Sertraline 50mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Sertraline 50 mg film-coated tablet
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 50 mg sertraline as sertraline hydrochloride For the full list of excipients see section 6.1
3 PHARMACEUTICAL FORM
Film-coated tablet.
White, capsule shaped, scored film-coated tablets coded SE | 50 on one side, approximate size 10.4mm x 4.2mm,
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
Sertraline is indicated for the treatment of:
Treatment of major depressive episodes. Prevention of recurrence of major depressive episodes.
Panic disorder, with or without agoraphobia.
Obsessive compulsive disorder (OCD) in adults and paediatric patients aged 617 years.
Social anxiety disorder.
Post traumatic stress disorder (PTSD).
4.2 Posology and method of administration
Posology
Initial treatment Depression and OCD
Sertraline treatment should be started at a dose of 50 mg/day.
Panic Disorder, PTSD, and Social Anxiety Disorder
Therapy should be initiated at 25 mg/day. After one week, the dose should be increased to 50 mg once daily. This dosage regimen has been shown to reduce the frequency of early treatment emergent side effects characteristic of panic disorder.
Treatment of major depressive episodes, OCD, Panic Disorder, Social Anxiety Disorder and PTSD
The usual daily dose is 50 mg. If dose increments are required, these should be made in steps of 50 mg at minimum intervals of 1 week. Dose changes should not be performed more than once per week due to elimination half-life of sertraline of 24 hours. The maximum daily dose is 200 mg.The onset of therapeutic effect may be seen within 7 days. However, longer periods are usually necessary to demonstrate therapeutic response, especially in OCD.
During long-term therapy the aim is to administer the lowest possible dosage which provides adequate therapeutic efficacy.
Depression
Longer-term treatment may also be appropriate for prevention of recurrence of major depressive episodes (MDE). In most of the cases, the recommended dose in prevention of recurrence of MDE is the same as the one used during current episode. Patients with depression should be treated for a sufficient period of time of at least 6 months to ensure they are free from symptoms.
Panic disorder and OCD
Continued treatment in panic disorder and OCD should be evaluated regularly, as relapse prevention has not been shown for these disorders.
Children and adolescents under 18 years of age
Sertraline should not be used in the treatment of children and adolescents under the age of 18 years, except for patients with obsessive compulsive disorder aged 6-17 years old (see section 4.4. Special warnings and precautions for use)
Children and adolescents with obsessive compulsive disorder
Age 13-17 years: Initially 50 mg once daily.
Age 6-12 years: Initially 25 mg once daily. The dosage may be increased to 50 mg once daily after one week.
Subsequent doses may be increased in case of less than desired response in 50 mg increments over a period of some weeks, as needed. The maximum dosage is 200 mg daily. However, the generally lower body weights of children compared to those of adults should be taken into consideration when increasing the dose from 50 mg. Dose changes should not occur at intervals of less than one week.
Efficacy is not shown in paediatric major depressive disorder.
No data is available for children under 6 years of age (see also section 4.4).
Use in older people
Elderly should be dosed carefully, as elderly may be more at risk for hyponatraemia (see section 4.4). As the elimination half-life may be prolonged in elderly patients, it should be advised that the dosage should be as low as possible in the elderly.
Patients with impaired hepatic function/Use in hepatic insufficiency
In patients with hepatic disease/impaired hepatic function sertraline tablets should be used with caution. Although it is not clear if dosage adjustments are necessary in case of impaired hepatic function, it is recommended that the dose is reduced or the interval between the dosage prolonged (see section 4.4). Sertraline should not be used in case of severe hepatic impairment as no clinical data are available (see section 4.4).
Patients with impaired renal function/Use in renal insufficiency
Dose adjustment is not necessary in patients with renal insufficiency (see 4.4 “Special warning and special precautions for use”).
Method and duration of administration
Sertraline tablets should be taken as a single daily dose either in the morning or in the evening. Tablets can be taken with or without food, with a sufficient amount of liquid.
The onset of antidepressant effect may occur within 7 days, however, the maximum effect is generally reach after 2-4 weeks of treatment,; it is advisable that the patients are informed of this.
The duration of treatment depends upon the nature and severity of the disorder. After remission of the symptoms of depression, patients should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.
Withdrawal symptoms seen on discontinuation of SSRI
Abrupt discontinuation should be avoided. When stopping treatment with sertraline the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 Special Warnings and Special Precautions for Use and section 4.8 Undesirable Effects). 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.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Concomitant use with MAO inhibitors including moclobemide and selegiline (see
4.4 “Special warnings and precautions for use”).
• Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Sertraline must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Sertraline must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see section 4.5).
• Sertraline is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).
• Concomitant use with pimozide is contraindicated (see 4.5 “Interaction with other medicinal products and other forms of interaction”).
4.4 Special warnings and precautions for use
Use in children and adolescents under 18 years of age
Sertraline should not be used in the treatment of children and adolescents under the age of 18 years, except for patients with obsessive compulsive disorder aged 617 years old. In clinical trials increased suicidal related behaviours (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in children and adolescents treated with sertraline compared to those treated with placebo.
If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see section 4.8 Undesirable Effects). Physicians must monitor paediatric patients on long term treatment for abnormalities in these body systems.
Suicide/suicidal thoughts/suicide attempts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). 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 with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions, for which sertraline is prescribed, can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
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 placebo-controlled 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.
Akathisia/psychomotor restlessness
The use of sertraline has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)
The development of potentially life-threatening syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported with SSRIs, including treatment with sertraline. Concomitant treatment with serotonin re-uptake inhibitors (SSRIs), including sertraline and MAO inhibitors (MAOIs) must be avoided because of the risk of potentially life threatening serotonin syndrome (SS) (see 4.3 “Contraindications”) or Neuroleptic Malignant Syndrome (NMS).
The risk of SS or NMS with SSRIs is increased with concomitant use of serotonergic drugs (including triptans), drugs which impair metabolism of serotonin (including MAOIs e.g. methylene blue), antipsychotics and other dopamine antagonists and with opiate drugs
For patients previously treated with MAOIs and who have discontinued this treatment, an interval of at least 14 days should elapse before the patient is switched to sertraline. Conversely, an interval of 14 days should elapse before patients treated with sertraline are switched to an MAOI. Serious and sometimes fatal reactions have been reported following combination treatment with sertraline and MAOIs, and also in combination with the selective MAOI selegiline and the reversible MAOIs moclobemide and linezolid. Some cases have resembled serotonin syndrome. The symptoms of an interaction between SSRIs and MAOIs include hyperthermia, rigidity, myoclonus, autonomic instability with the risk of rapid fluctuations of vital signs, mental status changes such as confusion, irritability and extreme agitation, progressing to delirium and coma. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see section 4.3 -
Contraindications).Treatment with sertraline should be discontinued immediately and symptomatic treatment indicated.
Changeover from SSRIs or other antidepressants or antiobsessional drugs
Accordingly a changeover from use of selective serotonin reuptake inhibitors or other antidepressants should be done cautiously in order to avoid possible pharmacodynamic interactions (see 4.5 “Interactions with other medicinal products and other forms of interaction”). Careful clinical monitoring and prudent medical judgment is of special importance when sertraline is initiated after discontinuation of an antidepressant with long half-life such as e.g. fluoxetine. There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or antiobsessional drugs to sertraline.
Other serotoninergic drugs/medicinal products e.g. tryptophan, fenfluramine and 5-HT agonists
Co-administration of sertraline with other drugs which enhance the effects of serotonergic neurotransmission eg. trypthophan, 5-HT agonists,_fenfluramine, or the herbal medicine, St John's Wort (hypericum perforatum), dextromethrophan, pethidine, tramadol and other SSRIs should be undertaken with caution and avoided whenever possible due to the potential for a pharmacodynamic interaction. (see 4.5 “Interactions with other medicinal products and other forms of interaction”).
Activation of mania / hypomania
Manic/hypomanic symptoms have been reported to emerge in a small proportion of patients treated with marketed antidepressant and anti-obsessional drugs, including sertraline. In approximately 0.4 % of patients treated with sertraline in clinical studies mania or hypomania has been reported. Therefore sertraline should be used with caution in patients with a history of mania / hypomania. Close surveillance by the physician is required. Sertraline should be discontinued in any patient entering a manic phase.
Convulsive disorders/Seizures
During studies on depression epileptic seizures were observed in approx. 0.08 % of the patients treated with sertraline.
Seizures may occur with sertraline therapy. As sertraline has not been studied in patients with convulsive disorders, the use of this medicinal product should be avoided in patients with unstable epilepsy and seizures and should be administered in patients with controlled stable epilepsy only with careful monitoring. If an epileptic seizure occurs, treatment with sertraline should be discontinued.
Electric convulsive therapy (ECT)
Since there is little clinical experience of concurrent administration of sertraline and ECT, caution is advisable. There are no clinical studies establishing the risks or benefits of the combined use of ECT and sertraline.
Diabetes
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Blood glucose levels should be checked regularly. Insulin and/or oral hypoglycaemic dosage may be needed to be adjusted.
Hyponatraemia
Hyponatraemia may occur as a result of treatment with SSRIs or SNRIs including sertraline. Hyponatraemia probably due to a syndrome of inappropriate antidiuretic hormone secretion (SIADH), has been reported in many cases with the use of SSRIs and generally resolves on discontinuation of therapy. Cases of serum sodium levels lower than 110 mmol/l have been reported. Caution should be exercised in patients at risk, such as the elderly, cirrhotic patients or patients concomitantly treated with medications known to cause hyponatraemia. 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 (see Use in elderly). 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.
Withdrawal symptoms seen on discontinuation of SSRI treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In clinical trials, among patients treated with sertraline, the incidence of reported withdrawal reactions was 23% in those discontinuing sertraline compared to 12% in those who continued to receive sertraline treatment.
The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that sertralin should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see "Withdrawal Symptoms Seen on Discontinuation of SSRIs", Section 4.2 Posology and Method of Administration).
Abnormal bleeding/Haemorrhage
There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura and other hemorrhagic events such as gastrointestinal or gynaecological bleeding including fatal haemorrhage with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with anticoagulants, medicinal products/drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non-steroids anti-inflammatory medicinal product (NSAIDs)) as well as in patients with a history of bleeding disorders (see 4.5 “Interaction with other medicinal products and other forms of interaction”).
Cardiac disease
The safety of sertraline has not been established in patients who have recently suffered a heart attack or patients with instable cardiac disease. Patients diagnosed with these disorders were excluded from clinical studies. The electrocardiograms of patients receiving sertraline in double-blind clinical studies indicate that sertraline is not associated with significant ECG abnormalities.
Use in Elderly
Over 700 elderly patients (>65 years) have participated in clinical studies. The pattern and incidence of undesirable effects in the elderly are comparable to the effects in younger patients. However, the elderly may be more sensitive to the undesirable effects of antidepressants.
SSRIs or SNRIs including sertraline have however been associated with cases of clinically significant hyponatraemia in elderly patients, who may be at greater risk for this adverse event (see Hyponatraemia in section 4.4).
Schizophrenia
Psychotic symptoms might become aggravated in schizophrenic patients.
Impaired hepatic function/Hepatic impairment
Sertraline is extensively metabolised in the liver. A multiple dose pharmacokinetic study of repeated doses in patients with mild and stabilised cirrhosis revealed a prolonged elimination half life and an approximately three times greater AUC and maximum plasma concentration (Cmax) compared to patients with normal liver function. No significant difference in plasma protein binding was observed between the two groups. The use of sertraline in patients with hepatic disease must be approached with caution. If sertraline is administered to patients with hepatic impairment, a lower or less frequent dose should be considered. Sertraline should not be used in patients with severe hepatic impairment (see 4.2 “Posology and method of administration”).
Impaired renal function/Renal impairment
As a result of the extensive hepatic metabolism only a negligible portion of sertraline is eliminated unchanged via the renal pathway. In studies of patients with mild to moderate (creatinine clearance 30 to 60 ml/min) or moderate to severe (creatinine clearance 10 to 29 ml/min) impairment of renal function the pharmacokinetic parameters (AUC0-24 and Cmax), after repeated doses, were not found to differ significantly from those in patients with normal renal function. The half-lives were similar, and no differences in plasma protein binding could be established between the groups studied. This study shows that, as would be expected in view of the low renal elimination rate, the dosage of sertraline does not have to be adjusted in case of impaired renal function.
Grapefruit juice
The administration of sertraline with grapefruit juice is not recommended (see section 4.5).
Interference with urine screening tests
False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas
chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.
Angle-Closure Glaucoma
SSRIs including sertraline may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in patients pre-disposed. Sertraline should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions:
Contraindicated
MAOIs
Serious and sometimes fatal reactions have been reported following combined treatment with sertraline and MAOIs. Sertraline should therefore not be used concomitantly with MAO inhibitors, including the selective MAO inhibitor selegiline and the reversible MAO inhibitors linezolid (unless there are facilities for close observation and monitoring of blood pressure) and moclobemide. (see 4.3 “Contraindications” and 4.4 “Special warnings and special precautions for use”).
Irreversible MAOIs (e.g. selegiline)
Sertraline must not be used in combination with irreversible MAOIs such as selegiline Sertraline must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Sertraline must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see section 4.3).
Reversible, selective MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, the combination of sertraline with a reversible and selective MAOI, such as moclobemide, should not be given. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of sertraline treatment. It is recommended that sertraline should be discontinued for at least 7 days before starting treatment with a reversible MAOI (see section 4.3).
Reversible, non-selective MAOI (linezolid)
The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with sertraline (see section 4.3). Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI e.g Methylene blue and started on sertraline, or have recently had sertraline therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.
Serotoninergic substances
Concomitant treatment with sertraline and other serotoninergic medicinal agents such as trypthophan, 5-HT agonists, fenfluramine, dextromethrophan, pethidine and tramadol is not recommended because of the risk of serotonin syndrome (see 4.4 “Special warnings and special precautions for use”).
Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain.
Co-administration with sertraline is not recommended CNS depressants and alcohol
The co-administration of sertraline 200 mg daily did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of sertraline and alcohol is not recommended.
Other serotonergic drugs See section 4.4.
Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain, other serotonergic drugs (including other serotonergic antidepressants, triptans), and with other opiate drugs.
Special Precautions
Lithium
On concomitant administration of lithium and sertraline in placebo-controlled studies in healthy subjects, there were no changes in the pharmacokinetics of lithium, although there was an increased incidence of tremor in comparison with patients receiving placebo, indicating that there may be a Pharmacodynamic influence. Patients receiving lithium and sertraline or other substances with a serotonergic mode of action should be appropriately monitored.
Triptans e.g. Sumatriptan
With concomitant treatment of sertraline and sumatriptan weakness, hyperreflexia, incoordination, confusion, anxiety and agitation were reported in rare post-marketing cases. Symptoms of serotonergic syndrome may also occur with other products of the same class (triptans). If concomitant treatment with sertraline and sumatriptan is clinically required, appropriate monitoring of the patient is recommended.(See Section 4.4)
Oral anticoagulants, salicylic acid, NSAlDs, atypical antipsychotics, phenothiazines and most tricyclic antidepressants
Pharmacodynamic interactions with medicinal products which are associated with increased risk for bleeding such as anticoagulants, salicylic acid derivatives, nonsteroidal anti-inflammatory analgesics, atypical antipsychotics, phenothiazines and most tricyclic antidepressants, may occur. This should be taken into account because of the potentially increased risk for bleeding when SSRIs are administered concomitantly.
Hypericum perforatum
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.
Diuretics
Diuretics used concomitantly with sertraline may predispose (elderly patients) to hyponatraemia and SIADH.
Hypoglycaemic substances
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Blood glucose levels should be checked regularly. Insulin and/or oral hypoglycaemic dosage may be needed to be adjusted.
Pharmacokinetic interactions Pimozide
In a clinical study, concomitant administration of sertraline and low single dose pimozide (2 mg) showed elevated pimozide levels (approximately 35%). These increased levels were not associated with any changes in EKG. While the mechanism of this interaction is unknown, Because of the narrow therapeutic index of pimozide, concomitant administration of sertraline and pimozide is contraindicated (see section 4.3).
Warfarin
Co-administration with sertraline 200 mg daily and warfarin resulted in a small but significant increase in prothombin time, which may in some rare cases unbalance the INR value. Accordingly, the prothrombin time should be carefully monitored after beginning or discontinuing the sertraline therapy.
Phenytoin
A placebo-controlled trial suggests that long-term treatment with sertraline 200 mg daily in healthy volunteers did not exert any clinically significant inhibitory effect on the metabolism of phenytoin. Nonetheless, as single cases of elevated phenytoin concentrations in patients using sertraline have been reported. Therefore plasma phenytoin concentration should be monitored after beginning or discontinuing the sertraline therapy, followed by appropriate adjustment of the phenytoin doses. In addition, concomitant administration of phenytoin can reduce plasma sertraline levels. It cannot be excluded that other CYP3A4 inducers, e.g. phenobarbital, carbamazepine, St Johns Wort, rifampicin may cause a reduction of sertraline plasma levels.
Cimetidine
Co-administration with cimetidine caused a substantial decrease in sertraline clearance. Cimetidine inhibits the metabolism of sertraline increasing the AUC and peak plasma concentration by 20 to 30%. Clinical importance of these changes is unknown.
Active substances bound to plasma proteins
Due to high protein binding of sertraline the interactions with other substances highly bound to plasma proteins are possible. However, in three interaction studies, sertraline had no significant effects on the plasma protein binding of diazepam, tolbutamide and warfarin.
Other interactions observed in studies
Concomitant administration of sertraline and diazepam or tolbutamide resulted in slight, but statistically signiificant changes to various pharmacokinetic parameters. Sertraline proved to have no effect on the the beta-adrenergic blocking-capabilities of atenolol. Interactions between sertraline 200 mg daily and glibenclamide or digoxin were not seen. The effects of carbamazepine, haloperidol, phenytoin and alcohol did not potentiated cognitive and psychomotor performance in healthy subjects after concomitant administration of sertraline 200mg daily: however, it is advisable not to consume alcohol during therapy with sertraline.
Antipyrine
The half-life of antipyrine is reduced by concomitant administration of sertraline, which points to a clinically non-significant hepatic enzyme induction.
Active substances metabolised by Cytochrome P450
Sertraline is a mild-moderate inhibitor of the CYP2D6: Chronic dosing with sertraline 50 mg daily caused a slight increase (mean 23 to 37%) in steady state plasma concentration of desipramine (a marker substrate for CYP2D6 isoenzyme activity). Inhibition of CYP2D6 can increase at higher doses of sertraline. The clinical significance depends on the degree of inhibition and the therapeutic index of the medicinal product used concomitantly with sertraline. Clinical relevant interactions may occur with other CYP2D6 substrates with narrow therapeutic index that include tricyclic antidepressants and class IC antiarrhythmic medicinal products such as propafenone and flecainide. TCAs and typical antipsychotics, especially at higher sertraline dose levels.
CYP3A4: In vivo interaction studies have shown that long-term treatment with sertraline 200 mg daily does not inhibit CYP3A4-catalysed metabolism of carbamazepine or terfenadine and endogenous cortisol. In addition, it was shown that that long-term treatment with sertraline 50 mg daily did not inhibit CYP3A4-catalysed metabolism of alprazolam. Results from these studies implicate that sertraline is not a clinically relevant inhibitor of CYP3A4.
CYP2C9: It has been confirmed by in-vivo Interaction studies with CYP2C9 substrates tolbutamide, glibenclamide, phenytoin and warfarin that Sertraline does not act as inhibitor of CYP2C9 to a clinically significant degree.
CYP2C19: No clinically significant effects of sertraline 200 mg daily on diazepam pharmacokinetics were observed. This indicates that sertraline is not a clinically significant inhibitor of CYP2C19.
CYP 1A2: In vitro investigations have demonstrated that sertraline has little or no potential for inhibition of CYP 1A2.
Intake of three glasses of grapefruit juice daily increased the sertraline plasma levels by approximately 100% in a cross-over study in eight Japanese healthy subjects. Interaction with other CYP3A4 inhibitors has not been established. Therefore, the intake of grapefruit juice should be avoided during treatment with sertraline (see section 4.4).
Based on the interaction study with grapefruit juice, it cannot be excluded that the concomitant administration of sertraline and potent CYP3A4 inhibitors, e.g. protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin and nefazodone, would result in even larger increases in exposure of sertraline. This also concerns moderate CYP3A4 inhibitors, e.g. aprepitant, erythromycin, fluconazole, verapamil and diltiazem. The intake of potent CYP3A4 inhibitors should be avoided during treatment with sertraline.
Sertraline plasma levels are enhanced by about 50% in poor metabolizers of CYP2C19 compared to rapid metabolizers (see section 5.2). Interaction with strong inhibitors of CYP2C19, e.g. omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, fluvoxamine cannot be excluded.
Drugs affecting platelet function
The risk of bleeding may be increased when medicines acting on platelet function (e.g. NSAIDs, acetylsalicylic acid and ticlopidine) or other medicines that might increase bleeding risk are concomitantly administered with SSRIs, including sertraline (see section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy
Data on a limited number (n = 147) of exposed pregnant women indicate no undesirable effects of sertraline on pregnancy or on the health of the foetus / neonate. Animal studies showed evidence for effects on reproduction probably due to maternal toxicity caused by the pharmacodynamic action of the compound and/or direct pharmacodynamic action of the compound on the foetus (see 5.3).
Sertraline should only be used in pregnancy if the clinical condition of the woman is such that the potential benefits of treatment to the mother outweigh the possible risks to the developing foetus.
Use of sertraline during pregnancy has been reported to cause symptoms, compatible with withdrawal reactions, in some neonates, whose mothers had been on sertraline. This phenomenon has also been observed with other SSRI antidepressants.
Neonate infants should be observed if maternal use of sertraline continues into the later stages of pregnancy, particularly the third trimester. Abrupt discontinuation should be avoided during pregnancy.
The following symptoms may occur in the New-born infant after maternal SSRI/SNRI (sertraline) use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting,
hypoglycaemia, hypertonia, hypotonia, hyperflexia, tremor, jitterness, irritability, lethargy, constant crying, somnolence and difficulty in sleeping. These symptoms could be due to either serotonergic effects of withdrawal symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.
Breast-feeding
Published data concerning sertraline levels in breast milk show that Sertraline (milk/plasma-ratio approx. 1.8) and its metabolite N-desmethyl sertraline are known to be excreted in small quantities in breast milk. Generally, very low or nondetectable plasma concentrations of sertraline have been determined in breastfed infants with one exception of an infant with serum levels about 50% of the maternal level (but without a noticeable health effect in this infant). To date, no adverse effects on the health of infants nursed by mothers using sertraline have been reported, but a risk cannot be excluded. Use in nursing mothers is not recommended unless, in the judgement of the physician; the expected benefit outweighs potential risks to the child
Fertility
Animal data did not show an effect of sertraline on fertility parameters (see section 5.3.).
Human case reports with some SSRI’s have shown that an effect on sperm quality is reversible.
Impact on human fertility has not been observed so far.
4.7 Effects on ability to drive and use machines
Clinical pharmacology studies have shown that sertraline has no or negligible influence on the psychomotor behaviour/performance. Following treatment with
psychotropic agents, however, the reaction time (mental or physical abilities) can be impaired in some patients for the performance of potentially hazardous tasks. Patients are therefore to be advised to be careful when engaging with activities that require attention, such as driving or using dangerous machines, until they know, how they react to sertraline treatment.
4.8 Undesirable effects
Nausea may occur commonly. Male sexual dysfunction has been reported in 23 % of the male patients (corrected for placebo) in clinical trials of treatment of social phobias.
In the treatment of social anxiety disorder, sexual dysfunction (ejaculation failure) in men occurred in 14% for sertraline vs 0% in placebo.
The adverse reactions of the medicinal product are dose dependent and often transient in nature when the treatment is continued.
The undesirable effects profile commonly observed in double-blind, placebo-controlled studies in patients with OCD, panic disorder, PTSD and social anxiety disorder was similar to that observed in clinical trials in patients with depression.
Table 1 displays adverse reactions observed from postmarketing experience (frequency not known) and placebo-controlled clinical trials (comprising a total of 2542 patients on sertraline and 2145 on placebo) in depression, OCD, panic disorder, PTSD and social anxiety disorder.
Some adverse drug reactions listed in Table 1 may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.
Table 1: Adverse Reactions
Frequency of adverse reactions observed from placebo-controlled clinical trials in depression, OCD, panic disorder, PTSD and social anxiety disorder. Pooled analysis and postmarketing experience (frequency not known).
|
System organ class |
Very common (>1/10) |
Common (>1/100, <1/10) |
Uncommon (>1/1,000, <1/100) |
Rare (>1/10,000,<1/1,000 ) |
Very Rare (<1/10000) |
Frequency not known (cannot be estimated from the available data) |
|
Blood and lymphatics system disorders |
Platelet disorders Prolonged bleeding time$ |
Leucopenia, Thrombocytopenia, Lymphadenopathy | ||||
|
Immune system disorders |
Hypersensitivity |
Allergic reactions including anaphylaxis, Anaphylactoid Reaction |
, Allergy | |||
|
Endocrine disorders |
Hypothyroidism |
Hyperprolactina emia, Syndrome of inappropriate ADH secretion (SIADH) | ||||
|
Metabolis m and nutrition disorders |
Anorexia |
Increased appetite*, Decreased appetite |
Hyponatraemia $$ , Hypercholesterolae mia, |
hyperglycaemia |
|
Hypoglycaemia, s Diabetes mellitus, | ||||||
|
Psychiatric disorders |
Insomnia (19%) |
Depression*, Depersonalis ation, Nightmare, Agitation* Anxiety* , Nervousness, Libido Decreased*, Bruxism |
Mania, Hypomania, Hallucinations*, Apathy, thinking abnormal, Aggression*, Euphoric mood* |
Conversion Disorder, Drug Dependence, Confusion Psychotic disorder*, Paranoia, Suicidal Ideation/behaviour* **, Sleep Walking, Premature Ejaculation |
Paroniria | |
|
Nervous system disorders |
Dizzines s (11%) Somnole nce (13%), Headach e (21%)* |
Changes in movement patterns**** Paraesthesias * Hypertonia Dysgeusia, Disturbance in Attention, tremor |
Migraine*, Convulsion*, Muscle Contractions Involuntary*, Coordination Abnormal, Hyperkinesia, Amnesia, Speech Disorder, Dizziness Postural, Hypoesthesia*, Syncope |
Psychomotor restlessness/ akathisia (see section 4.4) Unconsciousness, Signs and symptoms associated with serotonin syndrome or Neuroleptic Malignant Syndrome: Coma*, Choreoathetosis, Dyskinesia, Hyperaesthesia, Sensory Disturbance |
Cerebrovascula r Spasm (including reversible cerebral vasconstriction syndrome and call-fleming syndrome). | |
|
Eye disorders |
Blurred vision, Visual Distubance |
Mydriasis* |
Glaucoma, Lacrimal Disorder, Scotoma, Diplopia, Photophobia, Hyphaema |
Vision Abnormal, Pupils Unequal | ||
|
Ear and labyrinth disorders |
Tinnitus* |
Ear pain | ||||
|
Cardiac disorders |
Palpitations* |
Tachycardia |
Myocardial Infarction, Bradycardia, Cardiac Disorder | |||
|
Vascular disorders |
Vasodilation, Hot flush* |
Hypertension*, Flushing |
Peripheral Ischaemia, Hematuria |
Abnormal Bleeding (such as epistaxis, gastrointestinal bleeding or | ||
|
Respirator y, thoracic and mediastina l disorders |
Yawning* |
Bronchospasm*, Dyspnoea, Epistaxis |
Laryngospasm, Hyperventilation, Hypoventilation, Stridor, Dysphonia, Hiccups |
Interstitial lung disease |
|
Gastrointes tinal disorders |
Nausea (24%), Dry mouth (14%), Diarrhoe a /thin stools (18%) |
Dyspepsia Abdominal pain* Vomiting* Constipation *, Flatuence |
Oesophagitis, Dysphagia, Haemorrhoids, Salivary Hypersecretion, Tongue Disorder, Eructation |
Melaena, Haematochezia, Stomatitis, Tongue ulceration, Tooth Disorder, Glossitis, Mouth Ulceration |
Pancreatitis | |
|
Hepato biliary disorders |
Hepatic function abnormal |
Serious liver events (including hepatitis Jaundice) and Hepatic failure | ||||
|
Skin and subcutaneo us tissue disorders |
Rash*, Hyperhidrosi s |
Periorbital Oedema*, Purpura* Alopecia*, Cold sweat, Dry skin, Urticaria* Pruritus Erythema Multiforme |
Dermatitis, Dermatitis Bullous, Rash Follicular, Hair Texture Abnormal, Skin Odour Abnormal Photosensitivity Angiooedema Severe dermal exfoliation / severe cutaneous adverse reactions (SCAR) e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis |
Skin Reaction | ||
|
Musculosk eletal, connective tissue and bone disorders |
Myalgia, Arthralgia |
Osteoarthritis, Muscular Weakness, Back Pain, Muscle Twitching |
Bone disorder, Muscle cramps | |||
|
Renal and urinary disorders |
Nocturia, Urinary Retention*, Polyuria, Pollakiuria, Micturition disorder, Urinary incontinence* |
Oliguria , Urinary Hesitation | ||||
|
Reproducti ve system and breast disorders* * |
Ejaculati on Failure (14%) |
Erectile Dysfunction |
Vaginal Haemorrhage, Sexual Dysfunction, Female Sexual Dysfunction Menstrual Irregularities |
Priapism*, Menorrhagia, Atrophic Vulvovaginitis, Balanoposthitis, Genital Discharge, Galactorrhoea* |
Gynaecomastia | |
|
General disorders and |
Fatigue (10%)* |
Chest pain*, Diaphoresis, Malaise |
Fever* *, Chills, Thirst, Peripheral |
Facial oedema, Hernia, Injection Site Fibrosis, Drug |
|
administrat ion site conditions |
oedema, Asthenia* |
Tolerance Decreased, Gait Disturbance, Unevaluable Event | ||||
|
Investigati ons |
Weight loss* |
Weight gain*, Asymptomatic elevation of serum transaminases** **** (Alanine Aminotransferas e Increased*, Aspartate Aminotransferas e Increased*) Abnormal laboratory values |
Semen Abnormal |
Abnormal Clinical Laboratory Results, Altered Platelet Function, Increased Serum Cholesterol | ||
|
Injury and poisoning |
Injury | |||||
|
Infections and Infestation s |
Pharyngitis |
Upper Respiratory Tract Infection, Rhinitis |
Diverticulitis, Gastroenteritis, Otitis Media | |||
|
Neoplasms benign, malignant (including cysts and polyps) |
Neoplasm f | |||||
|
Surgical and medical procedures |
Vasodilation procedure |
If adverse experience occurred in depression, OCD, panic disorder, PTSD and social anxiety disorder, body term reclassified by depression studies body term.
f One case of neoplasm was reported in one patient receiving sertraline compared with no cases in the placebo arm.
$ Prolonged bleeding time leading to gastrointestinal haemorrhage, epistaxis, ecchymoses, haematuria, vaginal bleeding, etc.).
$$ Hyponatraemia. This remitted on discontinuation of therapy. Isolated cases may have been attributable to syndrome of inappropriate ADH secretion. These undesirable effects have mainly occurred in elderly patients and in patients using diuretics or other medicinal products.
* these adverse reactions also occurred in postmarketing experience
** the denominator uses the number of patients in that sex group-combined:
sertraline (1118 males, 1424females) placebo (926 males, 1219 females)
For OCD, short term, 1-12 week studies only
*** Cases of suicidal ideation and suicidal behaviours have been reported during sertralin therapy or early after treatment discontinuation (see section 4.4).
**** Changes in movement patterns e.g. extrapyramidal symptoms like hyperkinesia, increased muscular tone, dystonia, jaw rigidity, involuntary mouth movements, teeth grinding, or abnormal gait.
***** Signs and symptoms associated with serotonin syndrome agitation, confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and tachycardia. In some cases, these symptoms occurred in association with the concomitant use of serotonergic agents (see section 4.5 Interaction with other medicinal products and other forms of interaction).
****** Asymptomatic elevation of serum transaminases. Alterations to transaminase levels mainly occurred in the initial 9 weeks of treatment and rapidly disappeared after discontinuation of therapy.
More than 700 elderly patients (aged >65 years) participated in a clinical study to demonstrate the efficacy of sertraline in this patient group. The types and frequency of undesirable effects in the elderly patients were similar to those in younger patients.
Withdrawal symptoms seen on discontinuation of SSRI/sertraline treatment Discontinuation of sertraline (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when sertraline treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).
Although withdrawal reactions may occur on stopping therapy, the available preclinical and clinical evidence does not suggest that SSRIs cause dependence.
Elderly population
SSRIs or SNRIs including sertraline have been associated with cases of clinically significant hyponatraemia in elderly patients, who may be at greater risk for this adverse event (see section 4.4).
Paediatric population
In over 600 paediatric patients treated with sertraline, the overall profile of adverse reactions was generally similar to that seen in adult studies. The following adverse reactions were reported from controlled trials (n=281 patients treated with sertraline): Very common 1/10): Headache (22%), insomnia (21%), diarrhoea (11%) and
nausea (15%).
Common ^ 1/100 to <1/10): Chest pain, mania, pyrexia, vomiting, anorexia, affect lability, aggression, agitation, nervousness, disturbance in attention, dizziness, hyperkinesia, migraine, somnolence, tremor, visual disturbance, dry mouth, dyspepsia, nightmare, fatigue, urinary incontinence, rash, acne, epistaxis, flatulence. Uncommon ^ 1/1000 to <1/100): ECG QT prolonged, suicide attempt, convulsion, extrapyramidal disorder, paraesthesia, depression, hallucination, purpura, hyperventilation, anaemia, hepatic function abnormal, alanine aminotransferase increased, cystitis, herpes simplex, otitis externa, ear pain, eye pain, mydriasis, malaise, haematuria, rash pustular, rhinitis, injury, weight decreased, muscle twitching, abnormal dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual disorder, alopecia, dermatitis, skin disorder, skin odour abnormal, urticaria, bruxism, flushing.
Frequency not known: enuresis
Class effects
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms
The symptoms of sertraline overdosage take the form of serotonin-mediated side-effects such as drowsiness/somnolence, gastrointestinal disorders (e.g. nausea and vomiting), tachycardia, tremor, agitation and dizziness. Coma has been less frequently reported in rare cases.
Toxicity
Sertraline has a margin of safety dependent on patient population and/or concomitant medication. Deaths have been reported involving overdoses of sertraline, alone or in combination with other drugs and/or alcohol.
Available data show that sertraline has a broad safety index on overdosage. There are reports of ingestion of up to 13.5 g sertraline alone. Fatality mainly occurred after sertraline intoxication when other medicinal products and/or alcohol were ingested concomitantly. It is thus advisable to take an aggressive approach in the treatment of overdosage.
Treatment
There is no known specific antidote to sertraline. The following measures are recommended: ensure airways are free and adequate ventilation and O2 therapy are provided, if necessary. Administration of activated charcoal, in combination with sorbitol solution or another purgative if necessary, is at least as or more effective as gastric lavage and should be considered in treating overdose. Induction of vomiting is not advisable. General monitoring of cardiovascular function and other vital sign monitoring is advisable and general supportive and symptomatic measures should be provided.
Forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be effective in view of the large volume of distribution of sertraline.
Sertraline overdose may prolong the QT-interval, and ECG-monitoring is recommended in all ingestions of sertraline overdoses.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidepressant, Selective serotonin reuptake inhibitors
ATC code: N06A B06
Sertraline is a potent specific neuronal serotonin (5-HT) re-uptake inhibitor in vitro, which results in a potentiation of the effect of 5-HT in animals. Sertraline has only very poor effect on the neuronal re-uptake of noradrenalin and dopamine. In clinical doses sertraline blocks re-uptake of serotonin in human platelets. Sertraline has no stimulating, sedative or anticholinergic activity and is not cardiotoxic in animals. In controlled studies with healthy subjects sertraline had no sedating effect and did not affect the psychomotor behaviour. In accordance with the selective inhibition of the 5-HT re-uptake sertraline does not intensify the catecholaminergic activity. Sertraline has no affinity to muscarine (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA or benzodiazepinergic receptors. Chronic administration of sertraline in animals resulted in down-regulation of non-adrenergic receptors of the brain. This was also seen after other clinically effective antidepressants.
No physical or mental dependence on sertraline was seen.
5.2 Pharmacokinetic properties
Absorption
After 14 days at a daily oral dose of 50-200 mg peak plasma concentrations of sertraline will occur 4.5 - 8.4 hours after the daily administration in humans. On the basis of recovery rates in urine and faeces, it can be estimated that absorption after oral administration is at least 70 %. Bioavailability is reduced by the first pass effect. Taking of food does not significantly change the bioavailability of sertraline tablets.
Distribution
Approximately 98 % of the circulating active substance are bound to plasma proteins. Data from animal studies indicate that sertraline has a large volume of distribution. Steady-state concentrations are reached after approximately 1 week with once daily administration.
Metabolism
Sertraline has marked first-pass hepatic metabolism. The main metabolite in plasma: N-desmethyl sertraline is significantly less active than sertraline (approximately 20 fold) in vitro and there is no signs of activity in vivo. The halflife of N-desmethyl sertraline ranges between 62-104 hours. Both sertraline and N-desmethyl sertraline are metabolised to a great extent and the resulting metabolites are excreted in faeces and urine in equal amounts. Only a small amount of unchanged sertraline (less than 0.2 %) is excreted in the urine. It has been demonstrated in in vitro investigations that the metabolism of sertraline is mainly mediated by the CYP 3A4 enzyme, with only limited involvement of CYP 2D6. At the standard dose of 50 mg, sertraline has only limited effects on the CYP 2D6- and CYP 3A4-mediated metabolism of other substances.
Elimination
The mean half-life of sertraline is approximately 26 hours (22-36 hours). In accordance with this there is an approximate two-fold accumulation up to the steady state concentrations, which are reached after a daily dose for one week. In the range from 50 to 200 mg the pharmacokinetics of sertraline are dose proportional.
Special populations
Elderly
The pharmacokinetic profile in elderly people does not differ significantly from that of adults between 18 and 65 years of age.
Adolescents
In clinical studies the pharmacokinetics of sertraline in adolescent OCD patients (age 13-17 years) was comparable to in adults.
Impaired organ function
Following multiple dose treatment, the pharmacokinetics of sertraline are unchanged in patients with moderately to severely impaired renal function (creatinine clearance 10-29 ml/min). In patients with hepatic impairment, the half-life of sertraline is prolonged and the AUC increased threefold.
5.3 Preclinical safety data
Preclinical data does not indicate any special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenesis. Reproduction toxicity studies in animal showed no evidence of teratogenicity or adverse effect on male fertility. Animal data from rodents and nonrodents does not reveal effects on fertility. Conventional studies on sertraline did not demonstrate mutagenicity nor carcinogenicity. No teratogenic effects have been observed in studies on reproduction toxicity in rats and rabbits. However, delay of ossification occurred in foetus of rats and rabbits in dosages exceeding the maximal therapeutic dose in humans 2.5- up to 10-fold.
Observed foetotoxicity was probably related to maternal toxicity. Postnatal pup survival and body weight were decreased only during the first days after birth. Evidence was found that the early postnatal mortality was due to in-utero exposure after day 15 of pregnancy. Postnatal developmental delays found in pups from treated dams were probably due to effects on the dams and therefore not relevant for human risk.
Administration of sertraline in rats during the last third of gestation till end of lactation in a dosage exceeding 5-fold the maximal therapeutic dose in humans resulted in an increased number of stillbirths as well as in decreased survival rate and body weight of descendants. It could be demonstrated that lower survival rate of descendants is implicated by intrauterine exposure.
PHARMACEUTICAL PARTICULARS
6
6.1 List of excipients
Tablet core
Cellulose, microcrystalline
Calcium hydrogen phosphate dihydrate
Hyprolose
Sodium starch glycollate (Type A) Magnesium stearate
Film-coating material
Hypromellose
Talc
Titanium dioxide (E 171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blister (PVC/PVDC)
Pack sizes: 10, 14, 15, 20, 28, 30, 50, 50 x 1, 60, 98, 100.
Polyethylene tablet container with tamper evident screw cap (polyethylene) Pack size: 30, 50, 100, 250, 300, 500.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots
Cambridgeshire PE19 8ET UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0491
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation:01/12/2010
10 DATE OF REVISION OF THE TEXT
15/07/2016