Consumer medicine information

Sertraline-DRLA Tablets

Sertraline

BRAND INFORMATION

Brand name

Sertraline-DRLA Tablets

Active ingredient

Sertraline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Sertraline-DRLA tablets.

It does not contain all the available information.

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

All medicines have risks and benefits.

Your doctor has weighed the risks of you taking Sertraline-DRLA tablets against the benefits it is expect to have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What Sertraline-DRA tablets are used for

Sertraline-DRLA tablets are used to treat depression and conditions called obsessive compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder) and premenstrual dysphoric disorder (PMDD).

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

Sertraline belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). They are thought to work by blocking the uptake of a chemical called serotonin into nerve cells in the brain.

Serotonin and other chemicals called amines are involved in controlling mood.

Your doctor, however, may prescribe Sertraline-DRA for another purpose.

Ask your doctor if you have any questions about why Sertraline-DRLA tablets have been prescribed for you.

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

There is no evidence that sertraline is addictive.

Before you take Sertraline-DRLA tablets

When you must not take it

Do not take Sertraline-DRLA tablets if:

  1. you have ever had an allergic reaction to sertraline or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction to Sertraline-DRLA tablets may include a skin rash, itchiness, difficulty breathing and swelling of the face.
  2. you have epilepsy not properly controlled by medication.
  3. you are taking another medicine for depression called a monoamine oxidase inhibitor (MAOI) or have been taking it within the last 14 days.
    Taking Sertraline-DRLA with a MAOI (eg Aurorix, Eldepryl, Nardil, Parnate) may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and convulsions (fits).
  4. you are taking phentermine (used to help weight loss), tryptophan, tramadol or medicines used to treat migraines, eg sumatriptan (Imigran).
    These medicines can cause an exaggerated response to Sertraline-DRLA.
  5. you are taking pimozide (used to treat disturbances in thinking, feeling and behaviour).

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

Do not give Sertraline-DRLA tablets to children unless the doctor has prescribed it for the treatment of OCD. Sertraline is not suitable for children under 6 years of age.

If you are not sure whether you should be taking Sertraline-DRLA tablets, talk to your doctor.

Do not take Sertraline-DRLA tablets if:

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

If this is the case, take the tablets to your pharmacist.

Before you start to take it

Tell your doctor if:

You are allergic to any foods, dyes, preservatives or any other medicines.

You have any health problems, including:

  • Any other mental illness
  • Epilepsy or seizures
  • Liver or kidney problems
  • A tendency to bleed more than normal

You are pregnant or intend to become pregnant.

The effects of sertraline on the developing baby are not yet known.

There have been reports that babies exposed to sertraline and other antidepressants during the second or third trimester of pregnancy may develop complications after birth.

You are breastfeeding or wish to breastfeed.

Sertraline passes into breast milk and may affect your baby.

Your doctor will discuss the risks and benefits of using sertraline when pregnant or breastfeeding.

Taking other medicines

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

Some medicines should not be taken with Sertraline-DRLA tablets.

These include:

  • Other medicines for the treatment of depression called monoamine oxidase inhibitors (MAOIs).
    Taking Sertraline-DRLA tablets with, or within 14 days of stopping a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and convulsions.
  • Medicines that can increase the effects of sertraline such as tramadol, tryptophan, or phentermine (weight-reducing medicines) and medicines used to treat migraine, eg sumatriptan.
  • Pimozide (used to treat disturbances in thinking, feeling and behaviour).

You may respond differently to Sertraline-DRLA tablets, or to some other medicines, if you take them together. These include (not all brands given):

  • Other medicines for depression, panic disorder, social anxiety disorder or obsessive illnesses (eg Prothiaden, Pertofran, Prozac, Aropax, Luvox, Cipramil, Efexor)
  • Other medicines for PMDD (eg Prozac and Lovan)
  • St John’s wort, a herbal remedy used to treat mood disorders
  • Clozapine (eg Clozaril) a medicine used to treat schizophrenia
  • Medicines for irregular heart beat (eg Tambocor)
  • Warfarin (eg Marevan, Coumadin) or other medicines that stop the blood from clotting
  • Medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis (eg aspirin or NSAIDs such as ibuprofen or diclofenac)
  • Lithium (eg Lithicarb), a medicine used to treat mood swings
  • Phenytoin (eg Dilantin), a medicine used to treat epilepsy
  • Sumatriptan (eg Imigran), a medicine used to treat migraine
  • Diazepam or other medicines that act on the brain or nervous system (eg Serepax, Valium)
  • Cimetidine (eg Tagamet), a medicine used to treat reflux and ulcers
  • Tolbutamide (eg Rastinon), a medicine used to treat diabetes
  • Methadone, a medicine used to treat drug addiction

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Sertraline-DRLA tablets.

If you have not told your doctor or pharmacist about these things, tell them before you start taking Sertraline-DRLA tablets.

How to take Sertraline-DRLA tablets

Take Sertraline-DRLA tablets exactly as your doctor has prescribed.

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

How much to take

For DEPRESSION IN ADULTS
the usual starting dose for Sertraline-DRLA is one 50 mg tablet each day. The dose can be increased gradually up to 200 mg a day if necessary.

For OBSESSIVE COMPULSIVE DISORDER IN CHILDREN (6-12 YEARS)
the usual starting dose for Sertraline-DRLA 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 Sertraline-DRLA is one 50 mg each day.

For PANIC DISORDER IN ADULTS
the usual starting dose for Sertraline-DRLA is 25 mg per day, increasing to 50 mg/day after one week.

For SOCIAL PHOBIA (SOCIAL ANXIETY DISORDER) IN ADULTS
the usual starting dose for Sertraline-DRLA is 25 mg/day, increasing to 50 mg/day after one week.

The maximum recommended dose of Sertraline-DRLA tablets for the conditions listed above is 200 mg per day.

For PREMENSTRUAL DYSPHORIC DISORDER
the usual starting dose for Sertraline-DRLA tablets is one 50 mg tablet each day, either throughout the menstrual cycle (to a maximum of 150 mg daily) or for the last 14 days before the start of menses (to a maximum of 100 mg daily).

However, depending on your condition and how you react to the medicine, your doctor may ask you to take some other dose.

How to take it

Swallow the tablet(s) with a glass of water.

Try to take your tablet(s) at the same time each day, either morning or evening.

Sertraline-DRLA tablets can be taken with or without food.

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 Sertraline-DRLA tablets.

Even when you feel well, you may need to take Sertraline-DRLA tablets for several months or longer. Continue taking Sertraline-DRLA tablets 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 Sertraline-DRLA tablets, or change the dose, without first checking with your doctor.

If you forget to take it

Do not take an extra dose. Wait until the next day and take your normal dose then.

Do not try to make up for the dose you missed by taking more than one dose at a time.

If you take too much (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency (Casualty) at your nearest hospital if you think that you or anyone else may have taken too much Sertraline-DRLA tablets, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

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

While you are taking Sertraline-DRLA tablets

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking Sertraline-DRLA tablets.

Tell your doctor and pharmacist that you are taking Sertraline-DRLA tablets if you are about to be started on any new medicine.

Tell your doctor if you become pregnant while taking Sertraline-DRLA tablets.

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

Tell your doctor immediately if you have any suicidal thought 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 Sertraline-DRLA or when the doctor changes your dose. These symptoms should be controlled when the full effect of Sertraline-DRLA takes place.

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

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

Signs and symptoms of suicide include:

  • Thoughts or talk of death or suicide
  • Thoughts or talk of self-harm or harm to others
  • Any recent attempts of 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 Sertraline-DRLA, contact your doctor or a mental health professional right away.

Things you must not do

Do not stop taking Sertraline-DRLA tablets, or change the dose, without first checking with your doctor.

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

Suddenly stopping Sertraline-DRLA tablets may cause dizziness, lightheadedness, numbness, unusual tingling feelings or shakiness.

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

Do not use Sertraline-DRLA tablets to treat any other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how Sertraline-DRLA tablets affect you.

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

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

You should wait at least 14 days after stopping Sertraline-DRLA tablets before starting medicines for depression or obsessive illnesses from the MAOI group, such as Aurorix, Elderpryl, Nardil, Parnate.

All of the above precautions are important even after you have stopped taking Sertraline-DRLA tablets.

The effects of Sertraline-DRLA tablets may last for some days after you have stopped taking it.

Side Effects

Check with your doctor as soon as possible if you have any problems while taking Sertraline-DRLA tablets, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, Sertraline-DRLA tablets can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

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

  • Fits or seizures
  • Signs of allergy such as rash or hives, swelling of the face, lips or tongue, wheezing or difficulty breathing
  • Symptoms of sudden fever with sweating, fast heart beat and muscle stiffness, which may lead to loss of consciousness
  • Palpitations or chest pain
  • Abnormal bleeding
  • Difficulty in passing urine or blood in the urine
  • Severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • Fever, sore throat, swollen glands, mouth ulcers, unusual bleeding or bruising under the skin
  • 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 Sertraline-DRLA tablets.

These symptoms are usually rare but may be serious and need urgent medical attention.

Tell your doctor if you experience:

  • Headaches, dizziness, shakiness, muscle stiffness or weakness, decrease or loss of touch or other senses
  • Dry mouth, increased sweating, feeling sick, diarrhoea, indigestion, vomiting, constipation, stomach pain
  • Tiredness, hot flushes, fever, feeling unwell
  • Weight increase or loss
  • Sleeping difficulties, sleepiness
  • Sexual problems
  • Agitation, nervousness, anxiety, frightening dreams, yawning, abnormal thinking, teeth grinding, loss of appetite, impaired concentration
  • Vision disturbances
  • Menstrual irregularities
  • Loss of control of your bladder
  • Unusually overactive
  • Shaking or tremors
  • Unusual hair loss or thinning
  • Swelling of hands, ankles or feet
  • Tingling or numbness of the hands or feet
  • Breast enlargement in men or the unusual secretion of breast milk in men or women
  • Increased sensitivity of the skin to sun
  • Ringing or other persistent noise in the ears

These side effects are usually mild.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you do not understand anything in this list.

After taking Sertraline-DRLA tablets

Storage

Keep your tablets where young children cannot reach them.

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

Keep Sertraline-DRLA tablets in a cool, dry place where the temperature stays below 25°C. Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

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

Disposal

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

Product Description

What it looks like

Sertraline-DRLA tablets come in two strengths:

  • Sertraline-DRLA 50 mg tablets - white to off white capsule shaped, biconvex film coated tablets embossed with ‘50’ on one side and ‘SET’ on the other side with a bisect line separating S from ET.
  • Sertraline-DRLA 100 mg tablets - white to off white capsule shaped, biconvex film coated tablets embossed with ‘100’ on one side and ‘SET’ on the other side with a bisect line separating S from ET.

A box contains 10, 14, 28 or 30 tablets.

Ingredients

Active ingredients:

  • Sertraline-DRLA 50 mg tablets contain 50 mg of sertraline (as sertraline hydrochloride) per tablet
  • Sertraline-DRLA 100 mg tablets contain 100 mg of sertraline (as sertraline hydrochloride) per tablet

Other ingredients:

  • Microcrystalline cellulose,
  • calcium hydrogen phosphate,
  • colloidal anhydrous silica,
  • sodium starch glycollate,
  • hydroxypropylcellulose,
  • magnesium stearate,
  • polysorbate 80,
  • Opadry white OY58900.

Sponsor

Sertraline-DRLA tablets are supplied in Australia by:
Dr Reddy’s Laboratories (Australia) Pty Ltd
Level 1, 181 Bay Street
Brighton
VIC 3186

This leaflet was prepared in January 2011.

Australian Registration Numbers:
Sertraline-DRLA Tablets 50 mg AUST R 160766
Sertraline DRLA Tablets 100 mg AUST R 160777

BRAND INFORMATION

Brand name

Sertraline-DRLA Tablets

Active ingredient

Sertraline

Schedule

S4

 

Name of the medicine

Sertraline (as hydrochloride).

Excipients.

Microcrystalline cellulose, calcium hydrogen phosphate, colloidal anhydrous silica, sodium starch glycollate, hydroxypropylcelluloase, magnesium stearate, Opadry complete film coating system OY-58900 White and polysorbate 80.

Description

Chemical name: (1S,4S)-4- (3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl- 1- naphthalenamine hydrochloride. Molecular formula: C17H17NCl2.HCl. Molecular weight: 342.7. 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.
Sertraline-DRLA is an antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.
Sertraline-DRLA tablets are supplied as film coated tablets containing sertraline hydrochloride equivalent to 50 and 100 mg sertraline.
Sertraline-DRLA tablets also contain the following excipients: Microcrystalline cellulose, calcium hydrogen phosphate, colloidal anhydrous silica, sodium starch glycollate, hydroxypropylcelluloase, magnesium stearate, Opadry complete film coating system OY-58900 White and polysorbate 80.

Pharmacology

Pharmacodynamics.

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 hypothesised to be associated with various anticholinergic, sedative and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain noradrenaline receptors as has been observed with other clinically effective antidepressant and antiobsessional drugs. Sertraline does not inhibit monoamine oxidase.

Pharmacokinetics.

Systemic bioavailability.

In man, 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 post-dosing to 5.5 hours. These changes were not considered clinically significant. Animal studies indicate that sertraline has a large apparent volume of distribution.

Metabolism.

Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation and glucuronide conjugation. In a study of radiolabelled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. 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 faeces, 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.

Protein binding.

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 Precautions).

Age.

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 metabolised by the liver. A multiple dose pharmacokinetic study in subjects with mild, stable cirrhosis administered sertraline 50 mg/day for 21 days demonstrated a prolonged elimination half-life and approximately a three-fold greater AUC and Cmax for sertraline and a two-fold greater AUC and Cmax for the metabolite in comparison to normal subjects. Patients with moderate and severe hepatic impairment have not been studied. If Sertraline-DRLA tablets are administered to patients with hepatic impairment a lower or less frequent dose should be considered (see Precautions and Dosage and 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.

Clinical Trials

Major depression.

Adults.

The efficacy of sertraline in the treatment of a major depressive episode in adults was established in controlled trials of 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 hospitalised 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 randomised to continuation on sertraline or placebo demonstrated a significantly lower relapse rate over the next eight weeks for patients taking sertraline compared to those on placebo. Therefore, the physician who elects to use sertraline for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Premenstrual dysphoric disorder (PMDD).

Adults.

The effectiveness of sertraline for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over three menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as PMDD in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD.
The DSM-IV criteria include markedly depressed mood, anxiety or tension, affective lability and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses. The disturbance markedly interferes with work or school or with usual social activities and relationships by prospective daily ratings during at least two consecutive symptomatic cycles.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomised patients, sertraline treatment was initiated at
50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the range of 50-150 mg/day on the basis of clinical response and tolerance.
In Study 2, involving n=281 randomised patients, sertraline treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle, on the basis of clinical response and tolerance. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle.
Sertraline administered continuously (Study 1) or intermittently (Study 2) was significantly more effective than placebo on all primary efficacy parameters as shown in Table 1.

Indications

Adults.

Sertraline tablets are indicated for the treatment of major depression.
Sertraline tablets are indicated for the treatment of premenstrual dysphoric disorder (PMDD) as defined by DSM-IV criteria.

Contraindications

Sertraline tablets are contraindicated in patients with known hypersensitivity to sertraline.
Concomitant use in patients taking pimozide is contraindicated (see Interactions with Other Medicines).

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. Cases of serious reactions, such as potentially life-threatening serotonin syndrome (characterised by neuromuscular excitation, altered mental status and autonomic dysfunction) have been reported in patients receiving an SSRI in combination with MAOIs and RIMA, and in patients who have recently discontinued an SSRI and have been started on a MAOI. 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.

Precautions

General.

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. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.
While these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with sertraline. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of 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 Adverse Effects, Use in lactation and Dosage and Administration).

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

The development of potentially life-threatening syndromes liker serotonin syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) has been reported with SSRIs including treatment with sertraline. The risk of SS or NMS with SSRIs is increased with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), antipsychotcis and other dopamine antagonists. SS symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Some signs of SS, including hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes resemble NMS. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see Contraindications).

Other serotonergic drugs.

Coadministration of SSRIs such as sertraline with other drugs which enhance the effects of serotonergic neurotransmission, such as tryptophan, phentermine, tramadol or 5-HT agonists should be undertaken only with caution and avoided whenever possible due to the potential for pharmacodynamic interaction (see Interactions with Other Medicines).

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 Interations with Other Medicines).

Switching from other antidepressants.

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

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 drugs.

Weight loss.

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

Seizures.

Seizures are a potential risk with antidepressant and antiobsessional drugs. Seizures were reported in three out of 4000 patients (0.08%) treated with sertraline in the development program for depression. No seizures were reported in patients treated with sertraline in the development program for panic. Seizures/convulsions were not noted in 6 to 12 year old patients. In all these cases, the relationship to sertraline therapy was uncertain. Since sertraline has not been evaluated in patients with a seizure disorder it should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. Sertraline should be discontinued in any patient who develops seizures.

Clinical worsening and suicide risk.

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients.
Because of the coexistence of PMDD and depression, the same precautions observed when treating patients with depression should be observed when treating patients with PMDD.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), or psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the initial treatment period (generally the first one to two months) in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients treated with placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescents patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
A further pooled analysis of short-term placebo-controlled trials of antidepressant medicines (SSRIs and others) showed the increased risk of suicidal thinking and behaviour (suicidality) during the initial treatment period (generally the first one to two months) extends to young adults (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 treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. 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 sertraline tablets 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.

Haemorrhage.

Bleeding abnormalities of the skin and mucous membranes have been reported with the use of SSRIs (including purpura, haematoma, epistaxis, vaginal bleeding and gastrointestinal bleeding). This risk may be potentiated by concurrent use of 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.

Hyponatraemia.

Hyponatraemia may occur as a result of treatment with SSRIs and SNRIs including sertraline. In many cases, hyponatraemia appears to be the result of a syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatraemia with SSRIs and SNRIs. Also patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of sertraline should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatraemia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest and death.

Use in patients with concomitant illness.

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

Interference with cognitive and motor performance.

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

Use in renal insufficiency.

Sertraline is extensively metabolised. Excretion of unchanged drug in urine is a minor route of elimination. In a study of patients with mild to moderate renal impairment (creatinine clearance 30-60 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 hepatic insufficiency.

Sertraline is extensively metabolised by the liver. A multiple dose pharmacokinetic study in subjects with mild, stable cirrhosis administered sertraline 50 mg/day for 21 days demonstrated a prolonged elimination half-life and approximately a three-fold greater AUC and Cmax for sertraline and a two-fold greater AUC and Cmax for the metabolite in comparison to normal subjects. There were no significant differences in plasma protein binding observed between the two groups. The use of sertraline in patients with hepatic disease should be approached with caution. Patients with moderate and severe hepatic impairment have not been studied. A lower or less frequent dose should be used in patients with hepatic impairment.

Carcinogenicity, mutagenicity.

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.
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.

Impairment of 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).

Use in pregnancy.

(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 hospitalisation, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.

Teratogenic effects.

Reproduction studies have been performed in rats and rabbits at doses up to 80 and 40 mg/kg, respectively, giving rise to plasma drug exposure levels similar to or slightly higher than that achieved following the maximum recommended human dose of 200 mg.
There was no evidence of teratogenicity at any dose level. However, sertraline was associated with delayed ossification in 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 judgement of the physician, the expected benefit justifies the risk to the fetus. The use of SSRIs in the third trimester may result in a withdrawal state in the newborn infant.
Women of childbearing potential should avoid becoming pregnant if taking sertraline.
In a retrospective case-control study the risk for developing persistent pulmonary hypertension in the newborn (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.
There is currently no corroborative evidence regarding the risk of PPHN following exposure to SSRIs in pregnancy.

Labour and delivery.

The effect of sertraline on labour and delivery in humans is unknown.

Use in lactation.

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.

Use in children and adolescents (<18 years).

Safety and effectiveness in paediatric patients have not been established.
Sertraline should not be used in children and adolescents below the age of 18 years for the treatment of major depressive disorder. The efficacy and safety of sertraline has not been satisfactorily established for the treatment of major depressive disorder in this age group.

Use in the elderly.

Several hundred elderly patients have participated in clinical studies with sertraline. The pattern of adverse reactions in the elderly was similar to that in younger patients.

Interactions

Monoamine oxidase inhibitors.

See 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 Contraindications).

Coadministration of drugs with serotonergic action.

Sumatriptan.

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

Serotonergic drugs.

(See Precautions).

St John's Wort.

(See Precautions).

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 subsections Warfarin and Other drug interactions).

Warfarin.

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

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.

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 metabolised 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 metabolised by CYP2D6 with sertraline may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from co-therapy, an increased dose of the co-administered drug may be required. CYP2D6 substrates with a narrow therapeutic index include 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 metabolised by other CYP enzymes (CYP3A3/4, CYP2C9, CYP2C19, CYP1A2).

CYP3A3/4.

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

CYP2C9.

The apparent lack of clinically significant effects of the chronic administration of sertraline at the high dose of 200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin suggests that sertraline is not a clinically important inhibitor of CYP 2C9 (see subsections Other drug interactions, Phenytoin, Warfarin).

CYP2C19.

The apparent lack of clinically significant effects of the chronic administration of sertraline at the high dose of 200 mg daily on plasma concentrations of diazepam suggests that sertraline is not a clinically important inhibitor of CYP 2C19 (see subsection Other drug interactions).

CYP1A2.

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

Other drug interactions.

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

Cimetidine.

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

Atenolol/digoxin.

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

Diazepam.

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

Glibenclamide.

No interaction was observed with glibenclamide.

Clozapine.

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

Microsomal enzyme induction.

Preclinical studies have shown 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.

Adverse Effects

Adverse events are listed within body system and categorised by frequency according to the following definitions: very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%.

Placebo-controlled clinical trial data.

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

Autonomic nervous system.

Common: increased sweating.

Body as a whole.

Very common: fatigue. Common: hot flushes, fever, malaise, weight decrease, weight increase.

Cardiovascular.

Common: palpitations.

Central and peripheral nervous system.

Very common: tremor.
Common: convulsions (including myoclonus), hyperkinesia, hypertonia, teeth grinding, hypoaesthesia.

Gastrointestinal.

Very common: nausea. Common: vomiting, dyspepsia.

Psychiatric.

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

Reproductive.

Common: menstrual irregularities, sexual dysfunction (principally ejaculatory delay in males), vaginal haemorrhage.

Skin.

Common: rash, urticaria.

Urinary.

Common: urinary retention.

Vision.

Common: abnormal vision.
Other adverse events reported (incidence > 10%) and not meeting the above criteria were dry mouth, dizziness, diarrhoea/ loose stools and headache.
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 PMDD was similar to that observed in clinical trials patients with depression.

Adverse effects from clinical trials in paediatric MDD.

In clinical trials in children and adolescents aged 6 to 17 years with major depressive disorder the following adverse events were reported at a frequency of at least 2% of subjects and occurred at a rate of at least twice that of placebo: diarrhoea (9.5% vs 1.6%), agitation (6.3% vs 1.1%), 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% (n=17) with sertraline and 2.1 (n=4) with placebo. The most common reasons for discontinuation due to adverse events, whether or not related to sertraline, were 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 (2/189, 1.1%) and placebo (2/184, 1.1%) with an incidence of suicide attempts in sertraline-treated subjects of 1.1% (2 attempts in 2/189 subjects) versus 1.6% in placebo-treated subjects (3 attempts in 2/184 subjects). Suicidal ideation was reported by 3 sertraline-treated patients (1.6%) and no placebo treated patients. This difference is not statistically significant. Note that sertraline should not be used in children and adolescents to treat MDD (see Precautions).

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.

Autonomic nervous system.

Uncommon: mydriasis.
Rare: priapism.

Body as a whole.

Common: asthenia.
Rare: allergic reaction, allergy, anaphylactoid reaction, face oedema.

Cardiovascular.

Common: chest pain.
Uncommon: hypertension, peripheral oedema, periorbital oedema, syncope, tachycardia.
Rare: atrial arrhythmia, bradycardia, A-V block.

Central and peripheral nervous system.

Common: movement disorders (such as extrapyramidal symptoms and gait abnormalities), paraesthesia.
Uncommon: migraine.
Rare: coma, involuntary muscle contractions. Also reported were signs and symptoms associated with serotonin syndrome: in some cases associated with concomitant use of serotonergic drugs, that included agitation, confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and tachycardia.

Endocrinological.

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

Gastrointestinal.

Common: constipation.
Uncommon: appetite increased.
Rare: pancreatitis.

Hearing/vestibular.

Common: tinnitus.

Haematopoietic.

Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes, including purpura, epistaxis, haematomas, vaginal bleeding and gastrointestinal bleeding.
Rare: altered platelet function, haematuria, leukopenia, thrombocytopenia, increased coagulation times.

Laboratory changes.

Rare: abnormal clinical laboratory results.

Liver/biliary.

Rare: serious liver events (including hepatitis, jaundice and liver failure), asymptomatic elevations in serum transaminases (AST and ALT).

Metabolic/nutritional.

Rare: hyponatraemia, increased serum cholesterol, hyperglycaemia.

Musculoskeletal.

Uncommon: arthralgia, muscle cramps.
Rare: vasculitis.

Psychiatric.

Uncommon: depressive symptoms, euphoria, hallucination.
Rare: aggressive reaction, psychosis, manic reaction, neuroleptic malignant syndrome.

Respiratory.

Rare: bronchospasm.

Skin.

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

Urinary.

Uncommon: urinary incontinence.
Rare: enuresis

Vision.

Uncommon: eye pain.
Rare: visual field defect.

Discontinuation symptoms.

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

Drug abuse and dependence.

In human studies, sertraline has not demonstrated potential for abuse. In a placebo-controlled, double-blind, randomised study of comparative abuse liability of sertraline, alprazolam and d-amphetamine in humans, sertraline did not produce positive subjective effects indicative of abuse potential, such as euphoria or drug liking. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of sertraline misuse or abuse (e.g. development of tolerance, incrementation of dose, drug-seeking behaviour).

Dosage and Administration

Adults (18 years and older).

Major depression.

Sertraline treatment should be initiated with a dose of 50 mg once daily. The usual therapeutic dose for depression is 50 mg/day. While a relationship between dose and antidepressant has not been established, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the antidepressive 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.

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 versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

Maintenance/continuation/extended treatment.

There is evidence to suggest that depressed patients responding during an initial 8 week treatment phase will continue to benefit during an additional 16 weeks of treatment.
While there are insufficient data regarding benefits from treatment beyond 24 weeks, it is generally agreed among expert psychopharmacologists that acute episodes of depression require several months or longer of sustained pharmacological therapy.
Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Discontinuation should be accomplished by a gradual reduction in dosage.

General.

The daily dose for all indications may be increased in 50 mg increments over a period of weeks. However, dose titrations in 50 mg increments will depend on tolerability and clinical response. The interval between dose increments should be at least one week. The maximum recommended dose of sertraline is 200 mg/day.
The onset of therapeutic effect may be seen after a week, however, most responders can be expected to show a good response within 2-4 weeks.
During prolonged maintenance therapy for any indication, dosage should be kept at the lowest effective level.
Sertraline tablets should be administered once daily, either in the morning or evening. Sertraline tablets may be administered with or without food.
As indicated under Precautions, particular care should be taken in patients with hepatic impairment.
Use in the elderly requires no special precautions. The usual adult dosage is recommended.

Overdosage

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. Overdosages of 400 and 500 mg in two children have resulted in serotonin syndrome.

Symptoms.

Symptoms of overdose include serotonin-mediated side effects such as 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 respiration and cutaneous vasodilatation have also been reported. Minor ECG abnormalities, palpitations, prolonged tachycardia and increased pulse rate have also been reported following paediatric overdose. Seizures have been reported rarely.
Serotonin syndrome may result following significant overdose, and onset may be delayed. A death due to asthma exacerbation has been reported following sertraline overdose.
Deaths have been reported involving overdoses of sertraline, primarily in combination with other drugs and/or alcohol. Therefore any overdosage should be treated aggressively.
Elevated liver enzymes and elevated creatinine phosphokinase levels have been noted following acute overdose. Hyponatraemia secondary to SIADH has been reported following overdose and has been severe enough to cause seizures.

Treatment.

In managing overdose, consider the possibility of multiple drug involvement. Treatment should consist of those general measures employed in the management of overdose with any antidepressant. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Establish and maintain an airway, ensure adequate oxygenation and ventilation, if necessary. Patients should be monitored for potential cardiovascular, gastrointestinal or hepatic abnormalities. Also monitor for signs/symptoms of serotonin syndrome (mental status changes, hyperthermia, myoclonus, autonomic instability, high CK levels) and possible seizures.
There are no specific antidotes for sertraline. Activated charcoal should be considered in treating overdose and is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Routine use of a cathartic with activated charcoal is not recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse events such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension.
Induction of emesis is not recommended because of the potential for CNS depression and seizures. Due to the large volume of distribution of sertraline, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.
Contact the Poisons Information centre (131 126) for advice on the management of an overdose.

Presentation

Sertraline-DRLA 50 mg tablets are white to off-white, capsule-shaped, biconvex, film coated tablets, embossed with “50” on one side, and “SET” with a breakline separating the “S” and “ET” on the other side, each containing sertraline 50 mg (as sertraline hydrochloride).
Sertraline-DRLA 100 mg tablets are white to off-white, capsule-shaped, biconvex, film coated tablets, embossed with “100” on one side, and “SET” with a breakline separating the “S” and “ET” on the other side, each containing sertraline 100 mg (as sertraline hydrochloride).
Sertraline-DRLA tablets are packaged in blister packs of 10, 14, 28 or 30 tablets.

Storage

Store below 25°C.

Poison Schedule

S4.