Secondary pharmacologic properties of SSRIs¹

The clinical consequences of Sigma receptor activity: ²

Involved in the modulation of various neurotransmitter systems e.g. NMDA-type -
glutamate receptors.

Implicated in higher-ordered brain functions.

Plays important roles in the pathophysiology of neuropsychiatric diseases such as
schizophrenia, depression, anxiety disorders, and dementia.

SSRIs: Selective serotonin re-uptake inhibitors; NMDA: N-methyl-D-aspartate MDD: Major Depressive Disorder

Sertraline pharmacologic properties¹

      Adapted from Stahi SM 2nd ed. NY: Cambridge University Press 2000.

Possible drug interactions:³

TCAs: Tricyclic antidepressants; CYP: Cytochrome MDD: Major Depressive Disorder

EARLY CLINICAL RESPONSE^1,2

Mean CGI improvement score by treatment group and visit¹

+week 1 N= 133-135: week 8 N= 76-85. For statistical comparisons between placebo and both active agents: ¶ 0.05 ≥ p > 0.01: # 0.01≥ p > 0.001: $ 0.001> p. For statistical comparisons between Lustral and amitriptyline: ¶ 0.05 ≥ p >0.01: ++ 0.01 ≥ p > 0.001

A double-blind, placebo- and amitriptyline-controlled comparison study was performed to evaluate the antidepressant efficacy of Lustral, a specific serotonin uptake inhibitor. Patients with DSM-III-defined major depression randomly received either Lustral (N = 149), amitriptyline (N = 149), or placebo (N = 150) once daily for the 8-week study period. The mean final daily medication dose for the all-patients group was 145 mg and 104 mg for the Lustral- and amitriptyline-treatment groups, respectively

CGI: Clinical Global Impressions, DSM III: Diagnostic and Statistical Manual of Mental Disorders 3rd edition; MDD: Major Depressive Disorder

Change in CGI improvement scale scores by visit²

Three hundred twenty-four nondepressed outpatients with OCD from 11 sites followed identical protocols using a double-blind parallel design. Following 1 week of single-blind placebo, patients were randomly assigned to 12 weeks of treatment with one of three fixed dosages of Lustral (50, 100, or 200 mg/d) or placebo. Treatment responders (moderate or marked improvement on the Clinical Global Impression (CGI) Scale Efficacy Index at the end of week 12) were offered an additional 40 weeks of double- blind treatment; nonresponders underwent down titration over a 2 week period, and treatment was discontinued

OCD: Obsessive Compulsive Disorder MDD: Major Depressive Disorder

- Might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.¹
- Well tolerated in patients with acute myocardial infarctions and unstable angina and without other life-threatening medical conditions.²
- Daily doses of 50-200 mg of sertraline showed safety, efficacy and tolerability in the long-term treatment of patients with OCD.³

Dosage and Administration:⁴
Dosage Form: Film-Coated Tablets Dose: 50 mg / day

MDD: Major Depressive Disorder OCD: Obsessive Compulsive Disorder

Lustral^® Abbreviated Prescribing Information:

PRESENTATION: Lustral^® (Sertaline) is available as 50 mg film-coated tablets.

INDICATIONS: Sertraline is indicated for the treatment of 1) Major depressive episodes. Prevention of the recurrence of major depressive episodes. 2) Panic disorder, with or without agoraphobia. 3) Obsessive-compulsive disorder (OCD) in adults and paediatric patients aged 6-17 years. 4) Social anxiety disorder. 5) Post-Traumatic Stress Disorder (PTSD).

DOSAGE AND ADMINISTRATION: Sertraline should be administered once daily, either in the morning or evening. Sertraline tablets can be administered with or without food. Initial treatment; Depression and OCD, Sertraline treatment should be started at a dose of 50 mg per day. Panic Disorder, PTSD and Social Anxiety Disorder, Therapy should be started at a dose of 25 mg per day. After one week, the dose should be increased to 50 mg once per day. This dose regimen has been shown to reduce the frequency of early treatment emergent side effects characteristic of panic disorder. Titration; Depression, OCD, Panic Disorder, Social Anxiety Disorder and PTSD, Patients not responding to a 50 mg dose may benefit from dose increases. Dose changes should be made in steps of 50 mg at intervals of at least one week, up to a maximum of 200 mg/day. Changes in dose should not be made more frequently than once per week given the 24-hour elimination half life of Lustral. The onset of therapeutic effect may be seen within 7 days. However, longer periods are usually necessary to demonstrate therapeutic response, especially in OCD. Maintenance; Dosage during long-term therapy should be kept at the lowest effective level, with subsequent adjustment depending on therapeutic response. 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. Elderly patients, Elderly should be dosed carefully, as elderly may be more at risk for hyponatraemia. Patients with hepatic impairment, the use of Lustral in patients with hepatic disease should be approached with caution. A lower or less frequent dose should be used in patients with hepatic impairment. Lustral should not be used in cases of severe hepatic impairment as no clinical data are available. Patients with renal impairment, No dosage adjustment is necessary in patients with renal impairment. Paediatric population; Children and adolescents with Obsessive-Compulsive Disorder, A) Age 13-17 years: Initially 50 mg once daily. B) Age 6-12 years: s 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. Withdrawal symptoms seen on discontinuation of sertraline; Abrupt discontinuation should be avoided. When stopping treatment with Lustral 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. 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.

CONTRAINDICATIONS: Hypersensitivity to the active substance or any of the excipients. 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. Lustral must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Lustral must be discontinued for at least 7 days before starting treatment with an irreversible MAOI. Concomitant intake of pimozide is contraindicated.

WARNINGS AND PRECAUTIONS: 1) 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 Lustral. The risk of SS or NMS with SSRIs is increased with concomitant use of other serotonergic drugs (including other serotonergic antidepressants, amphetamines, triptans), with drugs which impair metabolism of serotonin (including MAOIs e.g. methylene blue), antipsychotics and other dopamine antagonists, and with opiate drugs. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome. 2) Switching from Selective Serotonin Reuptake Inhibitors (SSRIs), antidepressants or antiobsessional drugs: There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or antiobsessional drugs to Lustral. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents such as fluoxetine. 3) Other serotonergic drugs e.g. tryptophan, fenfluramine and 5-HT agonists: Co-administration of Lustral with other drugs which enhance the effects of serotonergic neurotransmission such as amphetamines, tryptophan or fenfluramine or 5-HT agonists, or the herbal medicine, St John’s Wort (hypericum perforatum), should be undertaken with caution and avoided whenever possible due to the potential for a pharmacodynamic interaction. 4) QTc Prolongation/Torsade de Pointes (TdP): Cases of QTc prolongation and TdP have been reported during post-marketing use of Lustral. The majority of reports occurred in patients with other risk factors for QTc prolongation/TdP. Effect on QTc prolongation was confirmed in a thorough QTc study in healthy volunteers, with a statistically significant positive exposure-response relationship. Therefore Lustral should be used with caution in patients with additional risk factors for QTc prolongation such as cardiac disease, hypokalaemia or hypomagnesemia, familial history of QTc prolongation, bradycardia and concomitant use of medications which prolong QTc interval. 5) Activation of hypomania or mania: Manic/hypomanic symptoms have been reported to emerge in a small proportion of patients treated with marketed antidepressant and antiobsessional drugs, including Lustral. Therefore Lustral should be used with caution in patients with a history of mania/hypomania. Close surveillance by the physician is required. Lustral should be discontinued in any patient entering a manic phase. 6) Schizophrenia: Psychotic symptoms might become aggravated in schizophrenic patients. 7) Seizures: Seizures may occur with Lustral therapy: Lustral should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Lustral should be discontinued in any patient who develops seizures. 8) 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 that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions, for which Lustral 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. 9) Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms of sexual dysfunction . There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.10) Paediatric population: Lustral 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. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants 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 only limited clinical evidence is available concerning, long-term safety data in children and adolescents including effects on growth, sexual maturation and cognitive and behavioural developments A few cases of retarded growth and delayed puberty have been reported post-marketing. The clinical relevance and causality are yet unclear. Physicians must monitor paediatric patients on long term treatment for abnormalities in growth and development. 11) Abnormal bleeding/haemorrhage: There have been reports of bleeding abnormalities with SSRIs including cutaneous bleeding (ecchymoses and purpura) and other haemorrhagic events such as gastrointestinal or gynaecological bleeding, including fatal haemorrhages. SSRIs/SNRIs may increase the risk of postpartum haemorrhage. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. anticoagulants, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non- steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders. 12) Hyponatraemia: Hyponatraemia may occur as a result of treatment with SSRIs or SNRIs including Lustral. In many cases, hyponatraemia appears to be the result of a syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatraemia with SSRIs and SNRIs. Also patients taking diuretics or who are otherwise volume-depleted may be at greater risk (see Use in elderly). Discontinuation of Lustral 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. 13) Withdrawal symptoms seen on discontinuation of Lustral treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. In clinical trials, among patients treated with Lustral, the incidence of reported withdrawal reactions was 23% in those discontinuing Lustral compared to 12% in those who continued to receive Lustral 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 Lustral should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs. 14) Akathisia/psychomotor restlessness: The use of Lustral has been associated with the development of akathisia, characterised 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. 15) Hepatic impairment: Lustral is extensively metabolised by the liver. A multiple dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half life and approximately three- fold greater AUC and Cmax in comparison to normal subjects. There were no significant differences in plasma protein binding observed between the two groups. The use of Lustral in patients with hepatic disease must be approached with caution. If Lustral is administered to patients with hepatic impairment, a lower or less frequent dose should be considered. Lustral should not be used in patients with severe hepatic impairment. 16) Renal impairment: Lustral is extensively metabolised, and excretion of unchanged drug in urine is a minor route of elimination. In studies of patients with mild to moderate renal impairment (creatinine clearance 30-60 ml/min) or moderate to severe renal impairment (creatinine clearance 10-29 ml/min), multiple- dose pharmacokinetic parameters (AUC0-24 or Cmax) were not significantly different compared with controls. Lustral dosing does not have to be adjusted based on the degree of renal impairment. 17) Use in elderly: Over 700 elderly patients (>65 years) have participated in clinical studies. The pattern and incidence of adverse reactions in the elderly was similar to that in younger patients. SSRIs or SNRIs including Lustral have however been associated with cases of clinically significant hyponatraemia in elderly patients, who may be at greater risk for this adverse event. 18) Diabetes: In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted. 19) Electroconvulsive therapy: There are no clinical studies establishing the risks or benefits of the combined use of ECT and Lustral. 20) Grapefruit juice: The administration of Lustral with grapefruit juice is not recommended. 21) Interference with urine screening tests: False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking Lustral. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of Lustral therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish Lustral from benzodiazepines. 22) Angle-Closure glaucoma: SSRIs including Lustral 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. Lustral should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.

PREGNANCY AND LACTATION: Pregnancy: There are no well controlled studies in pregnant women. However, a substantial amount of data did not reveal evidence of induction of congenital malformations by Lustral. 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. Use of Lustral during pregnancy has been reported to cause symptoms, compatible with withdrawal reactions, in some neonates, whose mothers had been on Lustral. This phenomenon has also been observed with other SSRI antidepressants. Lustral is not recommended in pregnancy, unless the clinical condition of the woman is such that the benefit of the treatment is expected to outweigh the potential risk. Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth. Neonates should be observed if maternal use of Lustral continues into the later stages of pregnancy, particularly the third trimester. The following symptoms may occur in the neonate after maternal Lustral use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty in sleeping. These symptoms could be due to either serotonergic effects or 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 Lustral levels in breast milk show that small quantities of Lustral and its metabolite N- desmethylsertraline are excreted in milk. Generally negligible to undetectable levels were found in infant serum, with one exception of an infant with serum levels about 50% of the maternal level (but without a noticeable health effect in this infant). There are no data on the effects of sertraline on milk production. To date, no adverse effects on the health of infants nursed by mothers using Lustral have been reported, but a risk cannot be excluded. Use in nursing mothers is not recommended unless, in the judgment of the physician, the benefit outweighs the risk. Fertility: Animal data did not show an effect of Lustral on fertility parameters. 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. (A) Contraindicated: (1) Monoamine oxidase inhibitors (i) Irreversible MAO inhibitors (e.g. selegiline): Lustral must not be used in combination with irreversible MAOIs such as selegiline. Lustral must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Lustral must be discontinued for at least 7 days before starting treatment with an irreversible MAOI. (ii) Reversible and selective MAO inhibitor (moclobemide): Due to the risk of serotonin syndrome, the combination of Lustral 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 Lustral treatment. It is recommended that Lustral should be discontinued for at least 7 days before starting treatment with a reversible MAOI. (iii) 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 Lustral. Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI (e.g. methylene blue) and started on Lustral, or have recently had Lustral 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. 2) Pimozide Increased pimozide levels of approximately 35% have been demonstrated in a study of a single low dose pimozide (2 mg). These increased levels were not associated with any changes in EKG. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant administration of Lustral and pimozide is contraindicated. (B) Co-administration with Lustral is not recommended: (1) CNS depressants and alcohol: The co-administration of Lustral 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 Lustral and alcohol is not recommended. (2) Other serotoninergic drugs. Caution is also advised with fentanyl (used in general anaesthesia or in the treatment of chronic pain), other serotonergic drugs (including other serotonergic antidepressants, amphetamines, triptans), and with other opiate drugs. (C) Special precautions: (1) Drugs that Prolong the QT Interval: The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) may be increased with concomitant use of other drugs which prolong the QTc interval (e.g. some antipsychotics and antibiotics). (2) Lithium: In a placebo-controlled trial in normal volunteers, the co-administration of Lustral with lithium did not significantly alter lithium pharmacokinetics, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. When co-administering Lustral with lithium, patients should be appropriately monitored. (3) Phenytoin: A placebo-controlled trial in normal volunteers suggests that chronic administration of Lustral 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, as some case reports have emerged of high phenytoin exposure in patients using Lustral, it is recommended that plasma phenytoin concentrations be monitored following initiation of Lustral therapy, with appropriate adjustments to the phenytoin dose. In addition, co-administration of phenytoin may cause a reduction of Lustral plasma levels. It cannot be excluded that other CYP3A4 inducers, e.g. phenobarbital, carbamazepine, St John´s Wort, rifampicin may cause a reduction of Lustral plasma levels. (4) Triptans: There have been rare post-marketing reports describing patients with weakness, hyperreflexia, incoordination, confusion, anxiety and agitation following the use of Lustral and sumatriptan. Symptoms of serotonergic syndrome may also occur with other products of the same class (triptans). If concomitant treatment with Lustral and triptans is clinically warranted, appropriate observation of the patient is advised. (5) Warfarin: Co-administration of Lustral 200 mg daily with warfarin resulted in a small but statistically significant increase in prothrombin time, which may in some rare cases unbalance the INR value. Accordingly, prothrombin time should be carefully monitored when Lustral therapy is initiated or stopped. (6) Other drug interactions, digoxin, atenolol, cimetidine: Co-administration with cimetidine caused a substantial decrease in Lustral clearance. The clinical significance of these changes is unknown. Lustral had no effect on the beta-adrenergic blocking ability of atenolol. No interaction of Lustral 200 mg daily was observed with digoxin. (7) 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 Lustral. (8) Neuromuscular Blockers: SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium or other neuromuscular blockers. (9) Drugs Metabolized by Cytochrome P450: Lustral may act as a mild-moderate inhibitor of CYP 2D6. Chronic dosing with Lustral 50 mg daily showed moderate elevation (mean 23%-37%) of steady-state desipramine plasma levels (a marker of CYP 2D6 isozyme activity). Clinical relevant interactions may occur with other CYP 2D6 substrates with a narrow therapeutic index like class 1C antiarrhythmics such as propafenone and flecainide, TCAs and typical antipsychotics, especially at higher Lustral dose levels. Lustral does not act as an inhibitor of CYP 3A4, CYP 2C9, CYP 2C19, and CYP 1A2 to a clinically significant degree. This has been confirmed by in-vivo interaction studies with CYP3A4 substrates (endogenous cortisol, carbamazepine, terfenadine, alprazolam), CYP2C19 substrate diazepam, and CYP2C9 substrates tolbutamide, glibenclamide and phenytoin. In vitro studies indicate that Lustral has little or no potential to inhibit CYP 1A2. Intake of three glasses of grapefruit juice daily increased the Lustral plasma levels by approximately 100% in a cross-over study in eight Japanese healthy subjects. Therefore, the intake of grapefruit juice should be avoided during treatment with Lustral. Based on the interaction study with grapefruit juice, it cannot be excluded that the concomitant administration of Lustral 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 Lustral. 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 Lustral. Lustral plasma levels are enhanced by about 50% in poor metabolizers of CYP2C19 compared to rapid metabolizers. Interaction with strong inhibitors of CYP2C19, e.g. omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, fluvoxamine cannot be excluded.

OVERDOSING: Toxicity: Lustral has a margin of safety dependent on patient population and/or concomitant medication. Deaths have been reported involving overdoses of Lustral, alone or in combination with other drugs and/or alcohol. Therefore, any overdosage should be medically treated aggressively. Symptoms: Symptoms of overdose include serotonin-mediated side effects such as somnolence, gastrointestinal disturbances (e.g. nausea and vomiting), tachycardia, tremor, agitation and dizziness. Coma has been reported although less frequently. QTc prolongation/Torsade de Pointes has been reported following Lustral overdose; therefore, ECG- monitoring is recommended in all ingestions of Lustral overdoses. Management: There are no specific antidotes to Lustral. It is recommended to establish and maintain an airway and, if necessary, ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with a cathartic, may be as, or more effective than lavage, and should be considered in treating overdose. Induction of emesis is not recommended. Cardiac (e.g. ECG) and vital sign monitoring is also recommended, along with general symptomatic and supportive measures. Due to the large volume of distribution of Lustral, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.

ADVERSE EVENTS: Nausea is the most common undesirable effect. In the treatment of social anxiety disorder, sexual dysfunction (ejaculation failure) in men occurred in 14% for Lustral vs 0% in placebo. These undesirable effects are dose dependent and are often transient in nature with continued treatment. 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. Adverse reactions observed from post-marketing experience (frequency not known) and placebo-controlled clinical trials (comprising a total of 2542 patients on Lustral and 2145 on placebo) in depression, OCD, panic disorder, PTSD and social anxiety disorder. The very common adverse events (≥ 1/10) were Insomnia, Dizziness, somnolence, headaches, Diarrhea, nausea, dry mouth, ejaculation failure, Fatigue. The common adverse events (≥ 1/100 to < 1/10) were upper respiratory tract infection, pharyngitis, rhinitis, decreased appetite, increased appetite, anxiety, depression, agitation, libido decreased, nervousness, depersonalisation, nightmare, bruxism, tremor, movement disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, teeth grinding or gait abnormalities), paraesthesia, hypertonia, disturbance in attention, dysgeusia, visual disturbance, tinnitus, palpitations, hot flush, yawning, dyspepsia, constipation, abdominal pain, vomiting, flatulence, hyperhidrosis, rash, back pain, arthralgia, myalgia, menstruation irregular, erectile dysfunction, malaise, chest pain, asthenia, pyrexia, weight increased, injury. Withdrawal symptoms seen on discontinuation of Lustral treatment: Discontinuation of Lustral (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. 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 Lustral treatment is no longer required, gradual discontinuation by dose tapering should be carried out. Elderly population: SSRIs or SNRIs including Lustral have been associated with cases of clinically significant hyponatraemia in elderly patients, who may be at greater risk for this adverse event Pediatric population: In over 600 paediatric patients treated with Lustral, 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 Lustral): 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.

PHARMACEUTICAL PRECAUTIONS: Shelf life: 36 months. Special precautions for storage: Store below 30°C. Keep out of the sight and reach of children.

REFERENCE: Lustral^® [SmPC]. SPIMACO Al-Qassim Pharmaceutical Plant, Saudi Arabia Under license from PFIZER INC., New York, USA; October 2020.

DATE OF THIS DOCUMENT: 08 February 2022

Full prescribing information is available upon request