Download Amitriptylin Abcur film-coated tablet ENG SmPC

SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
Amitriptylin Abcur 10 mg film-coated tablets
Amitriptylin Abcur 25 mg film-coated tablets
Amitriptylin Abcur 50 mg film-coated tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Amitriptyline hydrochloride equivalent to amitriptyline 10 mg, 25 mg and 50 mg, respectively.
Excipient with known effect: Lactose monohydrate 96 mg, 79 mg and 158 mg respectively.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Film-coated tablet
10 mg tablet: pale pink, round, biconvex, film-coated tablet without embossing, tablet size 7 x 3.4 mm.
25 mg tablet: pink, round, biconvex, film-coated tablet without embossing, tablet size 7 x 3.4 mm.
50 mg: brown-pink, round, biconvex, film-coated tablet without embossing, tablet size 9 x 4.4 mm.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Major depression with melancholia, deep or prolonged major depressive episodes without melancholy.
Bipolar disorder with major depressive disorder.
4.2
Posology and method of administration
Posology
Initial dosage: 25 mg 3 times daily. The dosage is increased in increments of 25 mg, which are
primarily added as an evening dose, until the effect has been achieved, usually after 2-3 weeks. The
maximum recommended daily dose is 225 mg, occasionally 300 mg for institutionalized patients. If
troublesome drowsiness occur, the dose should be reduced. Cases of depression in the elderly and
patients with cardiovascular disease can initially be given 10 mg 3 times daily, with a gradual increase
up to 100-150 mg/day. Thereafter, the dose can be reduced slowly to the lowest maintenance dose,
usually about 25 mg 2-4 times daily in adults and 10 mg 2-4 times daily in elderly and patients with
cardiovascular disease.
In somatically healthy patients below 65 years, maintenance doses up to 150 mg/day can be given as a
single dose at bedtime.
Since the result of treatment with Amitriptylin Abcur generally cannot be assessed until after 2-4
weeks of treatment, therapy should not be interrupted before that time.
Treatment should be continued for at least 3, usually 6 months after improvement. Withdrawal should
take place gradually and under close monitoring, considering the risk of relapse. If an improvement in
the patient's condition is not observed within one month, a specialist should be consulted.
Discontinuation of treatment: see 4.4 Special warnings and precautions for use.
4.3
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Recent myocardial infarction.
Any degree of heart block or disorders of cardiac rhythm.
Concomitant treatment with MAOIs (monoamine oxidase inhibitors) (see section 4.4).
Untreated glaucoma.
4.4
Special warnings and precautions for use
Epilepsy – patients with epilepsy should always have an adequate antiepileptic medication during
treatment with Amitriptylin Abcur.
Urinary retention and prostate hypertrophy.
Severe orthostatic hypotension.
Hepatic impairment.
Cardiovascular diseases.
Hyperthyroidism or treatment with thyroid preparations.
Concomitant treatment with MAO inhibitors is contraindicated. Treatment with Amitriptylin Abcur
should be initiated no earlier than 14 days after discontinuation of treatment with MAO inhibitor.
Treatment with MAOIs may be initiated 14 days after discontinuation of Amitriptyline Abcur.
Concomitant administration of amitriptyline and MAOIs may cause serotonin syndrome.
Paediatric population
Amitriptylin Abcur should normally not be used in the treatment of children and adolescents under 18
years of age. Clinical studies of depression in this age group did not show any beneficial effect of TCA
medicinal products. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility
(predominantly aggression, oppositional behaviour and anger) were more frequent in clinical studies in
children and adolescents treated with antidepressants compared to those treated with a placebo. In
addition, TCAs are associated with a risk of cardiovascular adverse events in all age groups. In
addition, there is no data regarding long term safety in children and adolescents concerning growth,
maturation and cognitive and behavioural development.
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide. This risk
persists until significant remission occurs. As improvement may not occur during the first few weeks
or more of treatment, patients should be closely monitored until such improvement occurs. It is general
clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal
ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or
suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebocontrolled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an
increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25
years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy
especially in early treatment and following dose changes. Patients (and caregivers of patients) should
be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and
unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Patients receiving long-term treatment should be instructed about the importance of good oral hygiene
due to the fact that dry mouth can lead to an increased risk of dental caries.
In the treatment of depression associated with schizophrenia, treatment should always be combined
with antipsychotic medicines considering that tricyclic antidepressants can worsen the psychotic
symptoms. In patients with manic depressive psychosis a shift towards the manic phase may occur.
In patients treated with tricyclic antidepressants concurrently with other medicines with
anticholinergic activity the anticholinergic effect may be strengthened.
An episode of acute glaucoma, resulting from pupil dilation, can be triggered in persons with a shallow
anterior chamber and narrow chamber angle; however, the condition is uncommon.
Upon discontinuation: After prolonged use, a sudden withdrawal can result in nausea, headache and
malaise. Gradual reduction of the dose has been reported to cause, transient symptoms including
irritability, restlessness, sleep disorder and abnormal dreams within 2 weeks. These symptoms are
withdrawal symptoms, but not necessarily as a sign of addiction. Rare cases of mania or hypomania
have been reported to occur 2-7 days after discontinuation of a chronic treatment with tricyclic
antidepressants.
QT interval prolongation
Cases of QT interval prolongation and arrhythmia have been reported during the postmarketing
period. Caution is advised in patients with significant bradycardia, in patients with uncompensated
heart failure, or in patients concurrently taking QT-prolonging drugs. Electrolyte disturbances
(hypokalaemia, hyperkalaemia, hypomagnesaemia) are known to be conditions increasing the
proarrythmic risk.
Amitriptylin Abcur contains lactose monohydrate. Patients with any of the following rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.
4.5
Interaction with other medicinal products and other forms of interaction
Amitriptyline metabolism is catalyzed by the enzyme CYP2D6. Concomitant use of tricyclic
antidepressants with drugs that can inhibit cytochrome P450 2D6 (for example, quinidine, terbinafine,
cimetidine, most SSRIs, particularly paroxetine, fluoxetine, etc.) may require a reduction in the
amitriptyline dose.
If amitriptyline is combined with other drugs that are metabolized by the enzyme CYP2D6 there may
be an increase in plasma concentrations of amitriptyline or in the other competing drug. Examples of
drugs that are metabolised by CYP2D6 are several antidepressants, fentiazier, class IC
antiarrhythmics, propafenone and flecainide. If a medicinal product is discontinued, after combination
treatment, a dose adjustment may be required for the drug for which treatment continues.
The following combinations with Amitriptylin Abcur should be avoided:
Fluvoxamine:
During concomitant therapy with fluvoxamine and amitriptyline, imipramine, clomipramine, and
trimipramine, significant increases in plasma concentration of tricyclics have been observed.
Prospective studies in healthy volunteers show that fluvoxamine inhibits demethylation of imipramine
resulting in reduced clearance and a prolonged half-life. The mechanism is probably inhibition of
CYP 1 A2.
Quinidine:
Quinidine substantially inhibits the metabolism of nortriptyline, the major metabolite of amitriptyline.
The following combinations with Amitriptylin Abcur may require dose adjustment:
Bupropion:
Bupropion and its metabolite hydroxybupropion inhibit CYP 2D6 in vitro. During concomitant
therapy with drugs primarily metabolized by this enzyme (e.g. certain antidepressants) the risk of drug
interactions should be considered.
Cimetidine:
Cimetidine seems to be able to inhibit the demethylation of amitriptyline with elevated plasma
concentrations as a result. During concomitant treatment with the two drugs the plasma concentrations
of amitriptyline and nortriptyline should be monitored.
Dopamine:
Dopamine releases norepinephrine, the effects of which may be enhanced when its re-uptake in
adrenergic nerves is blocked. Dopamine should initially be given in lower doses to patients treated
with antidepressants and the circulatory effects should be carefully monitored.
Epinephrine:
The pressor effect of adrenaline (epinephrine) in acute experiments with high-dose IV demonstrated
intensified adverse effects of tricyclic antidepressants 2-3-fold in the ordinary dose. Prolonged
hypertension has been observed after 0.5 mg epinephrine subcutaneously in a person treated with
protriptyline. With asthma, isoprenaline, orciprenaline, fenoterol, terbutaline or salbutamol can be
used. The local anaesthesia in dental practice has no explicit reactions reported, but in recent years
felypressin has been used as a vasoconstrictor on preventative grounds.
Phenobarbital:
Barbiturates can reduce the concentration of tricyclic antidepressants in plasma (this has been shown
for e.g. nortriptyline). Nortriptyline's therapeutic plasma concentration is about 400 nmol/L (for
endogenous depression).
Fluconazole:
Three cases have been reported where the plasma concentration of amitriptyline rose dramatically after
the initiation of fluconazole. This is probably a drug metabolism interaction.
Fluoxetine:
Fluoxetine has a strong inhibitory effect on cytochrome P450 2 D6, which metabolises tricyclic
antidepressants. This means that the plasma concentration of amitriptyline may increase substantially
if fluoxetine is instituted. Due to the long half-life (days and weeks respectively) of fluoxetine and its
metabolite this interaction has a long duration and may even occur after discontinuation of fluoxetine.
Carbamazepine:
During concomitant treatment with carbamazepine the metabolism of amitriptyline is induced with
reduced levels of both amitriptyline and nortriptyline as a result. Determination of concentration of
amitriptyline-nortriptyline is therefore recommended.
Clonidine:
The antihypertensive effect of clonidine may possibly be reduced by tricyclic antidepressants.
Chlorpromazine:
A study of schizophrenic patients shows that the concentration of chlorpromazine in plasma rises
during concomitant treatment with amitriptyline.
Codeine:
Codeine is probably effective due to the fact that it is O- demethylated to morphine via CYP 2 D6.
This bioactivation is counteracted by several CYP 2 D6 inhibitors such as antidepressants that may,
therefore, counteract the effect of codeine.
Morphine:
Amitriptyline potentiates the analgesic effect of morphine. This may partly be related to the drug
increasing the bioavailability of morphine.
Antipsychotics:
Several antipsychotics (thioridazine, perphenazine, zuclopenthixol, haloperidol and risperidone) and
several antidepressants (such as amitriptyline and nortriptyline), are metabolized by cytochrome
P450 2 D6 and may therefore inhibit each other's metabolism. Perphenazine may, under certain
conditions, inhibit amitriptyline's metabolite, nortriptyline, which, therefore, reaches higher plasma
concentrations than normal.
Norepinephrine:
The effect of norepinephrine is enhanced by tricyclic antidepressants because they inhibit the uptake of
norepinephrine in adrenergic nerves. Risk of adrenergic syndrome (hypertension, palpitations, dilated
pupils, tremors and intense malaise).
Paroxetine:
Paroxetine has a strong inhibitory effect on cytochrome P450 2 D6, which metabolises tricyclic
antidepressants and serotonin uptake inhibitors. Therefore, plasma concentration of amitriptyline and
its metabolite nortriptyline can increase substantially.
Venlafaxine:
Venlafaxine is metabolized by CYP 2 D6 to O-desmethylvenlafaxine. Concomitant treatment with
drugs that inhibit CYP 2 D6, for example most antidepressants, may lead to elevated levels of
venlafaxine. Conversely, venlafaxine may inhibit the metabolism of other CYP 2 D6 substrates since
venlafaxine is a weak inhibitor of CYP 2 D6.
Sertraline:
Sertraline, compared with fluoxetine and paroxetine, has a weak inhibitory effect on CYP 2D6.
Experimental studies suggest that plasma concentrations of desipramine may increase by 30-60%
when coadministered with sertraline. In a study of 14 elderly (> 60 years) patients treated with
nortriptyline there were insignificant effects of sertraline on the plasma concentrations of nortriptyline
in a dose of 50 mg/day and a 40% increase with a dose of 100-150 mg/day.
Valproic acid:
Experimental studies suggest that valproate may inhibit the hydroxylation of amitriptyline with
elevated plasma concentrations as a result.
Serotonin Syndrome (awareness and behavioural disorders and impact on the autonomic nervous
system and neuromuscular activity) has been reported when Amitriptyline Abcur was administered
with other drugs that increase serotonin levels.
Treatment with tramadol may increase the risk of seizures.
Regarding MAO inhibitors, see 4.4 Special warnings and precautions.
The response to alcohol may be enhanced.
4.6
Fertility, pregnancy and lactation
Pregnancy
Tri- and tetracyclic agents with antidepressant effect crosses the placenta.
Tremor and seizures in newborns are described after treatment with clomipramine and imipramine.
The symptoms subside after days to weeks and are likely due to decreasing plasma concentrations of
the anti-depressant substance in the child. Desipramine has affected breathing and circulation, and
amitriptyline and nortriptyline have induced lethargy and urinary retention, respectively, in children.
During the third trimester, Amitriptylin Abcur should therefore only be given on strict indication and
after weighing the mother's needs against the risk to the child.
Breastfeeding
Amitriptyline is excreted in breast milk in amounts that constitute a risk to the child when
administered at therapeutic doses.
Fertility
There are no data available regarding fertility after exposure to amitriptyline (see section 5.3).
4.7
Effects on ability to drive and use machines
During treatment with Amitriptylin Abcur the ability to react may be affected. This should be
considered when heightened attention is required, for example when driving a car.
4.8
Undesirable effects
Most adverse events represent manifestations of anticholinergic effect and can often be controlled by
dose adjustment. Most common are fatigue and accomodation disturbances.
Adverse reactions are presented in order of decreasing severity using the following categories: very
common ( 1/10); common (1/100, <1/10); uncommon (1/1 000, <1/100), rare (1/10 000,
<1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Rare: Agranulocytosis, eosinophilia, leukopenia, thrombocytopenia.
Metabolism and nutrition disorders
Common: weight gain.
Rare : weight loss.
Psychiatric disorders
Commeen: drowsiness, dizziness
Uncommon: Hypomania, mania, anxiety, insomnia, nightmares.
Rare: Increased hallucinations in schizophrenic patients, delirium (older patients).
Not known: Suicidal thoughts, suicidal behaviour
Nervous system disorders
Common: headache, tremor, paresthesias, ataxia, Disorientation, difficulty concentrating.
Rare: Convulsions
Eye disorders
Common: Accomodation disturbances, mydriasis, blurred vision.
Uncommon: Elevated intraocular pressure.
Ear and labyrinth disorders
Uncommon: Tinnitus.
Cardiac disorders
Common: Palpitations, tachycardia, ECG changes (Electrocardiogram QT prolonged, flat or inverted T
wave), AV block, orthostatic hypotension.
Rare: Arrhythmia, myocardial infarction.
Vascular disorders
Uncommon: Hypertension.
Gastrointestinal disorders
Common: Nausea, constipation, dry mouth, altered taste perception.
Uncommon: Vomiting, diarrhea.
Rare: Paralytic ileus, parotid swelling.
Hepatobiliary disorders
Rare: Transaminase elevations, jaundice.
Skin and subcutaneous tissue disorders
Uncommon: Exanthema, urticaria, purpura, edema of the face and tongue.
Rare: Alopecia, photosensitivity
Renal and urinary disorders
Uncommon: Urinary retention.
Reproductive system and breast disorders
Common: Disruption of libido and potency.
Rare: Gynecomastia, galactorrhea.
General disorders and administration site conditions
Common: fatigue, sweating, increased appetite.
Rare: Loss of appetite, fever.
Cases of suicidal thoughts and suicidal behaviour have been reported during treatment with
amitriptyline and directly after the end of treatment (see section 4.4).
Epidemiological studies, mainly conducted in patients 50 years and older, show an increased risk of
bone fractures in patients receiving SSRIs and TCAs. The mechanism is unknown.
Rare cases of increased drowsiness and orthostatic symptoms may occur in the morning after
monodose administration at bedtime.
Hyperpyrexia has been reported when tricyclic antidepressants have been co-administered with
anticholinergics or neuroleptics, especially in hot weather.
Laboratory findings: Changes in liver function, increased or decreased blood sugar levels.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the national reporting system
listed in Appendix V.
4.9
Overdose
Toxicity:
Large individual variations. Children are more susceptible than adults. Fatalities have been described
after therapeutic doses in combination with MAO inhibitors.
Less than 1 g to adults and 375-500 mg to a 2-year old resulted in lethal intoxication. 50 mg to a 3 year
old resulted in mild intoxication, 60 mg to a 2-year old and 75 mg to a 3-year old resulted in moderate
intoxication. 75 mg to a 7-year-old resulted in mild intoxication, 125-250 mg to a 6-year-old after
gastric lavage resulted in moderate to severe intoxication. 100-125 mg to a 13-year-old and 200 mg to
a 14 year old resulted in moderate intoxication after gastric lavage. < 500 mg in adults caused mildmoderate, > 500 mg in adult caused moderate-severe intoxication.
Symptoms
Onset of symptoms may be delayed or appear very quickly and surprisingly. During the first hours
drowsiness or excitation, agitation, hallucinations and also extrapyramidal symptoms may occur.
Mydriasis, tachycardia, urinary retention, dry mucous membranes, decreased bowel motor function,
(toxic megacolon and ischemic colitis in isolated cases). Seizures. Fever. Later, sudden onset of CNS
depression, unconsciousness, respiratory depression. Ophthalmoplegia. Cardiac symptoms: widening
of the QRS complex, the QRS width is usually correlatedwith severity of intoxication. Arrhythmias,
mainly ventricular involve risk (VT, "torsades de pointes" ventricular fibrillation); heart failure,
hypotension, cardiogenic shock. Metabolic acidosis, hypokalaemia.During the awakening confusion,
agitation, hallucinosis, ataxia can possibly occur again. Rhabdomyolysis, acute respiratory distress
syndrome (ARDS) has been described in severe poisoning. Isolated cases of oesophageal spasm.
Treatment
Symptomatic and supportive. If necessary, gastric lavage, activated charcoal. Close monitoring of
electrolytes and blood gases. Special risk is hypoxia, metabolic acidosis and hypokalemia- should be
corrected carefully . Continuous ECG monitoring. Intubation and respirator treatment as indicated.
WideQRS complex, heart failure and ventricular arrhythmias may be reversed by alkaline pH in the
blood (bicarbonate and moderate hyperventilation) and rapid infusion of hypertonic sodium chloride
(100-200 mmol Na+ ). In the event of circulatory failure despite the above measures, it is appropriate
to monitor hemodynamics and, along with the management of this, IV fluids, dobutamine and
possibly norepinephrine can be given. Intravenous glucagon for 2 minutes, possibly followed by
infusion, can also be tried. In case of ventricular arrhythmias – lidocaine; "torsades de pointes" and
bradyarrhythmias – isoprenaline or pacemaker; ventricular arrhythmias of the "torsade de pointes"
type – infusion of magnesium sulphate can also be effective. In circulatory arrest, several hours of
resuscitation measures may be warranted. For agitation, hallucinations and convulsions, diazepam can
be given. In the event of prolonged convulsions sedation with propofol, muscle relaxation and
respiratory therapy.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antidepressants, non-selective monoamine reuptake inhibitors, ATC
code: N06AA09
Mechanism of action
Amitriptyline affects the monoaminergic neurons in the CNS and inhibits reuptake in nerve terminals,
primarily of serotonin but also norepinephrine. These effects will also involve an anticholinergic
activity, which is both central and peripheral.
In addition to an antidepressant effect amitriptyline has sedative, antianxiety properties.
Effect on the anxiety symptoms occurs rapidly, while an improvement in the basic mood will be noted
later during treatment.
Euphoria, addiction or withdrawal symptoms has not been detected.
5.2
Pharmacokinetic properties
Distribution
The biological half-life of the unchanged substance has large and individual variations from 9 to25
hours, on average 15 hours.
Biotransformation
Amitriptyline and its metabolites are mainly excreted in urine. The main metabolite nortriptyline is
therapeutically effective.
5.3
Preclinical safety data
There are no preclinical data on fertility or effects on reproduction after exposure to amitriptyline.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Lactose monohydrate
Corn starch
Povidone
Magnesium stearate
Talc
Polyvinyl alcohol
Macrogol
Titanium dioxide (E171)
Iron oxide (E172)
6.2
Incompatibilities
Not relevant.
6.3
Shelf life
Bottle: 3 years
Blister packaging: 3 years
6.4
Special precautions for storage
Bottle: This medicinal product does not require any special storage conditions.
Blister: Store below 30°C. Keep the blister in the outer carton in order to protect from light.
6.5
Nature and contents of container
HDPE-bottle with PP-cap: 20 and 100 tablets.
PVC/Al blister: 20 and 100 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special instructions.
7.
MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8.
MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
2014-05-22
10.
DATE OF REVISION OF THE TEXT
2017-02-14