefits of taking SETRONA during pregnancy.

The effects of SETRONA on the developing baby are not known yet. However, there have been reports that babies exposed to SETRONA and other SSRIs antidepressants during the third trimester of pregnancy may develop complications after birth.

Make sure your doctor know you are on SETRONA. When taken during pregnancy, particularly in the last 3 months of pregnancy, medicines like SETRONA 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 doctor immediately.

SETRONA passes into breast milk and may affect your baby. Side effects have been reported in babies exposed to sertraline during breastfeeding. Your doctor will discuss the risks and benefits of using SETRONA when breastfeeding.

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 should not be taken with SETRONA as it may increase the risk of serious side effects and are potentially life-threatening these include:

  • Medicines called monoamine oxidase inhibitors (MAOI) such as phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX) and selegiline (ELDEPRYL). Taking SETRONA with, or within fourteen days of stopping a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and convulsions.
  • Medicines that can increase the effects of SETRONA such as tramadol (pain reliever), tryptophan (a complementary medicine), or phentermine (a weight reducing medicine) and sumatriptan (medicine used to relieve migraine attack).
  • Pimozide (use to treat disturbances in thinking, feeling and behaviour).
  • St John's wort, a herbal remedy.

Some medicines may interfere with SETRONA and affect how it works.

You may respond differently to SETRONA, or to some other medicines, if you take them together. These include:

  • Phentermine, a weight loss medicine
  • Tryptophan, contained in some protein-based foods and herbal preparations
  • medicines for strong pain management (e.g. 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)
  • Dextromethorphan, used in cold and flu medicines to suppress cough
  • Medicines used to treat heart conditions (e.g. flecainide and propafenone)
  • Other medicines for depression, panic disorders, social anxiety disorders or obsessive compulsive disorder.
  • medicines for Pre-Menstrual Dysphoric Disorder (e.g. fluoxetine)
  • medicine used to treat mental illnesses or mood disorders (e.g. clozapine, lithium)
  • medicines for irregular heart beat (e.g. flecainide)
  • medicines that can cause abnormal bleeding such as non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, medicines that stop the blood from clotting like warfarin.
  • phenytoin (e.g. Dilantin), a medicine used for epilepsy
  • Diazepam or other medicines to treat sleeping disorders, anxiety or help to relax the muscles (e.g. Serepax, valium)
  • Tolbutamide (eg Rastinon), a medicine used to treat diabetes
  • Cimetidine (e.g. Tagamet), a medicines used to treat reflux and ulcers.
  • Methadone, a medicine used to treat drug addiction
  • Metamizole, an inducer of metabolising enzymes

These medicines may be affected by SETRONA tablets, or may affect how well it works. You may need to use different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist will be able to tell you what to do when taking/being given SETRONA tablets with other medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking SETRONA. If you have not told your doctor or pharmacist about these things, tell them before you start taking SETRONA.

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

4. How do I use SETRONA?

How much to take / use

  • SETRONA is to be taken by mouth, every morning or evening with or without food. Swallow the tablet whole with a full glass of water.
  • Take SETRONA exactly as your doctor has prescribed.

For Major Depression in Adults

  • The usual starting dose is one SETRONA 50 mg tablet taken once daily. It is possible that your doctor may decide to increase your daily doses, depending on your response to treatment. The maximum daily dose should not exceed 200 mg.

For Obsessive Compulsive Disorder in Children (6-12 years)

  • The usual starting dose for SETRONA is 25 mg/day (half a 50 mg tablet), increasing to 50 mg/day after one week.

For Obsessive Compulsive Disorder in Adults and Adolescents (13-18 years)

  • The usual starting dose for SETRONA is one 50 mg tablet each day.

For Panic Disorder in adults

  • The usual starting dose for SETRONA is 25 mg per day, increasing to 50 mg per day after one week.

For social phobia (social anxiety disorder) in adults

  • The usual starting dose for SETRONA is 25 mg per day, increasing to 50 mg per day after one week.
  • The maximum recommended dose of SETRONA for the conditions listed above is 200 mg per day.

For Premenstrual Dysphoric Disorder

  • The usual starting dose is one SETRONA 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 menses (to a maximum of 100 mg daily). However, depending on your condition and how you react to SETRONA, your doctor may ask you to take some other dose. The maximum recommended daily dose should not exceed 200 mg.
  • Your dosage would be different if you have liver problems.
  • Follow the instructions provided and use SETRONA until your doctor tells you to stop. Your doctor may need to regularly examine you to decide if it is necessary for you to continue taking or stop SETRONA tablets.

When to take / use SETRONA

  • Take your SETRONA tablets at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you to remember when to take the tablets.

How long to take it

  • Most medicines for depression and obsessive illness take time to work, so do not be discouraged if you do not feel better straight away.
  • It may take 2 to 4 weeks or even longer to feel the full benefit of SETRONA. 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 SETRONA for several months or even longer to make sure the benefits will last. Continue to take it until your doctor tells you to stop.
  • If you have PMDD, your doctor may ask you to take this medicine only at certain times of the month.
  • Do not stop taking SETRONA, or change the dose, without first checking with your doctor.

Occasionally the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide. It is possible that these symptoms may continue or increase until the full antidepressant 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 use SETRONA

SETRONA should be used regularly at the same time each day.

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, then go back to taking it as you would normally.

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

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

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

If you use too much SETRONA

If you think that you have used too much SETRONA, 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.

If you take too many SETRONA tablets, you may feel drowsy, sick in the stomach, have a fast heartbeat, have tremors, feel agitated or dizzy. Coma has also been reported with the overdose.

5. What should I know while using SETRONA?

Things you should do

Take SETRONA exactly as your doctor tells you to.

Try not to miss any doses and take the medicine even if you feel well.

Visit your doctor regularly for check ups.

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

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are taking SETRONA.

If you plan to have surgery make sure you tell your doctor, dentist or anaesthetist that you are taking SETRONA.

If you become pregnant or intend to become pregnant while taking SETRONA, you should make an appointment to see your doctor and have your treatment reviewed. It is important that you do not stop taking SETRONA suddenly. SETRONA is a medicine that can have withdrawal side effects if stopped suddenly. Withdrawal symptoms (e.g. feeding difficulty, vomiting, tremor, irritability, unstable temperature) have also been reported rarely in the newborn baby after maternal use in the last 3 months of pregnancy.

If you take this medicine during late pregnancy, the newborn may be at increased risk of developing troubled breathing, bluish skin, fits, changes in body temperature, feeding difficulties, vomiting and cough (signs of persistent pulmonary hypertension).

Your doctor will discuss the risks and benefits of taking SETRONA during pregnancy.

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes.

A worsening of depressive symptoms including thoughts of suicide or self-harm may occur in the first one or two months of you taking SETRONA or when the doctor changes your dose. These symptoms should be controlled when the full effect of SETRONA takes place.

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

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

Signs and symptoms of suicide include:

  • Thoughts of talk of death or suicide, self-harm or harm to others
  • Any recent attempts of self-harm
  • Increase in aggressive behaviour, irritability or agitation
  • Worsening of depression

All mentions of suicide or violence must be taken seriously.

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

Tell your doctor immediately if you develop symptoms and signs of serotonin syndrome.

Signs and symptoms of serotonin syndrome include:

  • Incoordination
  • Trembling, abrupt contraction of muscles
  • Confusion
  • Agitation
  • Sweating
  • Fever
  • Shivering
  • Diarrhoea.

Tell your doctor if you develop symptoms and signs of hyponatraemia (decreased level of sodium in blood), such as:

  • Headache
  • Difficulty in concentration
  • Memory impairment
  • Confusion
  • Weakness
  • Unsteadiness

In cases of sudden and/or severe hyponatraemia, symptoms such as hallucination (seeing, feeling or hearing things that are not there), fainting, seizure, coma, respiratory arrest, and death have also been reported.

Risk of developing hyponatraemia is greater if you:

  • are elderly
  • are on diuretics (fluid or water tablets)
  • have Syndrome of Inappropriate Antidiuretic Hormone Secretion

Things you should not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not use SETRONA tablets to treat any other complaints unless your doctor tells you to.

Do not stop taking SETRONA tablets, or lower the dose, without first checking with your doctor.

Suddenly stopping SETRONA may cause dizziness, lightheadedness, numbness, feeling sick, unusual tingling feelings, shakiness or anxiety.

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

Do not use SETRONA to treat any other complaints unless your doctor says to.

Things to be careful of

If you are to switch to another medicine for depression from the MAOI group such as Auroix, Nardil or Parnate, you should wait at least 14 days after stopping SETRONA before starting the MAOI medicine.

All the above precautions are important even after you have stopped taking SETRONA. The effects of SETRONA may last for some days after you have stopped taking it.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SETRONA affects you.

Some medicines for depression may affect your ability to drive or operate machinery or do things that could be dangerous if you are not alert.

SETRONA tablets may affect your ability to drive a car or operate machinery.

SETRONA may cause dizziness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

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

If you take the tablets out of the box or the blister pack they may not keep well.

Keep your SETRONA in a cool, dry place where it stays 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.

Keep it where young children cannot reach it.

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.

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
  • Nausea (feeling sick), vomiting (being sick), indigestion, loose stools (diarrhoea), dry mouth, abdominal pain, increased or decreased appetite, constipation
  • Headache, dizziness, lack of sleep or drowsiness, excessive sweating, inability to concentrate, nervousness, yawning, teeth grinding
  • Tingling and numbness in hands and feet
  • Decreased sexual performance including failure of ejaculation in males, decreased or increased sexual desire, impotence, lack of orgasm in female patients
  • Mental confusion or agitation, excessive excitement, hallucinations
  • Increased tendency to bleed or abnormal bleeding, predominantly of the skin and mucous membranes (including nasal, vaginal and gastrointestinal bleeding).
  • Urinary disturbances
  • Puffiness of face, fever, blushing, weight loss or gain, vague feeling of being unwell
  • Ringing in the ears
  • Increased production of the hormone prolactin, which may result in abnormal production of breast milk or breast enlargement
  • High or low blood pressure
  • Vision disturbances
  • Menstrual irregularities
  • Unusually overactive
  • Shaking and tremors
  • Unusual hair loss or thinning
  • Swelling of hands, ankles or feet
  • Increased sensitivity of the skin to sun
  • Symptoms of agitation, anxiety, confusion, dizziness, feeling tense and restless, feeling of tiredness, drowsiness, or lack of energy, headache, irritability, nausea, trouble sleeping and tingling or numbness of the hands and feet after stopping SETRONA.
  • Inflammation of the colon (causing diarrhea)
  • Laboratory abnormalities
    - Lowered sodium content of the blood
    - Increased blood cholesterol, and sugar
    - Abnormal liver function test
    - Decreased blood uric acid levels
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Symptoms of an allergic reaction may include rashes, hives, itching, difficulty breathing, shortness of breath or swelling of face, lips, tongue, hands/ feet, fainting, high temperature.
  • Severe skin reactions with blisters, sores or ulceration.
  • Marked behavioural changes including excessive excitement; abnormal body movements; combination of unresponsive body rigidity (inability to move or talk), high fever and profuse sweating.
  • Seizures or fits
  • Palpitations, fainting or chest pains
  • Symptoms of sudden fever with sweating, fast heart beat and muscle stiffness, which may lead to loss of consciousness
  • Marked changes in behaviour, emotions or mood including thoughts of suicide and self-harm, attempts at suicide.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
These are very serious side effects. You may need urgent medical attention or hospitalisation. All these side effects are very rare.

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.

Reporting side effects

After you have received medical advice for any side effectsyou 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 SETRONA contains

Active ingredient
(main ingredient)
sertraline (as hydrochloride)
Other ingredients
(inactive ingredients)
Microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium starch glycollate, hyprolose, magnesium stearate, and OPADRY complete film coating system OY-S-58910 WHITE (PI 11503).

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

What SETRONA looks like

SETRONA 50 mg tablets are available in a pack of 30 tablets.

SETRONA 50 mg are white film coated caplet shaped tablets debossed with ‘50' on one side and a break-line on the other.

SETRONA 100 mg tablets are available in a pack of 30 tablets.

SETRONA 100 mg are white film coated caplet shaped tablets debossed with ‘100' on one side and a breakline on the other.

Australian Registration Numbers:

SETRONA 50 mg tablets – AUST R 116623

SETRONA 100 mg tablets – AUST R 116636

Who distributes SETRONA

SETRONA is supplied in Australia by:

Sun Pharma ANZ Pty Ltd.
Macquarie Park NSW 2113
Australia

This leaflet was prepared in August 2022.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Setrona

Active ingredient

Sertraline

Schedule

S4

 

1 Name of Medicine

Sertraline hydrochloride.

2 Qualitative and Quantitative Composition

Each white, film coated caplet shaped tablet contains 50 mg or 100 mg of sertraline as sertraline hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Setrona 50 mg tablet is debossed with "50" on one side and a break line on the other.
Setrona 100 mg tablet is imprinted with "100" on one side and a break line on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Children and adolescents.

Setrona is indicated for the treatment of children (aged 6 years of age and older) and adolescents with Obsessive Compulsive Disorder (OCD).

Adults.

Setrona is indicated for the treatment of major depression, OCD and panic disorder.
Setrona is indicated for the treatment of social phobia (social anxiety disorder) and the prevention of its relapse.
Setrona is indicated for the treatment of Premenstrual Dysphoric Disorder (PMDD) as defined by DSM-IV criteria.

4.2 Dose and Method of Administration

Children and adolescents (6-18 years).

Obsessive compulsive disorder.

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

Adults (18 years and older).

Major depression/ obsessive compulsive disorder.

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 antiobsessive effect has not been established, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the antidepressive and antiobsessive 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 has been associated with sustained efficacy, safety and tolerability in up to 2 years of treatment of OCD. If no effect is apparent after six to eight weeks, discontinuation of treatment should be considered. Studies of efficacy did not examine the role of psychotherapy.

Panic disorder.

Therapy for panic disorder should commence at 25 mg/day, 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).

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

Premenstrual 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 vs 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 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

Setrona 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 that 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 antiobsessional 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

General.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Symptoms associated with discontinuation.

During marketing of sertraline and other SSRIs and SNRIs (serotonin and norepinephrine 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 Setrona. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).

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

Development of potentially life-threatening syndromes such as Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported with treatment with SSRIs, including sertraline. The risk of SS or NMS is increased with SSRIs given in combination with drugs which impair metabolism of serotonin including MAOIs, or other serotonergic agents including amphetamines, triptans, opioids (e.g. fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, pentazocine), antipsychotics and other dopamine antagonists. Symptoms and signs of SS 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), myoclonus, tremor, confusion, hypomania. Some signs of SS, including hyperthermia, muscle rigidity, autonomic instability with possible rapidly fluctuating vital signs and mental status changes, resemble NMS. Patients should be monitored for the emergence of signs and symptoms of SS or NMS (see Section 4.3 Contraindications). Treatment with Setrona should be discontinued if such events occur and supportive symptomatic treatment initiated.

Other serotonergic drugs.

Coadministration of SSRIs such as sertraline with other drugs which enhance the effects of serotonergic neurotransmission, such as amphetamines, tryptophan, phentermine, fentanyl and its analogues, tramadol, 5-HT agonists, dextromethorphan, tapentadol, pethidine or methadone should be undertaken only with caution and avoided whenever possible due to the potential for pharmacodynamic interaction (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 antiobsessional drugs to sertraline. Care and prudent medical judgment 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/torsade de pointes (TdP).

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

Activation of mania/hypomania.

During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder treated with other antidepressant and antiobsessional drugs.
Hyperkinesia has been noted in pediatric 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 pediatric patients, weight loss was seen in 2/53 (3.8%) versus 0/54 (0%) of 6 to 12 year old patients and 3/39 (7.7%) versus 0/41 (0%) of 13 to 17 year olds treated with sertraline vs placebo. It is recommended that pediatric 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 antiobsessional 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 pediatric OCD trial programme, the incidence of seizures in the adolescent (13 to 17 years old) population was 3/163 (1.8%) on sertraline compared with 0/41 (0%) on placebo. Seizures/ convulsions were not noted in 6 to 12 year old patients. In all these cases, the relationship 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 till significant remission occurs. This risk must be considered in all depressed patients.
Because of the coexistence of OCD and depression, panic disorder and depression and social phobia (social anxiety disorder) and depression, and PMDD and depression, the same precautions observed when treating patients with depression should be observed when treating patients with OCD, panic disorder, social phobia or PMDD.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (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 analysis of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorders (four trials) or other psychiatric disorders (four trials) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment 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 analysis included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone and 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 (ages 18-24) 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 tested with antidepressants or 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 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 Setrona 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 of the skin and mucous membranes 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.

Hyponatremia.

Hyponatremia 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, hyponatremia 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 hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk (see Use in the elderly). Discontinuation of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia 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 pre-disposed. Sertraline should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.

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.

Interference with cognitive and motor performance.

In controlled studies, sertraline did not cause sedation and did not interfere with psychomotor performance.

Drug dependence and abuse.

In human studies, sertraline has not demonstrated potential for abuse. In a placebo-controlled, double blind, randomized 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 behavior).

Use in hepatic impairment.

Sertraline is extensively metabolized in 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 metabolized. 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 30-60 mL/min) or moderate to severe renal impairment (creatinine clearance 10-29 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. 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.

The pattern of adverse reactions in the elderly was similar to that in younger patients.

Paediatric use.

Children and adolescents (< 18 years).

A total of 225 paediatric patients have completed OCD trials with sertraline. The safety profile of sertraline in these paediatric studies is comparable to that observed in the adult OCD studies. Safety and effectiveness in paediatric patients below the age of six have not been established.
Setrona 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

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

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

Monoamine oxidase inhibitors.

See Section 4.3 Contraindications.

Pimozide.

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

Drugs that prolong the QTc interval.

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

Coadministration of drugs with serotonergic action.

Sumatriptan.

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

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.

Potential effects of coadministration 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Warfarin).

Warfarin.

Coadministration of sertraline 200 mg daily with warfarin resulted in an 8% delay in normalization 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. Coadministering sertraline with medications, such as lithium, which may act via serotonergic mechanisms, should be undertaken with caution in patients and appropriately monitored.

Phenytoin.

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

Drugs metabolized by cytochrome P450 (CYP) 2D6.

There is variability among antidepressants in the extent to which they inhibit the activity of isozyme 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 metabolized by CYP 2D6 with sertraline may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from cotherapy, an increased dose of the co-administered drug may be required. CYP 2D6 substrates with a narrow therapeutic index include 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 23-37%).

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

CYP 3A3/4.

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 CYP 3A3/4 metabolism of carbamazepine or terfenadine. In addition, the administration of sertraline 50 mg daily for 14 days did not statistically significantly inhibit the CYP 3A3/4 mediated metabolism of alprazolam. The results of these studies suggest that sertraline is not likely to be a clinically important inhibitor of CYP 3A3/4.
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.

CYP 2C9.

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 CYP 2C9 (see other drug interactions: tolbutamide/ glibenclamide, phenytoin and warfarin).

CYP 2C19.

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 CYP 2C19.

CYP 1A2.

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

Other drug interactions.

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

Cimetidine.

Coadministration of cimetidine caused a statistically significant increase in sertraline mean AUC by 50% and Cmax by 24% and T½ by 26%.

Atenolol/ digoxin.

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

Diazepam.

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

Glibenclamide.

No interaction was observed with glibenclamide.

Clozapine.

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

Microsomal enzyme induction.

Preclinical studies have shown 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.

Other interactions.

Electroconvulsive therapy.

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

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.

Driving, use of machinery.

Clinical pharmacology studies have shown that sertraline appears to have no effect on 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.

4.6 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 (selective serotonin reuptake inhibitors), or SNRIs (serotonin and noradrenaline reuptake inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hyper-reflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or possibly a drug discontinuation syndrome.
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).

Teratogenic effects.

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

Non-teratogenic effects.

There was also decreased neonatal survival following maternal administration of sertraline at doses giving rise to plasma drug exposure levels similar to or slightly higher than that achieved following the maximum recommended human dose of 200 mg. The decrease in pup survival was shown to be most probably due to in utero exposure to sertraline. The clinical significance of these effects is unknown. Similar effects have been described with other antidepressants.
There are no adequate and well-controlled studies in pregnant women. SSRIs have had limited use in pregnancy without a reported increase in birth defects. Because animal reproduction studies are not always predictive of human response, sertraline should not be used during pregnancy unless in the judgment of the physician, the expected benefit justifies the risk to the fetus. The use of SSRIs in the third trimester may result in a withdrawal state in the newborn infant.
Women of childbearing potential should avoid becoming pregnant if taking 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 1.2-4.3) associated with patient reported maternal use of SSRIs "in early pregnancy" and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient reported maternal use of SSRIs "in early pregnancy" and an antenatal SSRI prescription "in later pregnancy." The effects of sertraline on labor and delivery in humans is unknown.
Only limited data concerning sertraline levels in breast milk are available. However, in breast-fed infants whose mothers were taking sertraline, there have been reports of adverse effects. Because sertraline is excreted in human milk, breastfeeding while on 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

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Driving, use of machinery.

4.8 Adverse Effects (Undesirable Effects)

Adverse events are listed within body system, categorized by frequency as: 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 (depression and OCD in adults and paediatric OCD in children and adolescents). These adverse effects were observed at doses of 50 to 200 mg/day. These events are not necessarily related to sertraline treatment.

Metabolism and nutrition disorders.

Common: decreased appetite.

Psychiatric.

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

Autonomic nervous system.

Common: increased sweating.

Central and peripheral nervous system.

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

Eye disorders.

Common: visual impairment.

Cardiac disorders.

Common: palpitations.

Vascular disorders.

Common: hot flush.

Respiratory, thoracic and mediastinal disorders.

Common: yawning.

Gastrointestinal.

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

Skin and subcutaneous tissue disorders.

Common: rash, hyperhidrosis, urticaria.

Renal and urinary disorders.

Common: urinary retention.

Reproductive system and breast disorders.

Common: ejaculation disorder, menstrual irregularities, sexual dysfunction (principally ejaculatory delay in males) (see Section 4.4 Special Warnings and Precautions for Use), vaginal hemorrhage.

General disorders and administration site conditions.

Very common: fatigue.
Common: fever, malaise.

Investigations.

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

Adverse effects from clinical trials in paediatric MDD.

In clinical trials in children and adolescents aged 6 to 17 years with major depressive disorder the following adverse events were reported at a frequency of at least 2% of subjects and occurred at a rate of at least twice that of placebo: diarrhea (9.5% vs 1.6%), agitation (6.3% vs 1.1%), anorexia (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% with sertraline and 2.1% with placebo. The most common reasons for discontinuation due to adverse events, whether or not related to sertraline, were aggressive reaction (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 (1.1%) and placebo (1.1%) with an incidence of suicide attempts in sertraline treated subjects of 1.1% (2 attempts) vs 1.6% in placebo-treated subjects (3 attempts). Suicidal ideation was reported by 3 sertraline-treated patients (1.6%) and no placebo treated patients. This difference is not statistically significant. Note that Setrona should not be used in children and adolescents under 18 years of age to treat MDD (see Section 4.4 Special Warnings and Precautions for Use).

Post-marketing data.

The following adverse events are not necessarily related to sertraline, as adverse events are 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.

Blood and lymphatic system disorders.

Rare: thrombocytopenia, leukopenia.

Immune system disorders.

Uncommon: hypersensitivity.
Rare: anaphylactoid reaction.

Endocrine disorders.

Rare: inappropriate antidiuretic hormone secretion, hyperprolactinaemia and hypothyroidism.

Metabolism and nutrition disorders.

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

Psychiatric disorders.

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

Nervous system disorders.

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

Eye disorders.

Uncommon: mydriasis, periorbital oedema, eye pain.

Ear and labyrinth disorders.

Common: tinnitus.

Cardiac disorders.

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

Vascular disorders.

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

Respiratory, thoracic and mediastinal disorders.

Uncommon: bronchospasm.
Unknown: dyspnoea.

Gastrointestinal disorders.

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

Hepatobiliary disorders.

Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased.
Rare: serious liver events (including hepatitis, jaundice and hepatic failure), asymptomatic elevations in serum transaminases (SGOT and SGPT).

Skin and subcutaneous tissue disorders.

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

Musculoskeletal and connective tissue disorders.

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

Renal and urinary disorders.

Uncommon: haematuria, urinary incontinence.
Rare: enuresis.

Reproductive system and breast disorders.

Rare: priapism, galactorrhoea, gynaecomastia.

General disorders and administration site conditions.

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

Investigations.

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

Injury, poisoning and procedural complications.

Rare: fracture.

Discontinuation symptoms.

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

Reporting suspected adverse effects.

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

4.9 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 of overdose include serotonin-mediated side effects such as electrocardiogram QT prolonged, TdP (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1 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 overdose should be treated aggressively.
Elevated liver enzymes and elevated creatine phosphokinase levels have been noted following acute overdose. Hyponatremia secondary to SIADH has been reported following overdosage 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. Patient should be monitored for potential cardiovascular, gastrointestinal or hepatic abnormalities. Also monitor for signs/ symptoms of serotonin syndrome (mental status changes, hyperthermia, myoclonus, autonomic instability, high CK levels) and possible seizures.
There are no specific antidotes for sertraline. Activated charcoal should be considered in treating overdose and is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once 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 occasional 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, hemoperfusion and exchange transfusion are unlikely to be of benefit.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on noradrenaline and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity to adrenergic (α1, α2, β) cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2) or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain noradrenaline receptors as has been observed with other clinically effective antidepressant and antiobsessional 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 in adults. The efficacy of sertraline in the treatment of a major depressive episode in adults was established in controlled trials of six to eight weeks in outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder. Efficacy and safety have been established in studies up to 24 weeks.
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of sertraline in hospitalized depressed patients has not been adequately studied. A study of depressed outpatients who had responded to sertraline during an initial eight week open treatment phase and were then randomized 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 for the treatment of OCD was first demonstrated in a 12-week, multicentre, parallel group study in a pediatric 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 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 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 was well tolerated with an adverse event profile generally similar to that observed in the acute 12-week pediatric 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 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 behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized 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 in adults. The efficacy and safety of sertraline 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 favor of sertraline 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 in the sertraline group and 5.4/week in the placebo group. At week 10 (last observation carried forward analysis), the mean changes from baseline were 4.9/week and 2.5/week for the sertraline and placebo groups, respectively. The proportion of patients having no panic attacks at the final evaluation was 69% in the sertraline 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 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) in 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 recognizes 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 (50-200 mg/day) to placebo, in which sertraline was initiated at 25 mg/day for the first week. Study outcome was assessed by the Liebowitz Social Anxiety Scale (LSAS), and by 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 (50-200 mg/day) to placebo. Study outcome was assessed by the Duke Brief Social Phobia Scale (BSPS), the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), and 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 randomized 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 randomized to placebo substitution.
Premenstrual dysphoric disorder (PMDD) in 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. In one of the studies patients met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as PMDD in DSM-IV. In another study patients 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 were observed to occur regularly during the luteal phase and remit within a few days following onset of menses. The disturbance markedly interfered 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 one of the clinical studies, 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 another study, 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 or intermittently was significantly more effective than placebo on all primary efficacy parameters as shown in Table 1.

5.2 Pharmacokinetic Properties

Absorption.

Following oral once daily dosing over the range of 50 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 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose of sertraline, with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution.
The effects of food on the bioavailability of sertraline were studied in subjects administered a single dose with and without food. AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration decreased from 8 hours postdosing to 5.5 hours. These changes were not considered clinically significant.

Distribution.

Animal studies indicate that sertraline has a large apparent volume of distribution.

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.

Excretion.

In a study of radiolabelled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline. Desmethylsertraline exhibits time-related, dose dependent increases in AUC(0-24 hour), Cmax and Cmin with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and day 14.
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).

Special populations.

Age.

Children and adolescent.

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

Adults.

Sertraline plasma clearance were compared in male and female young subjects (18-45 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.
Liver disease. Sertraline is extensively metabolized 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. 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 disease. In patients with mild to moderate renal impairment (creatinine clearance 30-60 mL/min) or moderate to severe renal impairment (creatinine clearance 10-29 mL/min) 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 10-40 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

Microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium starch glycollate type A, hyprolose, magnesium stearate, and Opadry complete film coating system OY-S-58910 white (PI 11503).

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

The tablets are supplied in blister strip (PVC/PVDC/Al) pack containing 30 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Setrona tablets contain (1S, 4S)-4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-N- methyl-1-naphthalenamine hydrochloride. The empirical formula of sertraline hydrochloride is C17H17NCl2.HCl and its molecular weight is 342.7.

Chemical structure.


CAS number.

79559-97-0.
Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol and sparingly soluble in ethanol.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes