Consumer medicine information

Dothep [8757]

Dosulepin (dothiepin) hydrochloride

BRAND INFORMATION

Brand name

Dothep

Active ingredient

Dosulepin (dothiepin) hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dothep [8757].

What is in this leaflet

This leaflet answers some common questions about Dothep.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Dothep against the benefits expected for you.

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

Please read this leaflet carefully and keep it with your medicine. You may need to read it again.

What Dothep is used for

Dothep is used to treat depression.

Dothep 25 mg capsules can be used at any stage in the treatment of depression. However, the higher strength Dothep 75 mg tablets are approved only for the maintenance treatment of depression (after your symptoms have improved).

Dothep belongs to a group of medicines called tricyclic antidepressants (TCAs). TCA medicines work by correcting the imbalance of certain chemicals in the brain. These chemicals, called amines, are involved in controlling mood. By correcting this imbalance, TCAs can help relieve the symptoms of depression.

Ask your doctor if you have any questions about why Dothep has been prescribed for you. Your doctor may have prescribed Dothep for another reason.

Dothep is not approved for use in children and adolescents below 18 years of age for the treatment of depression. The safe use and effectiveness of Dothep in treating depression, for this age group, has not been established.

Dothep is available only with a doctor's prescription.

Before you take Dothep

When you must not take it

Do not take Dothep if you are allergic to medicines containing dothiepin (e.g. Prothiaden) or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • discolouration of the skin upon exposure to sunlight

Do not take Dothep if you have:

  • epilepsy
    Dothep may increase the chance of fitting or having convulsions.
  • recently had a heart attack, for example within the past two months
    Dothep may cause irregular and/or rapid heartbeat.
  • liver failure.

Your body may not be able to remove Dothep from your body.

Do not take Dothep if you are taking a medicine called a monoamine oxidase inhibitor (MAOI), or have taken a MAOI within the last 14 days.

Stop taking MAOIs at least 14 days before starting Dothep. Taking Dothep with a MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions.

Ask your doctor or pharmacist if you are not sure if you have been taking a MAOI medicine. MAOIs are medicines used to treat depression and symptoms of Parkinson's disease, such as phenelzine (Nardil), tranylcypromine (Parnate), moclobemide (eg. Aurorix Arima) and selegiline (Eldepryl, Selgene).

Do not take Dothep if the expiry date (EXP.) printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Dothep if the packaging shows signs of tampering or the tablets or capsules do not look quite right.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant. There have been reports of some babies experiencing complications immediately after delivery. Your doctor will discuss the possible risks and benefits of taking Dothep during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed. Like many other medicines, Dothep passes into breast milk.

Your doctor will discuss the risks and benefits of taking Dothep when breastfeeding.

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

  • heart or blood vessel problems
  • liver problems or hepatitis
  • kidney problems or difficulty passing urine (water)
  • glaucoma, a condition characterised by an increased pressure in the eye
  • prostate problems
  • difficulty in passing urine
  • thyroid problems
  • any other mental illness, such as schizophrenia or manic depression (alternating periods of elation/overactivity and depressed mood)
  • family history of suicide or manic depression.

Tell your doctor if you plan to have surgery or if you are undergoing electroshock therapy.

If you have not told your doctor about any of the above, tell them before you start taking Dothep.

Taking other medicines

Do not take Dothep if you are taking a monoamine oxidase inhibitor (MAOI) such as:

  • phenelzine (Nardil) and tranylcypromine (Parnate), moclobemide (eg. Aurorix, Arima), used to treat depression
  • selegiline (Eldepryl, Selgene), used to treat symptoms of Parkinson's disease.

Wait at least 14 days after stopping your MAOI before starting Dothep.

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

Medicines that may be affected by Dothep or may affect how well it works include:

  • sleeping tablets/sedatives, anti-anxiety medicines
  • medicines used to treat epilepsy
  • some medicines used to treat high blood pressure or other heart conditions
  • some medicines used to relieve stomach cramps
  • medicines used to treat Parkinson's disease
  • medicines for travel sickness
  • some cough and cold preparations
  • some medicines for hayfever and allergies
  • certain medicines for weight loss
  • thyroid hormone medicines.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Dothep.

How to take Dothep

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

If you do not understand the instructions on the pack, ask your doctor or pharmacist.

How much to take

The dose varies from person to person.

Your doctor will tell you how much Dothep you need to take each day and when to take it. This depends how well you respond to Dothep and whether or not you are taking any other medicines.

The usual starting dose is 25 mg three times daily for one to two weeks. Your doctor may then increase your dose, up to a maximum of 200 mg per day.

Once your symptoms improve, your doctor will then slowly reduce your dose to the lowest effective dose which maintains relief of symptoms.

Elderly people over 65 years of age and those with liver or kidney problems may need smaller doses.

How to take it

Swallow the tablets or capsules with a glass of water. The 75 mg tablets can be divided in half along the breakline if advised by your doctor or pharmacist.

When to take it

Dothep can be taken as a single dose (e.g. at bedtime) or as divided doses (e.g. three times a day). Your doctor will advise you.

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

How long to take it for

Keep taking Dothep for as long as your doctor recommends. The length of treatment will depend on how quickly your symptoms improve.

Most medicines for depression take time to work, so do not be discouraged if you do not feel better right away. Some of your symptoms may improve in 1 or 2 weeks but it can take up to 4 or 6 weeks to feel the full benefit of Dothep.

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

If you forget to take it

IF YOU TAKE ONE DOSE A DAY (AT BEDTIME)

If you forget to take Dothep before you go to bed and wake up late in the night or early in the morning, do not take the missed dose until you have checked with your doctor. You may have difficulty waking up, or experience drowsiness in the morning and during the day.

IF YOU TAKE MORE THAN ONE DOSE A 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 the missed dose as soon as you remember, and then go back to taking Dothep 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 to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

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

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

Too much Dothep may make you tremble, agitated and/or have difficulty walking. Other signs include fitting or convulsions, unusual muscle movements, difficulty breathing, a very high temperature or irregular heartbeat as well as other serious heart problems.

Keep Dothep out of the reach of children. Children are much more sensitive than adults to medicines such as Dothep. An accidental overdose is especially dangerous in children.

While you are taking Dothep

Things you must do

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes. Occasionally, the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide.

These symptoms may continue or get worse during the first one to two months of treatment until the full antidepressant effect of the medicine becomes apparent. This is more likely to occur in young adults under 25 years of age.

Contact your doctor or a mental health professional right away or go to the nearest hospital for treatment if you or someone you know is showing any of the following warning signs of suicide:

  • worsening of your depression
  • 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 any other unusual changes in behaviour or mood.

All mentions of suicide or violence must be taken seriously.

Families and caregivers of children and adolescents being treated with Dothep need to monitor these patients for the emergence of:

  • anxiety
  • agitation
  • panic attacks
  • insomnia
  • irritability
  • aggressiveness
  • impulsivity
  • restlessness or difficulty sitting still
  • hypomania
  • mania
  • unusual changes in behaviour

This will help your doctor determine the best way to control these feelings.

Tell your doctor if you feel Dothep is not helping your condition.

Keep all of your appointments with your doctor so that your progress can be checked. If you are taking Dothep for a long time, your doctor may ask you to have your eyes tested regularly.

Tell your doctor immediately if you become pregnant while taking Dothep. Do not stop taking your tablets or capsules until you have spoken to your doctor.

Before starting any new medicine, tell your doctor or pharmacist that you are taking Dothep.

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

If you plan to have surgery, including dental surgery, tell your doctor that you are taking Dothep. Your doctor may ask you to temporarily stop taking Dothep a few days before elective surgery.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Things you must not do

Do not drive or operate machinery until you know how Dothep affects you.

Dothep may cause drowsiness, dizziness or light-headedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Do not stop taking Dothep, or lower the dose, without checking with your doctor. If you stop taking Dothep suddenly you may feel sick (nausea), irritable, have a headache, difficulty sleeping or excessive sweating. Other more serious complications such as fits (convulsions) or blood clots may occur.

Your doctor will tell you how to gradually reduce the amount of Dothep you are taking before stopping completely.

Do not use Dothep to treat any other conditions unless your doctor tells you to.

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

Things to be careful of

Be careful when drinking alcohol while taking Dothep. Combining Dothep and alcohol can make you more drowsy, dizzy or lightheaded. Your doctor may suggest you avoid alcohol while being treated for depression.

Be careful getting up from a sitting or lying position. Dizziness, light-headedness or fainting may occur, especially when you get up quickly. Getting up slowly may help.

Be careful if you are older than 65 years of age. Elderly people may become confused when taking Dothep. Families and carers should be aware of this. Special care may be needed.

Tell your doctor or dentist if your mouth continues to feel dry for more than 2 weeks. Dothep may cause dry mouth. This can be relieved by frequent sips of water, sucking sugarless lollies or chewing sugarless gum. However, continuing dryness of the mouth may increase the chance of dental disease, including tooth decay and gum disease.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Dothep. Dothep helps most people with depression, but it may have unwanted side effects in some people.

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

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

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

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

  • dry mouth
  • increased sweating
  • feeling sick (nausea), vomiting
  • constipation
  • blurred vision
  • drowsiness, dizziness, light-headedness
  • tremor
  • increased or decreased sex drive.

The above list includes the common and mild side effects of Dothep.

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

  • fast or irregular heart beat
  • ongoing difficulty with passing urine
  • signs of frequent infections such as fever, chills, sore throat or mouth ulcers
  • unusual bruising or bleeding
  • tingling or numbness of the hands or feet
  • severe pain in the stomach with bloating, gut cramps and vomiting
  • symptoms of liver disease such as yellowing of the eyes or skin (jaundice) and passing dark coloured urine
  • feeling anxious, restless, or confused
  • abnormal ideas, hallucinations
  • sudden mood swings alternating from one of excitement, overactivity and uninhibited behaviour to a depressed mood
  • uncontrollable movements, including trembling and shaking of the hands and fingers, twisting movements of the body, shuffling walk or stiffness of the arms and legs.

The above side effects are serious and may require medical attention.

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

  • chest pain
  • fainting or collapse
  • allergic symptoms such as skin blisters, rash, itching or hives; swelling of the face, mouth, lips, throat or neck; difficulty swallowing or breathing;
  • seizures or fits.

The above side effects are not common but very serious. You may require urgent medical attention or even hospitalisation if they occur.

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

After taking Dothep

Storage

Keep Dothep where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep Dothep in a cool, dry place where the temperature stays below 30°C for tablets and below 25°C for capsules.

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

Disposal

If your doctor tells you to stop taking Dothep, or your medicine has passed its expiry date, ask your pharmacist what to do with any that is left over.

Product description

What it looks like

Dothep is available in two strengths:

  • Dothep 25 - hard capsule with green and red cap in PVC/PVdC/aluminium blister packs. Each pack contains 50 capsules.
  • Dothep 75 - round, red, scored film-coated tablet marked "DT" over a breakline over "75" on one side and a Greek alpha symbol on the other. Each pack contains 30 tablets.

Ingredients

Dothep 25 capsules

Active ingredient:

  • dothiepin hydrochloride 25 mg.

Ingredients of known effect:

  • lactose (monohydrate and anhydrous)
  • sulfites (present in trace amounts)

Inactive ingredients:

  • povidone
  • sodium starch glycollate
  • purified talc
  • magnesium stearate
  • sodium lauryl sulfate
  • colloidal anhydrous silica
  • gelatin
  • erythrosine CI 45430 (127)
  • iron oxide red CI 77491 (172)
  • titanium dioxide (171)
  • brilliant blue FCF CI 42090 (133)
  • quinoline yellow CI 47005 (104).

Dothep 75 tablets

Active ingredient:

  • dothiepin hydrochloride 75 mg.

Ingredients of known effect:

  • lactose
  • sulfites (present in trace amounts)
  • soya bean products (present in trace amounts)

Inactive ingredients:

  • maize starch
  • povidone
  • sodium starch glycollate
  • purified talc
  • magnesium stearate
  • Opadry Red OY-B-25005 (includes colours brilliant scarlet 4R CI 16255 [124], titanium dioxide [171]).

Dothep tablets and capsules are gluten free.

Manufacturer

Dothep is made in Australia by:

Alphapharm Pty Limited
(ABN 93 002 359 739)
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.mylan.com.au

Australian registration numbers:

Dothep 25 - AUST R 34419

Dothep 75 - AUST R 62910

This leaflet was prepared on
05 July 2019.

Dothep_cmi\Jul19/00

Published by MIMS September 2019

BRAND INFORMATION

Brand name

Dothep

Active ingredient

Dosulepin (dothiepin) hydrochloride

Schedule

S4

 

1 Name of Medicine

Dosulepin (dothiepin) hydrochloride.

6.7 Physicochemical Properties

Chemical name: (E)-3-(dibenzo[b,e]thiepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride (1:1).
Molecular formula: C19H21NS.HCl. Molecular Weight: 331.9.

Chemical structure.


CAS number.

177036-94-1.

2 Qualitative and Quantitative Composition

Each capsule contains 25 mg of dosulepin (dothiepin) hydrochloride as the active ingredient.
Each tablet contains 75 mg of dosulepin (dothiepin) hydrochloride as the active ingredient.
Dothep 25 capsules contain lactose as well as sulfites (present in trace amounts).
Dothep 75 tablets contain lactose as well as sulfites and soya bean products (sulfites and soya bean are present in trace amounts).

3 Pharmaceutical Form

Dothep 25.

25 mg capsule: size 4 hard capsule with green body and red cap.

Dothep 75.

75 mg tablet: red film-coated tablet, normal convex, marked "DT/75" on one side, "α" on reverse.
Dothiepin hydrochloride is a white or faintly yellow, crystalline powder. It is freely soluble in water, in alcohol and in methylene chloride. The partition coefficient (log p) for dothiepin hydrochloride is 4.98 and the pKa is 9.76.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dothiepin is a thioanalogue of amitriptyline. It is generally equivalent to amitriptyline in antireserpine activity but less potent than imipramine.

Site and mode of action.

The mechanism by which dothiepin and all tricyclic antidepressants produce an antidepressant effect is unknown, although the therapeutic site of action is thought to be in the CNS. Dothiepin possesses anticholinergic, antihistamine and central sedative properties. It has been claimed that the cause of depression is associated with a functional abnormality of the biogenic amines, particularly the catecholamines, in the brain. The tricyclics increase the availability of noradrenaline and 5-hydroxytryptamine at central noradrenergic synapses by inhibiting their uptake from nerve endings.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Dothiepin is well absorbed from the small intestine. There are substantial interindividual variations in plasma concentrations after a single dose due to the interaction of exogenous and endogenous processes. The relationship between dose and concentration in plasma can be quite dynamic and unpredictable, leading to extremely large interindividual differences in steady-state drug concentrations in plasma. After a single oral dose of 150 mg, a maximum concentration of 30.4 nanogram/mL to 278.8 nanogram/mL was achieved within 2 to 3 hours.

Distribution.

Dothiepin crosses the blood brain and placental barriers in animals and low concentrations are excreted in breast milk. Studies in the dog and cat have shown maximal concentration after 24 hours in liver, uveal tract of the eye, lung, kidney, pituitary and thyroid in descending order. In dogs, the tissue/plasma ratio for uveal tract tissue was 257:1.

Protein binding.

Approximately 84% of unchanged drug is bound to serum protein.

Metabolism.

Dothiepin is extensively demethylated by first pass metabolism in the liver to its primary active metabolite, desmethyldothiepin (northiaden). In man, 12 basic metabolites have been found in the urine. Paths of metabolism are thought to include N-demethylation, S-oxidation and glucuronic acid conjugation. There is active enterohepatic circulation in animals but this has not been shown in humans.

Excretion.

Dothiepin is excreted in the urine, mainly in the form of its metabolites. Appreciable amounts are also excreted in the faeces. Following a 50 mg labelled dose, 71% is excreted in the urine and faeces within 4 days, with 56% being excreted by the renal route.

Half-life.

The elimination half-life is biphasic; the first phase is 15 to 18 hours. Mean whole body elimination half-life is 51 hours.

5.3 Preclinical Safety Data

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of major depression.
The 75 mg tablet is indicated only for the maintenance treatment of major depression (see Section 4.4. Special Warnings and Precautions for Use).

4.3 Contraindications

Epilepsy; seizure thresholds may be lowered by the drug.
Tricyclic antidepressants should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors since cerebral excitation followed by coma and dangerous hyperthermia may occur following administration of this combination.
Acute recovery phase following myocardial infarction; tricyclic antidepressants may produce conduction defects and arrhythmias.
Hepatic failure (see Section 4.2 Dose and Method of Administration, With impaired liver or renal function).
Hypersensitivity to dothiepin.

4.4 Special Warnings and Precautions for Use

Due to its toxicity in overdose, Dothep should only be used in patients intolerant of or unresponsive to alternative treatment options (see Section 4.9 Overdose).

Toxicity in overdose.

Dothiepin is associated with high mortality in overdose. There is a low margin of safety between the (maximum) therapeutic dose and potentially fatal doses. Onset of toxicity occurs within 4-6 hours.
A limited number of tablets should be prescribed to reduce the risk from overdose for all patients and especially for patients at risk of suicide.
A maximum prescription equivalent to two weeks supply of 75 mg/day should be considered in patients with increased risk factors for suicide at initiation of treatment, during any dosage adjustment and until improvement occurs.
Avoid concomitant medications that may increase the risk of toxicity associated with dothiepin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients should be advised to store the medicine securely, out of sight and reach of children.
In cases of overdose, patients should seek immediate medical attention (see Section 4.9 Overdose).

Clinical worsening and suicide risk associated with psychiatric disorders.

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.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviour (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 who are experiencing emergent suicidality symptoms that may be precursors to worsening depression or suicidality, if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analyses of short-term placebo controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behaviour (suicidality) in children, adolescents and young adults (aged 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term 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 with antidepressants compared to placebo in adults aged 65 and older.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the 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 given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adults and paediatric patients 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 patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted 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. Such monitoring should include daily observation by families and caregivers.
Prescriptions for Dothep should be written for the smallest quantity of tablets or capsules consistent with good patient management, in order to reduce the risk of overdose.
Latent schizophrenia may be activated by dothiepin.
Psychotic manifestations, including mania and paranoid delusions, with or without associated hostility, may be exaggerated during treatment with tricyclic antidepressants.

Screening patients for bipolar disorder.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) 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. Whether any of the symptoms described above represent such a conversion is unknown. However, 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.

Dothep 75 mg tablets.

The 75 mg tablets are indicated only for the maintenance treatment of major depression. The 75 mg tablets should not be used in acutely ill patients where there is a risk of suicide. There is an increased risk of completed suicide by overdose with the 75 mg tablet compared with the 25 mg capsule.

Electroconvulsive therapy (ECT).

The hazards of ECT may be increased as dothiepin lowers the convulsive threshold.

Elective surgery.

Dothiepin should be withdrawn prior to surgery as anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension.

Severe depression.

Patients with severe depression should be closely supervised during early therapy, as the possibility of suicide using dothiepin exists. These patients should not receive large quantities of the drug.

Manic depressive psychosis.

A shift towards the manic phase may be provoked by dothiepin.

Monoamine oxidase inhibitors.

Dothiepin should not be prescribed concurrently or within 14 days of treatment with MAOIs (see Section 4.3 Contraindications). After withdrawal of MAOIs, therapy should be initiated at low doses and gradually increased to the normal range.

Cardiovascular disorders.

Dothep may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse), especially in the elderly. Caution should be exercised in using Dothep in the elderly and in patients with suspected cardiovascular disease (see Section 4.3 Contraindications).

Hyperthyroidism or patients being treated with thyroid hormone.

These patients should be closely supervised as dothiepin may provoke cardiac arrhythmias or conduction defects.

Glaucoma, prostatic hypertrophy, urinary retention and concurrent anticholinergic therapy.

Dothiepin has an anticholinergic action and may aggravate glaucoma and urinary retention, and potentiate anticholinergics.

Concurrent therapy with sympathomimetic drugs.

Tricyclic antidepressants have been reported to produce possibly dangerous potentiation of the effects of sympathomimetic drugs.

Use in renal or hepatic impairment.

Use with care as toxic blood levels may develop (see Section 4.2 Dose and Method of Administration, With impaired liver or renal function).

Impairment of motor co-ordination.

Alertness is decreased and, hence, ability to drive or operate machinery may be impaired.

Ophthalmological examination.

Dothiepin or its metabolites may accumulate in the pigmented area of the eye. Therefore, the eyes should be examined regularly for visual acuity and colour fields checked during prolonged therapy.

Use in the elderly.

Dothiepin should be used with care as confusional states may occur.

Dependence and withdrawal.

The potential for dependency is unknown.
Abrupt withdrawal may produce headache, nausea, convulsions, insomnia, irritability, excessive perspiration and the possibility of thrombotic episodes. It is recommended that antidepressants be withdrawn gradually. Symptoms similar to insomnia, irritability and excessive perspiration have also been reported in neonates whose mothers received tricyclic antidepressants during the third trimester.

Paediatric use.

The safety and efficacy of Dothep for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Dothep should not be used in this age group for the treatment of depression or other psychiatric disorders.

Effects on laboratory tests.

No interference reported with laboratory tests.

Advice to be given to patients.

The main dose should be taken at night as this drug may produce drowsiness.
Do not discontinue the drug abruptly.
Warn patient about OTC preparations containing sympathomimetic drugs, particularly patent cold remedies, cough syrups, weight reducing tablets and sedatives/antihistamines.

Site and mode of action.

The mechanism by which dothiepin and all tricyclic antidepressants produce an antidepressant effect is unknown, although the therapeutic site of action is thought to be in the CNS. Dothiepin possesses anticholinergic, antihistamine and central sedative properties. It has been claimed that the cause of depression is associated with a functional abnormality of the biogenic amines, particularly the catecholamines, in the brain. The tricyclics increase the availability of noradrenaline and 5-hydroxytryptamine at central noradrenergic synapses by inhibiting their uptake from nerve endings.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alcohol.

Dothiepin may potentiate the effect of alcohol. One death has been associated with this combination.

Other drugs.

Barbiturates.

Potentiation of the sedative effect is possible.

Tranquillisers and CNS depressants.

Potentiation of the sedative effect is possible.

Guanethidine and other adrenergic neurone blocking drugs.

Dothiepin may block the antihypertensive effect.

Sympathomimetics.

Dothiepin may dangerously potentiate the sympathomimetic effect.

Monoamine oxidase inhibitors.

A potentially lethal interaction can occur between tricyclic antidepressants and MAOIs (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Anticholinergics.

Anticholinergic effects may be potentiated.

Antihistamines.

May be potentiated.

Diuretics.

There is an increased risk of postural hypotension when tricyclic antidepressants are given with diuretics.

Antiepileptics.

Tricyclic antidepressants may also antagonize the anticonvulsant effect of antiepileptics (convulsive threshold decreased).

Food.

No information available.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No information available.
(Category C)
Withdrawal symptoms in newborn infants have been reported with prolonged maternal use of this class of drugs. Tricyclic antidepressants have not been shown to be associated with an increased incidence of birth defects. However, there is evidence of interference with central monoamine neurotransmission in rats. Care should be taken that there are sound indications for the use of these antidepressants during pregnancy. (See Section 4.4. Special Warnings and Precautions for Use, Dependence and withdrawal.)
Small amounts of dothiepin are excreted in breast milk. The possible effect on the child must be carefully considered if it is necessary to give the drug to breastfeeding mothers.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects occur in about 30% of patients. In 10% of patients, the effects may be severe enough to discontinue the drug.

More common effects.

Central nervous system, neuromuscular.

Drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns.

Anticholinergic.

Dry mouth, sweating, urinary retention.

Cardiovascular.

Hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects.

Endocrine.

Increased or decreased libido in either sex.

Gastrointestinal.

Nausea, vomiting, constipation.

Ocular.

Disturbance of accommodation (blurred vision).
Several of the following reactions have not yet been reported with dothiepin, but should be borne in mind because of its similarity to other antidepressants.

Less common effects.

Central nervous system, neuromuscular.

Disturbed concentration, delusions, hallucinations, anxiety, fatigue, headaches, restlessness, excitement, insomnia, hypomania, nightmares, peripheral neuropathy, ataxia, incoordination, seizures.

Anticholinergic.

Paralytic ileus.

Cardiovascular.

Hypertension, heart block, myocardial infarction, stroke.

Endocrine.

Males: gynaecomastia, testicular swelling, impotence; females: galactorrhoea.

Gastrointestinal.

Epigastric distress, abdominal cramps, parotid swellings, diarrhoea, stomatitis, black tongue, peculiar taste sensations.

Haematological.

Bone marrow depression including thrombocytopenia, eosinophilia, agranulocytosis.

Hepatic.

Cholestatic jaundice, altered liver function, hepatitis.

Allergic.

Skin rash, urticaria, photosensitisation, skin blisters, angioneurotic oedema.

Other.

Weight loss, urinary frequency, mydriasis. Increased appetite and weight gain have been reported but it is not known whether they are due to relief of depression or to the drug.
Adverse events have been reported during postapproval use of dothiepin. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to dothiepin exposure. See Table 1.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The main dose should be taken at night as it may produce drowsiness.

Note.

Dosage should be reduced to the smallest amount necessary to maintain relief of the symptoms of depression, once a satisfactory response has been obtained. Plasma levels will reach a new steady state 10 to 14 days after each up or down adjustment.

Adults.

Begin with 25 mg three times daily for one to two weeks. The daily dosage should be increased by 25 to 50 mg at intervals of one to two weeks if the response is inadequate.
The daily dose should not exceed 200 mg.
Up to 150 mg of the daily dose may be given as a single night time dose once an effective dose has been established.

Use in children and adolescents (< 18 years).

The safety and efficacy of Dothep for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Dothep should not be used in this age group for the treatment of depression.

Use in the elderly.

Use adult dosage with care, particularly in patients with impaired liver or renal function (see below) or cardiovascular disorders (see Section 4.4. Special Warnings and Precautions for Use).

With impaired liver or renal function.

Dothiepin is contraindicated in hepatic failure. Reduce the dosage and use with caution in patients with impaired liver or renal function, since toxic blood levels may develop. Dothiepin is extensively metabolised by the liver, is thought to undergo enterohepatic circulation and its metabolites are excreted in the urine.

4.7 Effects on Ability to Drive and Use Machines

Because alertness is decreased whilst using Dothep, the ability to drive or operate machinery may be impaired.

4.9 Overdose

The onset of toxicity occurs within 4-6 hours.
Patients ingesting > 5 mg/kg should seek immediate medical attention.
All children ingesting Dothep should be assessed by a physician.

Symptoms.

The toxicity of tricyclic antidepressants is attributed mainly to their anticholinergic effects which produce dry mouth, blurred vision, mydriasis, paralytic ileus and urinary retention.
Common CNS symptoms are agitation, delirium, hyperpyrexia, convulsions, ataxia, respiratory depression, coma, unconsciousness, muscle twitching, hyperreflexia, hypothermia, visual hallucinations and respiratory or metabolic alkalosis.
Cardiovascular symptoms include cyanosis, shock, hypotension, sinus tachycardia and cardiac arrhythmias, which are often the major cause of death.
Individual response is variable, e.g. death has resulted from overdosage with 0.75 to 1 g of dothiepin (30 to 40 capsules), but recovery has occurred after as much as 2 g (80 capsules).
In children, serious overdosage with tricyclic antidepressants occurs more easily with a relatively small total dosage because the dose per weight ratio is higher.

Management.

A clear airway and adequate ventilation should be ensured. Hypoxia and acid-based imbalances should be corrected by assisted ventilation and intravenous sodium bicarbonate as appropriate.
Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses.
The use of activated charcoal should be considered as a preferred initial means of reducing absorption in patients presenting within 2 hours of ingestion.
Blood pressure, pulse and cardiac rhythm should be monitored for at least 6 hours after ingestion.
Arrhythmias are best treated by correcting hypoxia and acid-base disturbances. Specialist poisons advice should be sought before using any antiarrhythmic agents as these may exacerbate the arrhythmia.
In cases of cardiac arrest, persist with prolonged CPR (for at least 1 hour).
Convulsions should be controlled with intravenous diazepam or lorazepam.
Due to their respiratory depressant effects, barbiturates should be avoided, especially if the patient is thought to have been on MAOIs or if barbiturates have been taken in association with the antidepressant in the overdose.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dothep 25 capsules contain: povidone, sodium starch glycollate, lactose monohydrate, purified talc, magnesium stearate, purified water, colloidal anhydrous silica, iron oxide red, sodium lauryl sulfate, gelatin, quinoline yellow, titanium dioxide, brilliant blue FCF and erythrosine.
Dothep 75 tablets contain: povidone, maize starch, sodium starch glycollate, purified talc, magnesium stearate, isopropyl alcohol, purified water and Opadry Red OY-B- 25005.

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

Dothep 25.

Store below 25°C.

Dothep 75.

Store below 30°C.

6.5 Nature and Contents of Container

Dothep 25.

25 mg capsule: PVC/PVdc/Aluminium blister pack of 50's.

Dothep 75.

75 mg tablet: PVC/PVdc/Aluminium blister pack of 30's.

6.6 Special Precautions for Disposal

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

Summary Table of Changes