Lacvel

Lacvel is indicated for the treatment of:

- Schizophrenia.

Lacvel is indicated for treatment of bipolar disorder:

- For the treatment of moderate to severe manic episodes in bipolar disorder

- For the treatment of major depressive episodes in bipolar disorder

- For the prevention of recurrence of manic or depressed episodes in patients with bipolar disorder, who previously responded to Lacvel treatment.

Posology

Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear information on the appropriate dosage for their condition.

Lacvel can be administered with or without food.

Adults:

For the treatment of schizophrenia

For the treatment of Schizophrenia, Lacvel should be administered twice a day. The total daily dose for the first 4 days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4).

From Day 4 onwards, the dose should be titrated to the usual effective dose range of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.

For the treatment of moderate to severe manic episodes in bipolar disorder

For the treatment of manic episodes associated with bipolar disorder, Lacvel should be administered twice a day. The total daily dose for the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg/day. The usual effective dose is in the range of 400 to 800 mg/day.

For the treatment of major depressive episodes in bipolar disorder

Lacvel should be administered once daily at bedtime. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg.

In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group. Individual patients may benefit from a 600 mg dose. Doses greater than 300 mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered.

For preventing recurrence in bipolar disorder

For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have responded to Lacvel for acute treatment of bipolar disorder should continue therapy at the same dose. The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice daily. It is important that the lowest effective dose is used for maintenance therapy.

Elderly:

As with other antipsychotics, Lacvel should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of Lacvel was reduced by 30 - 50% in elderly subjects when compared to younger patients.

Efficacy and safety has not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder.

Paediatric population:

Lacvel is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group.8, 5.1 and 5.2.

Renal impairment:

Dosage adjustment is not necessary in patients with renal impairment.

Hepatic impairment:

Lacvel is extensively metabolised by the liver. Therefore, Lacvel should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with known hepatic impairment should be started with 25 mg/day. The dosage should be increased daily with increments of 25 - 50 mg/day until an effective dosage, depending on the clinical response and tolerability of the individual patient.

As Lacvel has several indications, the safety profile should be considered with respect to the individual patient's diagnosis and the dose being administered.

Paediatric population

Lacvel is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. Clinical trials have shown that in addition to the known safety profile identified in adults , certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope ) or may have different implications for children and adolescents (extrapyramidal symptoms and irritability) and one was identified that has not been previously seen in adult studies (increases in blood pressure).

Changes in thyroid function tests have also been observed in children and adolescents.

Furthermore, the long-term safety implications of treatment with Lacvel on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.

In placebo-controlled clinical trials with children and adolescent patients, Lacvel was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania and bipolar depression.

Suicide/suicidal thoughts or clinical worsening:

Depression in bipolar disorder 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.

In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of Lacvel treatment, due to the known risk factors for the disease being treated.

Other psychiatric conditions for which Lacvel 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 episodes. The same precautions observed when treating patients with major depressive episodes 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.

In shorter-term placebo-controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients (younger than 25 years of age) who were treated with Lacvel as compared to those treated with placebo (3.0% vs. 0%, respectively).

Metabolic Risk

Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose (see hyperglycemia) and lipids, which was seen in clinical studies, patients' metabolic parameters should be assessed at the time of treatment initiation and changes in these parameters should be regularly controlled for during the course of treatment.).

Extrapyramidal symptoms:

In placebo controlled clinical trials of adult patients Lacvel was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder.

The use of Lacvel 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.

Tardive Dyskinesia:

If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of Lacvel should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment..

Somnolence and dizziness:

Lacvel treatment has been associated with somnolence and related symptoms, such as sedation. In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.

Orthostatic hypotension:

Lacvel treatment has been associated with orthostatic hypotension and related dizziness which, like somnolence has onset usually during the initial dose-titration period. This could increase the occurrence of accidental injury (fall), especially in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.

Lacvel should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

Sleep apnoea syndrome:

Sleep apnoea syndrome has been reported in patients using Lacvel. In patients receiving apnoea, such as those who are overweight/obese or are male, Lacvel should be used with concomitant central nervous system depressants and who have a history of or are at risk for sleep caution.

Seizures:

In controlled clinical trials there was no difference in the incidence of seizures in patients treated with Lacvel or placebo. No data is available about the incidence of seizures in patients with a history of seizure disorder. As with other antipsychotics, caution is recommended when treating patients with a history of seizures.

Neuroleptic Malignant Syndrome:

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including Lacvel. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, Lacvel should be discontinued and appropriate medical treatment given.

Severe Neutropenia and agranulocytosis:

Severe neutropenia (neutrophil count <0.5 X 109/L) has been uncommonly reported in Lacvel clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with Lacvel. There was no apparent dose relationship. During post-marketing experience, some cases were fatal. Possible risk factors for neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced neutropenia. However, some cases occurred in patients without pre-existing risk factors Lacvel should be discontinued in patients with a neutrophil count <1.0 X 109/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 109/L)..

Neutropenia should be considered in patients presenting with infection or fever, particularly in the absence of obvious predisposing factor(s), and should be managed as clinically appropriate.

Patients should be advised to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during Lacvel therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors

Anticholinergic (muscarinic) effects:

NorLacvel, an active metabolite of Lacvel, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to ADRs reflecting anticholinergic effects when Lacvel is used at recommended doses, when used concomitantly with other medications having anticholinergic effects, and in the setting of overdose. Lacvel should be used with caution in patients receiving medications having anticholinergic (muscarinic) effects. Lacvel should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or narrow angle glaucoma.

Interactions

Concomitant use of Lacvel with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases Lacvel plasma concentrations, which could affect the efficacy of Lacvel therapy. In patients receiving a hepatic enzyme inducer, initiation of Lacvel treatment should only occur if the physician considers that the benefits of Lacvel outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).

Weight

Weight gain has been reported in patients who have been treated with Lacvel, and should be monitored and managed as clinically appropriate as in accordance with utilised antipsychotic guidelines.

Hyperglycaemia

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic agent including Lacvel, should be observed for signs and symptoms of hyperglycaemia, (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.

Lipids

Increases in triglycerides, LDL- and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with Lacvel. Lipid changes should be managed as clinically appropriate.

QT Prolongation

In clinical trials and use in accordance with the SPC, Lacvel was not associated with a persistent increase in absolute QT intervals. In post-marketing, QT prolongation was reported with Lacvel at the therapeutic doses and in overdose. As with other antipsychotics, caution should be exercised when Lacvel is prescribed either in patients with cardiovascular disease or family history of QT prolongation. Also caution should be exercised when Lacvel is prescribed with medicines known to increase QT interval or with concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.

Cardiomyopathy and Myocarditis

Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience, however, a causal relationship to Lacvel has not been established. Treatment with Lacvel should be reassessed in patients with suspected cardiomyopathy or myocarditis.

Withdrawal

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability have been described after abrupt cessation of Lacvel. Gradual withdrawal over a period of at least one to two weeks is advisable.

Elderly patients with dementia-related psychosis

Lacvel is not approved for the treatment of dementia-related psychosis.

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Lacvel should be used with caution in patients with risk factors for stroke.

In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However in two 10-week placebo-controlled Lacvel studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in Lacvel-treated patients was 5.5% versus 3.2% in the placebo group. These data do not establish a causal relationship between Lacvel treatment and death in elderly patients with dementia.

Dysphagia

Dysphagia has been reported with Lacvel.

Lacvel should be used with caution in patients at risk for aspiration pneumonia.

Constipation and intestinal obstruction

Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with Lacvel. This includes fatal reports in patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medications that decrease intestinal motility and/or may not report symptoms of constipation. Patients with intestinal obstruction/ileus should be managed with close monitoring and urgent care.

Venous Thromboembolism (VTE)

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs.

Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Lacvel and preventive measures undertaken.

Pancreatitis

Pancreatitis has been reported in clinical trials and during post marketing experience. Among post marketing reports, while not all cases were confounded by risk factors, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides , gallstones, and alcohol consumption.

Additional information

Lacvel data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3.

Misuse and abuse

Cases of misuse and abuse have been reported. Caution may be needed when prescribing Lacvel to patients with a history of alcohol or drug abuse.

Lactose

Lacvel tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Given its primary central nervous system effects, Lacvel may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility to this is known.

The most commonly reported Adverse Drug Reactions (ADRs) with Lacvel (>10%) are somnolence, dizziness, headache, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms

The incidences of ADRs associated with Lacvel therapy, are tabulated below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).

Table 1 ADRs associated with Lacvel therapy

The frequencies of adverse events are ranked according to the following: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100, rare (>1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

2. Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of Lacvel.

3. Asymptomatic elevations (shift from normal to >3 x ULN at any time) in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in some patients administered Lacvel. These elevations were usually reversible on continued Lacvel treatment.

4. As with other antipsychotics with alpha1 adrenergic blocking activity, Lacvel may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period.

5. Calculation of Frequency for these ADR's have been taken from postmarketing data only.

6. Fasting blood glucose >126mg/dL (>7.0 mmol/L) or a nonfasting blood glucose >200mg/dL (>11.1 mmol/L) on at least one occasion.

7. An increase in the rate of dysphagia with Lacvel vs. placebo was only observed in the clinical trials in bipolar depression.

8. Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.

9. The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.

10. Triglycerides >200mg/dL (>2.258 mmol/L) (patients >18 years of age) or >150 mg/dL (>1.694 mmol/L) (patients <18 years of age) on at least one occasion.

11. Cholesterol >240mg/dL (>6.2064 mmol/L) (patients >18 years of age) or >200 mg/dL (>5.172 mmol/L) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of >30 mg/dL (>0.769 mmol/L) has been very commonly observed. Mean change among patients who had this increase was 41.7 mg/dL (>1.07 mmol/L).

12. See text below.

13. Platelets ≤ 100 x 109/L on at least one occasion.

14. Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.

15. Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34 pmol/L) females at any time.

16. May lead to falls.

17. HDL cholesterol: <40 mg/dL (1.025 mmol/L) males; <50 mg/dL (1.282 mmol/L) females at any time.

18. Incidence of patients who have a QTc shift from <450 msec to > 450 msec with a > 30 msec increase. In placebo-controlled trials with Lacvel the mean change and the incidence of patients who have a shift to a clinically significant level is similar between Lacvel and placebo.

19. Shift from >132 mmol/L to ≤ 132 mmol/L on at least one occasion.

20. Cases of suicidal ideation and suicidal behaviours have been reported during Lacvel therapy or early after treatment discontinuation.

21.

22. Decreased haemoglobin to ≤ 13 g/dL (8.07 mmol/L) males, ≤ 12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of Lacvel patients in all trials including open label extensions. For these patients, the mean maximum decrease in haemoglobin at any time was -1.50 g/dL.

23. These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disease.

24. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.

25. Based upon the increased rate of vomiting in elderly patients (> 65 years of age).

26. Shift in neutrophils from > 1.5 x 109/L at baseline to <0.5 x 109/L at any time during treatment and based on patients with severe neutropenia (<0.5 x 109/L) and infection during all Lacvel clinical trials.

27. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in eosinophils are defined as >1 x 109 cells/L at any time.

28. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in WBCs are defined as ≤ 3 x 109 cells/L at any time.

29. Based on adverse event reports of metabolic syndrome from all clinical trials with Lacvel.

30. In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies

31.

32. May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with Lacvel.

Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.

Paediatric population

The same ADRs described above for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher frequency category in children and adolescents patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population.

Table 2 ADRs in children and adolescents associated with Lacvel therapy that occur in a higher frequency than adults, or not identified in the adult population

1. Prolactin levels (patients < 18 years of age):>20 ug/L (>869.56 pmol/L) males;>26 ug/L(>1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level>100 ug/L.

2. Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases>20mmHg for systolic or>10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.

3. Note: The frequency is consistent to that observed in adults, but irritability might be associated with different clinical implications in children and adolescents as compared to adults.

4.

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Symptoms

In general, reported signs and symptoms were those resulting from an exaggeration of the active substance's known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension and anticholinergic effects.

Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma and death.).

Management of overdose

There is no specific antidote to Lacvel. In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

Based on public literature, patients with delerium and agitation and a clear anticholinergic syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as standard treatment, because of potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening.

Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in severe poisonings and if possible to perform within one hour of ingestion. The administration of activated charcoal should be considered.

In cases of Lacvel overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of Lacvel-induced alpha blockade.

Close medical supervision and monitoring should be continued until the patient recovers.

Pharmacotherapeutic group: Antipsychotics.

ATC code: N05A H04

Mechanism of action:

Lacvel is an atypical antipsychotic agent. Lacvel and the active human plasma metabolite, norLacvel interact with a broad range of neurotransmitter receptors. Lacvel and norLacvel exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2- receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2- receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Lacvel compared to typical antipsychotics. Lacvel and norLacvel have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors, moderate affinity at adrenergic alpha2 receptors. Lacvel also has low or no affinity for muscarinic receptors, while norLacvel has moderate to high affinity at several muscarinic receptors, which may explain anti-cholinergic (muscarinic) effects. Inhibition of NET and partial agonist action at 5HT1A sites by norLacvel may contribute to Lacvel's therapeutic efficacy as an antidepressant.

Pharmacodynamic effects:

Lacvel is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.

In pre-clinical tests predictive of EPS, Lacvel is unlike atypical antipsychotics and has an atypical profile. Lacvel does not produce dopamine D2-receptor supersensitivity after chronic administration. Lacvel produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Lacvel demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Lacvel exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration..

Clinical efficacy:

Schizophrenia

In three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of Lacvel, there were no differences between the Lacvel and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics. A placebo-controlled trial evaluating fixed doses of Lacvel across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anticholinergics. The long-term efficacy of Lacvel IR in prevention of schizophrenic relapses has not been verified in blinded clinical trials. In open label trials, in patients with schizophrenia, Lacvel was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response, suggesting some long-term efficacy.

Bipolar disorder

In four placebo-controlled clinical trials, evaluating doses of Lacvel up to 800 mg/day for the treatment of moderate to severe manic episodes, two each in monotherapy and as combination therapy to lithium or divalproex, there were no differences between the Lacvel and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.

In the treatment of moderate to severe manic episodes, Lacvel demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. There are no data from long-term studies to demonstrate Lacvel's effectiveness in preventing subsequent manic or depressive episodes. Lacvel data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.

The mean last week median dose of Lacvel in responders was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.

In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, Lacvel IR 300 mg and 600 mg was significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline. There was no difference in magnitude of effect between the patients who received 300 mg Lacvel IR and those who received 600 mg dose.

In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on Lacvel IR 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.

In two recurrence prevention studies evaluating Lacvel in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with Lacvel was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed). Lacvel was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.

In a 6-week, randomised, study of lithium and Lacvel XR versus placebo and Lacvel XR in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was 2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs. 68% in the placebo add-on group).

In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes Lacvel was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the Lacvel group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to Lacvel, when comparing continued treatment with Lacvel to switching to lithium, the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.

Clinical trials have demonstrated that Lacvel is effective in schizophrenia and mania when given twice a day, although Lacvel has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study, which identified that for Lacvel, 5HT2- and D2-receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

Clinical safety:

In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for Lacvel and 8.0% for placebo; bipolar mania: 11.2% for Lacvel and 11.4% for placebo). Higher rates of extrapyramidal symptoms were seen in Lacvel-treated patients compared to those treated with placebo in short-term, placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for Lacvel compared to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for Lacvel XR and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for Lacvel XR and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in any treatment group.

In short-term, fixed dose (50 mg/d to 800 mg/d), placebo-controlled studies (ranging from 3 to 8 weeks), the mean weight gain for Lacvel-treated patients ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo-treated patients. The percentage of Lacvel-treated patients who gained >7% of body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily doses), compared to 3.7% for placebo-treated patients.

A 6-week, randomised, study of lithium and Lacvel XR versus placebo and Lacvel XR in adult patients with acute mania indicated that the combination of Lacvel XR with lithium leads to more adverse events (63% versus 48% in Lacvel XR in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the Lacvel XR with lithium add-on group (12.7%) compared to the Lacvel XR with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (>7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).

Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which patients were treated with Lacvel, followed by a randomised withdrawal period during which patients were randomised to Lacvel or placebo. For patients who were randomised to Lacvel, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomised period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomised to placebo, the mean weight gain during the open label period was 2.39 kg, and by week 48 of the randomised period the mean weight gain was 0.89 kg, compared to open label baseline.

In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in Lacvel-treated patients than in placebo-treated patients.

In all short-term placebo-controlled monotherapy trials in patients with a baseline neutrophil count > 1.5 X 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 109/L, was 1.9% in patients treated with Lacvel compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5-<1.0 x 109/L was the same (0.2%) in patients treated with Lacvel as with placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator) in patients with a baseline neutrophil count >1.5 X 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 109/L was 2.9%and to <0.5 X 109/L was 0.21% in patients treated with Lacvel.

Lacvel treatment was associated with dose-related decreases in thyroid hormone levels. The incidences of shifts in TSH was 3.2% for Lacvel versus 2.7% for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of Lacvel treatment, with no further reduction during long-term treatment. For about 2/3 of all cases, cessation of Lacvel treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.

Cataracts/lens opacities

In a clinical trial to evaluate the cataractogenic potential of Lacvel (200-800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in Lacvel (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.

Paediatric population

Clinical efficacy

The efficacy and safety of Lacvel was studied in a 3-week placebo controlled study for the treatment of mania (n= 284 patients from the US, aged 10-17). About 45% of the patient population had an additional diagnosis of ADHD. In addition, a 6-week placebo controlled study for the treatment of schizophrenia (n = 222 patients, aged 13-17) was performed. In both studies, patients with known lack of response to Lacvel were excluded. Treatment with Lacvel was initiated at 50 mg/day and on day 2 increased to 100 mg/day; subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given two or three times daily.

In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was -5.21 for Lacvel 400 mg/day and -6.56 for Lacvel 600 mg/day. Responder rates (YMRS improvement >50%) were 64% for Lacvel 400 mg/day, 58% for 600 mg/day and 37% in the placebo arm.

In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active minus placebo) was -8.16 for Lacvel 400 mg/day and -9.29 for Lacvel 800 mg/day. Neither low dose (400 mg/day) nor high dose regimen (800 mg/day) Lacvel was superior to placebo with respect to the percentage of patients achieving response, defined as >30% reduction from baseline in PANSS total score. Both in mania and schizophrenia higher doses resulted in numerically lower response rates.

In a third short-term placebo-controlled monotherapy trial with Lacvel XR in children and adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated.

No data are available on maintenance of effect or recurrence prevention in this age group.

Clinical safety

In the short-term pediatric trials with Lacvel described above, the rates of EPS in the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs. 1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The rates of weight gain > 7% of baseline body weight in the active arm vs. placebo were 17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 12.5% vs. 6% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended posttreatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on Lacvel at the time of the event.

Long-term safety

A 26-week open-label extension to the acute trials (n=380 patients), with Lacvel flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients. With respect to weight gain, when adjusting for normal growth over the longer term, an increase of at least 0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically significant change; 18.3% of patients who were treated with Lacvel for at least 26 weeks met this criterion.

Absorption

Lacvel is well absorbed and extensively metabolised following oral administration. The bioavailability of Lacvel is not significantly affected by administration with food. Steady-state peak molar concentrations of the active metabolite norLacvel are 35% of that observed for Lacvel.

The pharmacokinetics of Lacvel and norLacvel are linear across the approved dosing range.

Distribution

Lacvel is approximately 83% bound to plasma proteins.

BiotransformationLacvel is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled Lacvel. In vitroinvestigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of Lacvel. NorLacvel is primarily formed and eliminated via CYP3A4.

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.

Lacvel and several of its metabolites (including norLacvel) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of Lacvel with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that Lacvel can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of Lacvel.

Elimination

The elimination half lives of Lacvel and norLacvel are approximately 7 and 12 hours, respectively.

The average molar dose fraction of free Lacvel and the active human plasma metabolite norLacvel is <5% excreted in the urine.

Special populations

Gender

The kinetics of Lacvel do not differ between men and women.

Elderly

The mean clearance of Lacvel in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.

Renal impairment

The mean plasma clearance of Lacvel was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2), but the individual clearance values are within the range for normal subjects.

Hepatic impairment

The mean Lacvel plasma clearance decreases with approx. 25% in persons with known hepatic impairment (stable alcohol cirrhosis). As Lacvel is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients.

Paediatric population

Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg Lacvel twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, Lacvel, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norLacvel, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.

There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory animals at a clinically relevant exposure level the following deviations were seen, which as yet have not been confirmed in long term clinical research.

In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts..

In an embryofetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects were apparent at maternal exposure levels similar or slightly above those in humans at the maximal therapeutic dose. The relevance of this finding for humans is unknown.

In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to elevated prolactin levels and not directly relevant to humans because of species differences in hormonal control of reproduction

Not applicable

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.