INFORMATION FOR HEALTH PROFESSIONALS
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DOPRESS 25mg capsules: Brown OP body, Scarlet OP cap, size 4, containing a white powder. Each capsule contains 25mg dothiepin hydrochloride.
DOPRESS 75mg tablets: Dark red, film coated biconvex tablets, 11/32" diameter, imprinted DN75 on one side. Each tablet contains 75mg dothiepin hydrochloride.
Dothiepin hydrochloride is a tricyclic antidepressant. It is a thioanalogue of amitriptyline. In antireserpine activity it is generally equivalent to amitriptyline but less potent than imipramine.
Site and Mode of Action
The site of action is thought to be in the CNS, but the mechanism by which this
medicine and all tricyclic antidepressants produce an antidepressant effect is
unknown. Dothiepin possesses anticholinergic, antihistamine and central sedative
properties. It is postulated that the aetiology of depression is associated with
a functional abnormality of one or more of the biogenic amines, particularly the
catecholamines, in the brain. The tricyclics inhibit uptake of noradrenaline and
5-hydroxytryptamine from the nerve endings thus increasing their availability at
central noradrenergic synapses.
Absorption
Well absorbed. Animal studies show dothiepin is absorbed from the small
intestine. After a single 50mg oral dose in one patient, a peak level of 20
nanogram/mL was achieved after 3 hours, falling to 10 nanogram/mL at 6 hours.
There are substantial inter-individual variations in steady state
concentrations. In 10 patients taking 100 mg/day for two weeks, the serum
concentration ranged from 18 to 84 nanogram/mL (mean 41 ± 7 nanogram/mL). After
increasing the dose to 175 mg/day for a further two weeks the concentration
ranged from 43 to 196 nanogram/mL (mean 96 ± 15 nanogram/mL). Steady state
concentrations appear to be reached after 10 to 14 days.
Distribution
Dothiepin is present in low concentrations in breast milk. It crosses the
placental and blood-brain barriers in animals. Animal studies in the dog and cat
show 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
Unchanged drug is about 84% bound to serum protein.
Metabolism
Dothiepin is metabolised in the liver and in man 12 basic metabolites were found
in the urine, the bulk of which are northiaden sulphoxide and dothiepin
sulphoxide. The metabolic pathways are thought to consist of N-demethylation,
S-oxidation and glucuronic acid conjugation. There is active enterohepatic
circulation in animals but this has not been studied in humans.
Excretion
71% of a 50mg labelled dose is excreted in the urine and faeces within 4 days,
56% being by the renal route.
Half-life
The elimination half-life is biphasic; the first phase is 15 hours, the second
56 hours. Mean whole body elimination half-life is 51 hours.
Depression of any aetiology and the anxiety frequently associated with depressive illness.
75mg daily in divided doses or as a single dose at night increasing to 150mg daily. In certain circumstances, e.g. in hospital use, dosages up to 225mg daily have been used.
50-75mg daily initially. Half the normal adult dose may be sufficient to produce a satisfactory clinical response.
Not recommended for use in adolescent patients 13-18 years of age for the treatment of depression, unless under the supervision of a specialist.
The main dose may be taken at night as it may produce drowsiness. Ability to drive or operate machinery may be impaired. Do not abruptly discontinue the medicine. Warn patient about OTC preparations containing sympathomimetic medicines particularly patent cold remedies, cough syrups and weight reducing tablets.
Clinical Worsening and Suicide Risk
Patients of any age with Major Depressive Disorder may experience worsening of
their depression 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. Patients should be
closely monitored, especially at the beginning of therapy or when the dose is
changed, until such improvement occurs.
There has been a long-standing concern that some antidepressants may have a role in the emergence of suicidality in some patients. The possible risk of increased suicidality in patients applies to all classes of antidepressant medicines, as available data are not adequate to exclude this risk for any antidepressant. Therefore, 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. Generally, when stopping an antidepressant, doses should be tapered rather than stopped abruptly.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and paediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and non-psychiatric disorders.
Mania and 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 any antidepressant alone may increase the
likelihood of a mixed/manic episode in patients at risk for bipolar disorder.
Prior to initiating treatment with an antidepressant, patients should be
adequately screened to determine if they are at risk for bipolar disorder. It
should be noted that dothiepin is not approved for use in treating bipolar
depression.
Information for Patients and Families
Patients and their families should be alerted about the need to monitor for the
emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, impulsivity, akathisia, hypomania, mania, worsening of depression,
and suicidal ideation, especially early during antidepressant treatment. Such
symptoms should be reported to the patient's doctor, especially if they are
severe, abrupt in onset, or were not part of the patient's presenting symptoms.
The patient has the right to treatment meeting appropriate ethical and professional standards, and the patient needs to be fully informed with frank discussion of risk/benefit issues relating to the medicines efficacy and safety when used in the treatment regimen proposed.
Electroconvulsive Therapy
The hazards of ECT may be increased as the medicine lowers the convulsive
threshold.
Elective Surgery
The medicine should be withdrawn prior to surgery as anaesthetics given during
tricyclic antidepressant therapy may increase the risk of arrhythmias and
hypotension.
Monoamine Oxidase Inhibitors
Do not prescribe dothiepin concurrently or within 14 days of MAOIs (see
Contraindications). After withdrawal of MAOIs, initiate therapy at low doses and
gradually increase to the normal range.
Cardiovascular Disorders
Use with caution as the medicine may provoke conduction defects and arrhythmias.
Hyperthyroidism or Patients Being Treated with Thyroid Hormone
Closely supervise these patients as the medicine may provoke cardiac arrhythmias
or conduction defects.
Glaucoma, Prostatic Hypertrophy, Urinary Retention and Concurrent
Anticholinergic Therapy
Dothiepin has an anticholinergic action and can exacerbate glaucoma and urinary
retention and potentiate anticholinergics.
Concurrent Therapy with Sympathomimetic Medicines
Tricyclic antidepressants have been reported to produce possible dangerous
potentiation of the effects of sympathomimetic medicines.
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.
Renal or Hepatic Impairment
Use with care as toxic blood levels may develop.
Ophthalmological Examination
Eyes should be examined regularly for visual acuity and colour fields checked
during prolonged therapy since the medicine or its metabolites may accumulate in
the pigmented area of the eye in experimental animals.
Impairment of Motor Co-ordination
Ability to drive or operate machinery may be impaired as alertness is decreased.
Elderly Patients
Use with care as confusional states may occur.
Dependency potential 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 in neonates whose mothers received tricyclic antidepressants during the third trimester also have been reported.
Drug interactions may occur with several medicines (see Interactions).
Category C.
Withdrawal symptoms in newborn infants have been reported with prolonged maternal use of this class of medicines. 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.
Small amounts of dothiepin have been observed in breast milk and its possible effect on the child must be carefully considered if it is necessary to give the medicine to nursing mothers.
These occur in about 30% of patients and may be severe enough to discontinue the medicine in 10% of patients.
Central Nervous System, Neuromuscular
Drowsiness, dizziness, tremor, extrapyramidal symptoms, confusional states,
paraesthesia, alterations to EEG patterns, disorientation.
Anticholinergic
Dry mouth, urinary retention, sweating.
Cardiovascular
Hypotension, postural hypotension, tachycardia, arrhythmias, conduction defects,
palpitations.
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 must be borne in mind because of its similarity to other antidepressants.
Central Nervous System, Neuromuscular:
Disturbed concentration, delusions, hallucinations, excitement, anxiety,
hypomania, restlessness, insomnia, nightmares, peripheral neuropathy, ataxia,
incoordination, seizures, fatigue, headaches.
Anticholinergic
Paralytic ileus.
Cardiovascular
Hypertension, myocardial infarction, heart block, stroke.
Endocrine
Males: Gynaecomastia, testicular swelling, impotence; Females: Galactorrhoea.
Gastrointestinal
Epigastric distress, abdominal cramps, stomatitis, black tongue, peculiar taste
sensations, parotid swellings, diarrhoea.
Haematological
Bone marrow depression including agranulocytosis, thrombocytopenia,
eosinophilia.
Hepatic>
Cholestatic jaundice, hepatitis, altered liver function.
Allergic
Skin rash, urticaria, angioneurotic oedema, photosensitisation, skin blisters.
Other
Weight loss, urinary frequency, mydriasis. Increased appetite and weight gain
have been reported but it is not known whether it is due to relief of depression
or to the drug.
Alcohol
The effect of alcohol may be potentiated by dothiepin. One death has been
associated with this combination.
Barbiturates
The sedative effect may be potentiated.
Tranquillisers and CNS Depressants
The sedative effect may be potentiated.
Guanethidine and Other Adrenergic Neurone Blocking Drugs
The antihypertensive effect may be blocked by dothiepin.
Sympathomimetics
The sympathomimetic effect may be dangerously potentiated by dothiepin.
Monoamine Oxidase Inhibitors
A potentially lethal interaction can occur between MAOIs and tricyclic
antidepressants (see Contraindications and Warnings and Precautions).
Anticholinergics
Dothiepin may potentiate their anticholinergic effects.
Antihistamines
May be potentiated.
No information available.
No interference reported with laboratory tests.
The toxicity of tricyclic antidepressants is attributed mostly to their anticholinergic effects which produce dry mouth, blurred vision, mydriasis, ileus and urinary retention. Common CNS symptoms are agitation, delirium, ataxia, hyperpyrexia, convulsions, respiratory depression and coma. Cardiovascular symptoms include cyanosis, hypotension, shock, tachycardia and cardiac arrhythmias which are often the major cause of death.
Individual response varies, e.g. death has resulted from overdosage with 0.75 to 1g of dothiepin (30 to 40 capsules) but recovery has occurred after as much as 2g (80 capsules).
Serious overdosage with tricyclic antidepressants in children occurs more easily with a relatively small total dosage because the dose per weight ratio is higher.
Gastric lavage. Induce emesis with syrup of ipecacuanha. In the unconscious patient with no cough reflex, the lungs should be protected with a cuffed endotracheal tube. As the medicine is thought to undergo enterohepatic circulation, repeated aspiration may be of benefit by removing the medicine and its metabolites excreted into the gut via the bile. Haemodialysis is not recommended as the absorbed medicine rapidly enters the tissue compartment and is very slowly eliminated (whole body elimination half-life = 51 hours).
General support of the circulation and respiration may be required. ECG monitoring is required. Propranolol and xylocaine may be useful in controlling arrhythmias.
Convulsions may be controlled with diazepam. 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.
Store below 25°C.
Prescription Medicine.
DOPRESS 25mg capsules: Blister packs of 100 capsules.
DOPRESS 75mg tablets: Blister packs of 100 tablets.
Nil.
Mylan New Zealand Limited
PO Box 11-183
Ellerslie
AUCKLAND
Telephone 09-579-2792
2 February 2009