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Denzapine 50mg Tablets | Marketing authorisation holder | Britannia Pharmaceuticals Limited
200 Longwater Avenue
Green Park
Reading
Berkshire
RG2 6GP
UK
8. Marketing authorisation number(s)
PL 04483/0068
9. |
Denzapine 50mg Tablets | Date of first authorisation/renewal of the authorisation | 26 January 2012
10. |
Denzapine 50mg/ml Oral Suspension | Name of the medicinal product | Denzapine® 50 mg/ml Oral Suspension
As a consequence of a recent European regulatory initiative, the Denzapine Summary of Product Characteristics (SmPC) has been harmonised across Europe. The SmPC states that blood monitoring should be carried out in accordance with national-specific official recommendations. These are reproduced below.
The Denzapine Monitoring Service (DMS) was developed in order to manage the risk of agranulocytosis associated with clozapine. It is available 24 hours a day. When a monitoring service is not used, evidence suggests a mortality rate from agranulocytosis of 0.3%[1]. This is compared to a mortality rate when clozapine is used in conjunction with a Monitoring Service, of 0.01%[2].
The Denzapine Monitoring Service provides centralised monitoring of leucocyte and neutrophil counts which is a mandatory requirement for all patients in the UK and Ireland who are treated with Denzapine. The use of Denzapine is restricted to patients who are registered with the Denzapine Monitoring Service. In addition to registering their patients, prescribing physicians must register themselves and a nominated pharmacist with the Denzapine Monitoring Service. All Denzapine-treated patients must be under the supervision of an appropriate specialist and supply of Denzapine is restricted to hospital and retail pharmacies registered with the Denzapine Monitoring Service. Denzapine is not sold to, or distributed through wholesalers.
The patient's white cell count with a differential count must be monitored:
• At least weekly for the first 18 weeks of treatment
• At least at 2 week intervals between weeks 18 and 52
• After 1 year of treatment with stable blood counts (green range), patients may be monitored at least at 4 week intervals
• Monitoring must continue throughout treatment and for at least 4 weeks after discontinuation
If the blood result of a patient taking Denzapine is below the normal range (See Section 4.4), Britannia will contact the physician and pharmacist registered to the patient on the Denzapine Monitoring Service to inform them.
The Denzapine Monitoring Service maintains a database which includes all patients who have developed abnormal leucocyte or neutrophil findings and who should not be re-exposed to Denzapine or any other brand of clozapine.
Prescribers and pharmacists should adhere to brand prescribing and dispensing of clozapine in order to prevent the disruption to effective monitoring that may be caused if patients switch brands.
Furthermore, in order to protect patient safety, at any one time patients should only be prescribed one brand of clozapine and only registered with the monitoring service connected to that brand.
Advice on Monitoring Clozapine Blood Levels
Blood clozapine level monitoring is advised in certain clinical situations such as when a patient ceases smoking or switches to e-cigarettes, when concomitant medicines may interact to increase clozapine blood levels, where poor clozapine metabolism is suspected, when a patient has pneumonia or other serious infection and in the event of onset of symptoms suggestive of toxicity (see section 4.4).
For further information regarding Denzapine and the Denzapine Monitoring Service please call 0333 200 4141 (UK).
[1] De la Chapelle A, et al. Clozapine-induced agranulocytosis: a genetic and epidemiologic study. Hum Genet, 1977. 37: p. 183-194.
[2] Denzapine Monitoring Service, data on file.
Denzapine can cause agranulocytosis. Its use should be limited to patients:
• with schizophrenia who are non-responsive to or intolerant of antipsychotic drug treatment, or with psychosis in Parkinson's disease when other treatment strategies have failed (see section 4.1)
• who have initially normal leucocyte findings (white blood cell count of ≥3500/mm3 (≥3.5 x 109 /L), and an absolute neutrophil count (ANC) of ≥2000/mm3 (≥2.0 x 109 /L)), and
• in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) can be performed as follows: weekly during the first 18 weeks of therapy, at least 2 weeks between weeks 18 and 52, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine (see section 4.4).
Prescribing physicians should comply fully with the required safety measures. At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia (see section 4.4).
Denzapine must be dispensed under strict medical supervision in accordance with official recommendations (see section 4.4).
Myocarditis
Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. The increased risk of myocarditis is greatest in the first 2 months of treatment. Fatal cases of cardiomyopathy have also been reported rarely (see section 4.4).
Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first 2 months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction (see section 4.4).
If myocarditis or cardiomyopathy are suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist (see section 4.4).
Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine (see section 4.3 and 4.4).
2. |
Denzapine 50mg/ml Oral Suspension | Qualitative and quantitative composition | Each 1ml of oral suspension contains 50mg of Clozapine.
Excipient(s) with known effect:
Each 1ml of oral suspension also contains 150mg sorbitol, 2mg sodium methyl parahydroxybenzoate and 0.2mg sodium propyl parahydroxybenzoate.
For the full list of excipients, see section 6.1.
3. |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical form | Oral suspension
Free-flowing yellow suspension
4. |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment-resistant schizophrenia
Denzapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.
Psychosis during the course of Parkinson's disease
Denzapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed.
4.2 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Posology and method of administration | Posology and method of administration
24 hours before first use only (i.e., when first dispensed or after prolonged storage where there is visible settling of the suspension) shake the bottle vigorously for 90 seconds. Stand the bottle for 24 hours before dosing. Immediately before the first and each subsequent dose, shake the bottle for 10 seconds.
If dilution is required, the suspension may be mixed with water but not fruit juice or any other form of liquid.
Posology
The dosage must be adjusted individually. For each patient the lowest effective dose should be used. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure, and sedation.
Initiation of Denzapine treatment must be restricted to those patients with a WBC count ≥3500/mm3 (3.5 x 109/L) and an absolute neutrophil count (ANC) ≥2000/mm3 (2.0 x 109/L) within standardised normal limits.
Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacodynamic and pharmacokinetic interactions with Denzapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5).
Switching from a previous antipsychotic therapy to Denzapine
It is generally recommended that Denzapine should not be used in combination with other antipsychotics, including depot preparations, which may have a myelosuppressive effect. When Denzapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards.
The following dosages are recommended:
Treatment-resistant schizophrenic patients
Starting therapy
12.5 mg (0.25 ml of suspension) once or twice on the first day, followed by 25 mg (0.5 ml of suspension) or 50mg (1.0 ml of suspension) on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg (0.5 ml to 1.0 ml of suspension) in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg (1.0 ml to 2.0 ml of suspension) at half-weekly or, preferably, weekly intervals.
Therapeutic dose range
In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day (4 ml to 9 ml/day) given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. For maintenance dose, see below.
Maximum dose
To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e. not exceeding 100 mg or 2 ml) are permissible up to 900 mg/day (18 ml). The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day (9 ml/day) must be borne in mind.
Maintenance dose
After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may be appropriate.
Ending therapy
In the event of planned termination of Denzapine therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea (see section 4.4).
Re-starting therapy
In patients in whom the interval since the last dose of Denzapine suspension exceeds 2 days, treatment should be re-initiated with 12.5 mg (0.25 ml) given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see section 4.4), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.
Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed
Starting therapy
The starting dose must not exceed 12.5 mg/day (0.25 ml) taken in the evening. Subsequent dose increases must be by 12.5 mg increments (0.25 ml), with a maximum of two increments a week up to a maximum of 50 mg (1 ml), a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.
Therapeutic dose range
The mean effective dose is usually between 25 and 37.5 mg/day (0.5 and 0.75 ml/day). In the event that treatment for at least one week with a dose of 50 mg (1 ml) fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week (0.25 ml/week).
Maximum dose
The dose of 50 mg/day (1 ml/day) should only be exceeded in exceptional cases, and the maximum dose of 100 mg/day (2 ml/day) must never be exceeded.
Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.
Maintenance dose
When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach results in the recurrence of psychotic symptoms, Denzapine dosage may be increased by increments of 12.5 mg/week (0.25 ml/week) up to a maximum of 100 mg/day (2 ml/day), taken in one or two divided doses (see above).
Ending therapy
A gradual reduction in dose by steps of 12.5 mg (0.25 ml) over a period of at least one week (preferably two) is recommended.
Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis as indicated in section 4.4. In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
Special populations
Hepatic impairment
Patients with hepatic impairment should receive Denzapine with caution along with regular monitoring of liver function tests (see section 4.4).
Paediatric population
No paediatric studies have been performed. The safety and efficacy of Denzapine in children and adolescents under the age of 16 years have not yet been established. No data are available. It should not be used in this group until further data become available.
Patients 60 years of age and older
Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day.
Method of Administration
Oral
4.3 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• This product contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.
• Patients unable to undergo regular blood tests.
• History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
• History of clozapine-induced agranulocytosis.
• Denzapine treatment must not be started concurrently with drugs known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged.
• Impaired bone marrow function.
• Uncontrolled epilepsy.
• Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.
• Circulatory collapse and/or CNS depression of any cause.
• Severe renal or cardiac disorders (e.g. myocarditis).
• Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
• Paralytic ileus.
4.4 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Agranylocytosis
Denzapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring. The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations.
Because of the risks associated with Denzapine, its use is limited to patients in whom therapy is indicated as set out in section 4.1 and:
• who have initially normal leucocyte findings (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L), and
• in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least 4-week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine.
Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that might include an ECG, and the patient treated only if the expected benefits clearly outweigh the risks (see Section 4.3). The treating physician should consider performing a pre-treatment ECG.
Prescribing physicians must comply fully with the required safety measures.
Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts.
Immediate discontinuation of Denzapine is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109 /L) or the ANC is less than 1500/mm3 (1.5 x 109 /L) at any time during Denzapine treatment. Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Denzapine.
At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia. Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting Denzapine.
Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on Denzapine with the agreement of a haematologist.
White Blood Cell (WBC) Counts and Absolute Neutrophil Count (ANC) Monitoring
WBC and differential blood counts must be performed within 10 days prior to initiating Denzapine treatment to ensure that only patients with normal WBC counts (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L)) will receive the drug. After the start of Denzapine treatment the WBC count and ANC must be monitored weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least at four-week intervals thereafter.
Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine or until haematological recovery has occurred (see below Low WBC count/ANC). At each consultation, the patient must be reminded to contact the treating physician immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.
Low WBC count/ANC
If, during Denzapine therapy, either the WBC count falls to between 3500/mm3 (3.5 x 109/L) and 3000/mm3 (3.0 x 109/L) or the ANC falls to between 2000/mm3 (2.0 x 109/L) and 1500/mm3 (1.5 x 109/L), haematological evaluations must be performed at least twice weekly until the patient's WBC count and ANC stabilise within the range 3000-3500/mm3 (3.0 - 3.5 x 109/L) and 1500 - 2000/mm3 (1.5 - 2.0 x 109/L), respectively, or higher.
Immediate discontinuation of Denzapine treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109/L) or the ANC is less than 1500/mm3 (1.5 x 109/L) during Denzapine treatment. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Confirmation of the haematological values is recommended by performing two blood counts on two consecutive days; however, Denzapine should be discontinued after the first blood count.
Following discontinuation of Denzapine, haematological evaluation is required until haematological recovery has occurred.
Table 1
Blood cell count
Action required
WBC/mm3 (/L)
ANC/mm3 (/L)
≥3500 (≥3.5 x 109)
≥2000 (≥2.0 x 109)
Continue Denzapine treatment
≥3000 to <3500 (≥3.0 x 109 to <3.5 x 109)
≥1500 to <2000 (≥1.5 x 109 to <2.0 x 109)
Continue Denzapine treatment, sample blood twice weekly until counts stabilise or increase
<3000 (<3.0 x 109)
<1500 (<1.5 x 109)
Immediately stop Denzapine treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.
If Denzapine has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0 x 109/L) occurs or the ANC falls below 1000/mm3 (1.0 x 109/L), the management of this condition must be guided by an experienced haematologist.
Discontinuation of therapy for haematological reasons
Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies (see above) must not be re-exposed to Denzapine.
Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent the patient being accidentally rechallenged in the future.
Discontinuation of therapy for other reasons
Patients who have been on Denzapine for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If Denzapine treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment and the dose should be re-titrated (see section 4.2).
Other precautions
This medicinal product contains Sorbitol (E420)
The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.
Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product above doses of approximately 2 ml Oral Suspension per day (5 mg/kg/day of sorbitol).
Eosinophilia
In the event of eosinophilia, discontinuation of Denzapine is recommended if the eosinophil count rises above 3000/mm3 (3.0 x 109/L); therapy should be restarted only after the eosinophil count has fallen below 1000/mm3 (1.0 x 109/L).
Thrombocytopenia
In the event of thrombocytopenia, discontinuation of Denzapine therapy is recommended if the platelet count falls below 50 000/mm3 (50 x 109/L).
Cardiovascular disorders
Orthostatic hypotension, with or without syncope, can occur during Denzapine treatment. Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur with concurrent use of benzodiazepines or any other psychotropic agent (see section 4.5) and during initial titration in association with rapid dose escalation; on very rare occasions they may occur even after the first dose. Therefore, patients commencing Denzapine treatment require close medical supervision. Monitoring of standing and supine blood pressure is necessary during the first weeks of treatment in patients with Parkinson's disease.
Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases of myocarditis have been fatal.
Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with clozapine use; these reports also include fatalities. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist.
In patients who are diagnosed with cardiomyopathy while on clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see section 4.8).
Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to Denzapine.
Myocardial infarction
In addition, there have been post marketing reports of myocardial infarction which may be fatal. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.
QT interval prolongation
As with other antipsychotics, caution should be exercised in patients with cardiovascular disease or a family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval
Cerebrovascular Adverse Events
An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical 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. Denzapine should be used with caution in patients with risk factors for stroke.
Risk of thromboembolism
Since Denzapine may be associated with thromboembolism, immobilisation of patients should be avoided.
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 Denzapine and preventive measures undertaken
Seizures
Patients with a history of epilepsy should be closely observed during Denzapine therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced (see section 4.2) and, if necessary, anti-convulsant treatment should be initiated.
Anticholinergic effects
Denzapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction, paralytic ileus, megacolon and intestinal infarction ischaemia (see section 4.8). On rare occasions these cases have been fatal. Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that constipation is recognised and actively treated.
Fever
During Denzapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign. Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infection or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. If the diagnosis of NMS is confirmed, Denzapine must be discontinued immediately and appropriate medical measures should be administered.
Falls
Clozapine may cause seizures, somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions or medications that could exacerbate these effects, fall risk assessments must be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Metabolic changes
Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycaemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific profile.
Hyperglycaemia
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. A mechanism for this possible association has not yet been determined. Cases of severe hyperglycaemia with ketoacidosis or hyperosmolar coma have been reported very rarely in patients with no prior history of hyperglycaemia, some of which have been fatal. When follow-up data were available, discontinuation of clozapine resulted mostly in resolution of the impaired glucose tolerance, and reinstitution of clozapine resulted in its reoccurrence. Patients with an established diagnosis of diabetes mellitis who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. The discontinuation of clozapine should be considered in patients where active medical management of their hyperglycaemia has failed.
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.
Weight gain
Weight gain has been observed with atypical antipsychotic use, including Denzapine. Clinical monitoring of weight is recommended.
Rebound, withdrawal effects
Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea.
Special populations
Hepatic impairment
Patients with stable pre-existing liver disorders may receive Denzapine, but need regular liver function tests. Liver function tests should be performed in patients in whom symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, develop during Denzapine therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if symptoms of jaundice occur, treatment with Denzapine must be discontinued. It may be resumed (see “Re-starting therapy” under section 4.2) only when the results of liver function tests are normal. In such cases, liver function should be closely monitored after re-introduction of Denzapine.
Patients aged 60 years and older
Initiation of treatment in patients aged 60 years and older is recommended at a lower dose (see section 4.2).
Orthostatic hypotension can occur with Denzapine treatment and there have been reports of tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with compromised cardiovascular function, may be more susceptible to these effects.
Patients aged 60 years and older may also be particularly susceptible to the anticholinergic effects of Denzapine, such as urinary retention and constipation.
Increased mortality in older people with dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Denzapine is not approved for the treatment of dementia-related behavioural disturbances.
4.5 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Contraindication of concomitant use
Drugs known to have a substantial potential to depress bone marrow function must not be used concurrently with Denzapine (see section 4.3). These include co-trimoxazole, chloramphenicol, sulphonamides, pyrazolone analgesics e.g. phenylbutazone, penicillamine, carbamazepine or cytotoxic agents.
Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Denzapine because these cannot be rapidly removed from the body in situations where this may be required, e.g. neutropenia (see section 4.3).
Alcohol should not be used concomitantly with Denzapine due to possible potentiation of sedation.
Precautions including dose adjustment
Denzapine may enhance the central effects of CNS depressants such as narcotics, antihistamines, and benzodiazepines. Particular caution is advised when Denzapine therapy is initiated in patients who are receiving a benzodiazepine or any other psychotropic drug. These patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound and may lead to cardiac and/or respiratory arrest. It is not clear whether cardiac or respiratory collapse can be prevented by dose adjustment.
Because of the possibility of additive effects, caution is essential in the concomitant administration of drugs possessing anticholinergic, hypotensive, or respiratory depressant effects.
Owing to its anti-alpha-adrenergic properties, Denzapine may reduce the blood-pressure-increasing effect of norepinephrine or other predominantly α-adrenergic agents and reverse the pressor effect of epinephrine.
Concomitant administration of drugs known to inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for CYP 1A2 inhibitors such as caffeine (see below), perazine, and the selective serotonin reuptake inhibitor fluvoxamine. Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine and to a lesser degree sertraline are CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP 3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin, and protease inhibitors are unlikely, although some have been reported. Hormonal contraceptives (including combinations of estrogen and progesterone or progesterone only) are CYP 1A2, CYP 3A4 and CYP 2C19 inhibitors. Therefore initiation or discontinuation of hormonal contraceptives may require dose adjustment of clozapine according to the individual medical need. Because the plasma concentration of clozapine is increased by caffeine intake and decreased by nearly 50% following a 5-day caffeine-free period, dosage changes of clozapine may be necessary when there is a change in caffeine-drinking habit. In cases of sudden cessation of smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.
Cases have been reported of an interaction between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. The nature of this interaction has not been fully elucidated.
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine, leading to reduced efficacy. Drugs known to induce the activity of cytochrome P450 enzymes and with reported interactions with clozapine include, for instance, carbamazepine (not to be used concomitantly with clozapine, due to its myelosuppresive potential), phenytoin and rifampicin. Known inducers of CYP1A2 such as omeprazole, may lead to decreased clozapine levels. The potential for reduced efficacy of clozapine should be considered when it is used in combination with these drugs.
Others
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Denzapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
Caution is called for in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic antidepressants, phenothiazines and type IC anti-arrhythmics, which are known to bind to cytochrome P450 2D6, no clinically relevant interactions have been observed thus far.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QT interval, because they may increase the risk of ventricular arrhythmias, including Torsades de pointes. Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide, sertindole and haloperidol), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to cause electrolyte imbalance. Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.
An outline of drug interactions believed to be most important with Denzapine is given in Table 2 below (this is not an exhaustive list).
Table 2: Reference to the most common drug interactions with Denzapine
Drug
Interactions
Comments
Bone marrow suppressants (e.g. carbamazapine, chloramphenicol, sulphonamides (e.g. co-trimoxazole), pyrazolone analgesics (e.g. phenylbutazone), penicillamine, cytotoxic agents and long-acting depot injections of antipsychotics
Interact to increase the risk and/or severity of bone marrow suppression
Denzapine must not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see Section 4.3)
Benzodiazepines
Concomitant use may increase risk of circulatory collapse, which may lead to cardiac and/or respiratory arrest
Whilst the occurrence is rare, caution is advised when using these drugs together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when Denzapine is added to an established benzodiazepine regimen.
Anticholinergics
Denzapine potentiates the action of these drugs through additive anticholinergic activity
Observe patients for anticholinergic side – effects, e.g. constipation, especially when using to help control hypersalivation
Antihypertensives
Denzapine can potentiate the hypotensive effects of these drugs due to its sympathomimetic antagonistic effects
Caution is advised if Denzapine is used concomitantly with antihypertensive agents. Patients should be advised of the risk of hypotension, especially during the period of initial dose titration
Alcohol, MAOIs, CNS depressants, including narcotics and benzodiazepines
Enhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these drugs
Caution is advised if Denzapine is used concomitantly with other CNS active agents. Advise patients of the possible additive sedative effects and caution them not to drive or operate machinery
Highly protein bound drugs
(e.g. warfarin and digoxin)
Denzapine may cause an increase in plasma concentration of these drugs due to displacement from plasma proteins
Patients should be monitored for the occurrence of side effects associated with these drugs, and doses of the protein bound drug adjusted, if necessary
Phenytoin
Addition of phenytoin to Denzapine drug regimen may cause a decrease in the clozapine plasma concentrations
If phenytoin must be used, the patient should be monitored closely for a worsening or recurrence of psychotic symptoms
Lithium
Concomitant use can increase the risk of development of neuroleptic malignant syndrome (NMS)
Observe for signs and symptoms of NMS
CYP1A2 inducing substances (e.g. omeprazole)
Concomitant use may decrease clozapine levels
Potential for reduced efficacy of clozapine should be considered.
CYP1A2 inhibiting substances (e.g. fluvoxamine, caffeine, ciprofloxacin) , perazine, or hormonal contraceptives (CYP1A2, CYP3A4, CYP2C19)
Concomitant use may increase clozapine levels
Potential for increase in adverse effects. Care is also required upon cessation of concomitant CYP1A2 or CYP3A4 inhibiting medications as there will be a decrease in clozapine levels. The effect of CYP2C19 inhibition will be minimal.
4.6 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
For clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.
Neonates exposed to antipsychotics (including Denzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast-feeding
Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving Denzapine should not breast-feed.
Fertility
Limited data available on the effects of clozapine on human fertility are inconclusive. In male and female rats, clozapine did not affect fertility when administered up to 40mg/kg, corresponding to a human equivalence dose of 6.4mg/kg, or approximately a third of the maximum permissible human dose.
Women of child-bearing potential
A return to normal menstruation may occur as a result of switching from other antipsychotics to Denzapine. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
4.7 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Denzapine has a major influence on the ability to drive and use machines.
Owing to the ability of Denzapine to cause sedation and lower the seizure threshold, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.
4.8 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. An important exception is its propensity to cause agranulocytosis (see section 4.4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson's disease in cases where standard treatment has failed. While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse events, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.
The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see section 4.4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation.
Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients (from 7.1 to 15.6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leucopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder.
Blood and lymphatic system
Development of granulocytopenia and agranulocytosis is a risk inherent to Denzapine treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see section 4.4). Table 3 below summarises the estimated incidence of agranulocytosis for each Denzapine treatment period.
Table 3: Estimated incidence of agranulocytosis1
Treatment period
Incidence of agranulocytosis per 100,000 person-weeks2 of observation
Weeks 0 - 18
32.0
Weeks 19 - 52
2.3
Weeks 53 and higher
1.8
1 From the UK Patient Monitoring Service lifetime registry experience between 1989 and 2001.
2 Person-time is the sum of individual units of time that the patients in the registry have been exposed to clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000 = 100,000), or in 200 patients who were in the registry for 500 weeks (200*500 = 100,000) before experiencing agranulocytosis.
The cumulative incidence of agranulocytosis in the UK since monitoring began is (0 - 11.6 years between 1989 and 2001) is 0.78%. The majority of cases (approximately 70%) occur within the first 18 weeks of treatment.
Metabolic and Nutritional Disorders
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. On very rare occasions, severe hyperglycaemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported in patients on clozapine treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of clozapine and in a few cases hyperglycaemia recurred when treatment was reinitiated. Although most patients had risk factors for non-insulin-dependent diabetes mellitus, hyperglycaemia has also been documented in patients with no known risk factors (see section 4.4.).
Nervous System Disorders
The very common adverse events observed include drowsiness/sedation, and dizziness.
Denzapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures. These symptoms are more likely to occur with rapid dose increases and in patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant drugs the possibility of a pharmacokinetic interaction should be considered. In rare cases, patients treated with Denzapine may experience delirium.
Very rarely, tardive dyskinesia has been reported in patients on clozapine who had been treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other antipsychotics have improved on clozapine.
Cardiac Disorders
Tachycardia and postural hypotension with or without syncope may occur, especially in the initial weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and magnitude of dose titration. Circulatory collapse as a result of profound hypotension, in particular related to aggressive titration of the drug, with the possible serious consequences of cardiac or pulmonary arrest, has been reported with clozapine.
A minority of clozapine-treated patients experience ECG changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which normalise after discontinuation of clozapine. The clinical significance of these changes is unclear. However, such abnormalities have been observed in patients with myocarditis, which should therefore be considered.
Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion and myocarditis have been reported, some of which have been fatal. The majority of the cases of myocarditis occurred within the first 2 months of initiation of therapy with clozapine. Cardiomyopathy generally occurred later in the treatment.
Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known, however, whether eosinophilia is a reliable predictor of carditis.
Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest, palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms.
Very rare events of ventricular tachycardia and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine.
Sudden, unexplained deaths are known to occur among psychiatric patients who receive conventional antipsychotic medication but also among untreated psychiatric patients. Such deaths have been reported very rarely in patients receiving clozapine.
Vascular Disorders
Rare cases of thromboembolism have been reported.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs. The frequency is unknown.
Respiratory System
Respiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see sections 4.4 and 4.5).
Gastrointestinal System
Constipation and hypersalivation have been observed very frequently, and nausea and vomiting frequently. Very rarely ileus may occur (see section 4.4). Rarely Denzapine treatment may be associated with dysphagia. Aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.
Hepatobiliary Disorders
Transient, asymptomatic elevations of liver enzymes and rarely, hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, DENZAPINE should be discontinued (see section 4.4.). In rare cases, acute pancreatitis has been reported.
Renal Disorders
Isolated cases of acute interstitial nephritis have been reported in association with Denzapine therapy.
Reproductive and Breast Disorders
Very rare reports of priapism have been received.
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6) has been reported. The frequency of this is not known.
General Disorders
Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving clozapine either alone or in combination with lithium or other CNS-active agents.
Acute withdrawal reactions have been reported (see section 4.4).
Tabulated list of adverse reactions
The table below (Table 4) summarises the adverse reactions accumulated from reports made spontaneously and during clinical studies.
Table 4: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical trial reports
Adverse reactions are ranked under headings of frequency, using the following convention: Very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Infections and infestations
Not known
Sepsis*
Blood and lymphatic system disorders
Common
Leucopenia/decreased WBC/neutropenia, eosinophilia, leucocytosis
Uncommon
Agranulocytosis
Rare
Anaemia
Very rare
ThrombocytopeniaThrombocythaemia
Immune system disorders
Not known
Angioedema*, leucocytoclastic vasculitis*
Endocrine disorders
Not known
Pseudophaeochromocytoma*
Metabolism and nutrition disorders
Common
Weight gain
Rare
Impaired glucose tolerance, diabetes mellitus, obesity*
Very rare
Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia
Psychiatric disorders
Common
Dysarthria
Uncommon
Dysphemia
Rare
Restlessness, agitation
Nervous system disorders
Very common
Drowsiness/sedation, dizziness
Common
Blurred vision, headache, tremor, rigidity, akathisia, extra pyramidal symptoms, seizures/convulsions/myoclonic jerks
Rare
Confusion, delirium
Very rare
Tardive dyskinesia, obsessive compulsive disorder
Not known
Cholinergic syndrome (after abrupt withdrawal)*, EEG changes*, pleurothotonus*, restless leg syndrome*
Cardiac disorders
Very common
Tachycardia
Common
ECG changes
Rare
Circulatory collapse, Ventricular arrhythmias (VF, VT), myocarditis, pericarditis/pericardial effusion
Very rare
Cardiomyopathy, cardiac arrest, QT prolongation, Torsades de pointes
Not known
Myocardial infarction which may be fatal*, chest pain/angina pectoris*, atrial fibrillation*, palpitations*, mitral valve incompetence associated with clozapine related cardiomyopathy*
Vascular disorders
Common
Hypertension, postural hypotension, syncope
Rare
Thromboembolism
Not known
Hypotension*, Venous thromboembolism
Respiratory, thoracic and mediastinal disorders
Rare
Aspiration of ingested food, pneumonia and lower respiratory tract infection which may be fatal, sleep apnoea syndrome*
Very rare
Respiratory depression/arrest
Not known
Pleural effusion*, nasal congestion*
Gastrointestinal disorders
Very common
Constipation, hypersalivation
Common
Nausea, vomiting, anorexia, dry mouth
Rare
Dysphagia
Very rare
Parotid gland enlargement, intestinal obstruction/paralytic ileus/faecal impaction
Not known
Megacolon*, intestinal infarction/ischaemia*, diarrhoea*, abdominal discomfort/heartburn/dyspepsia*, colitis*
Hepatobiliary disorders
Common
Elevated liver enzymes
Rare
Hepatitis, cholestatic jaundice, pancreatitis
Very rare
Fulminant hepatic necrosis
Not known
Hepatic steatosis*, hepatic necrosis*, hepatotoxicity*, hepatic fibrosis*, hepatic cirrhosis*, liver disorders including those hepatic events leading to life-threatening consequences such as liver injury (hepatic, cholestatic and mixed), liver failure which may be fatal, and liver transplant*.
Skin and subcutaneous tissue disorders
Very rare
Skin reactions
Not known
Pigmentation disorder*
Musculoskeletal and connective tissue disorders
Not known
Rhabdomyolysis*, muscle weakness*, muscle spasms*, muscle pain*, systemic lupus erythematous*
Renal and urinary disorders
Common
Urinary incontinence, urinary retention
Very rare
Interstitial nephritis
Not known
Renal failure*, Nocturnal enuresis*
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Very rare
Priapism
Not known
Retrograde ejaculation*
General disorders and administration site conditions
Common
Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation
Uncommon
Neuroleptic malignant syndrome
Very rare
Sudden unexplained death
Not known:
Polyserositis*
Investigations
Rare
Increased CPK
Injury, poisoning and procedural complications
Uncommon
Falls (associated with clozapine-induced seizures, somnolence, postural hypotension, motor and sensory instability)*
* Adverse drug reactions derived from post-marketing experience via spontaneous case reports and literature cases for the drug substance, Clozapine.
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 MHRA Yellow Card Scheme: https://yellowcard.mhra.gov.uk/ Or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Denzapine 50mg/ml Oral Suspension | Clinical particulars - Overdose | Overdose
In cases of acute intentional or accidental clozapine overdosage for which information on the outcome is available, mortality to date is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000 mg (40 ml). There have been reports of patients recovering from an overdose in excess of 10 000 mg (200 ml). However, in a few adult individuals, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg (8 ml) led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 to 200 mg (1 to 4 ml) resulted in strong sedation or coma without being lethal.
Signs and symptoms
Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extra pyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.
Treatment
There are no specific antidotes for Denzapine.
Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a 'reverse epinephrine' effect.
Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.
5. Pharmacological properties
5.1 |
Denzapine 50mg/ml Oral Suspension | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The absorption of orally administered Denzapine is 90 to 95%; neither the rate nor the extent of absorption is influenced by food.
Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.
Distribution
In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 L/kg. Clozapine is approximately 95% bound to plasma proteins.
Biotransformation/metabolism
Clozapine is almost completely metabolised before excretion by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Of the main metabolites only the desmethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of short duration.
Elimination
Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). After single doses of 75 mg (1.5 ml) the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg (1.5 ml) for at least 7 days. Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.
Linearity/non-linearity
Dosage increases from 37.5 mg to 75 mg (0.75 to 1.5 ml) and 150 mg (3 ml) given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.
5.3 |
Denzapine 50mg/ml Oral Suspension | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see section 4.6).
6. |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical particulars - List of excipients | List of excipients
Glycerol (E422)
Sodium dihydrogen phosphate dihydrate (E339(i))
Sorbitol (E420)
Xanthan gum (E415)
Povidone (E1201)
Sodium methyl parahydroxybenzoate (E219)
Sodium propyl parahydroxybenzoate (E217)
Hydrochloric acid (for pH adjustment) (E507)
Sodium hydroxide (for pH adjustment) (E524)
Water, Purified
6.2 |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Clozapine Suspension is not compatible with orange juice. Therefore it is recommended that if Clozapine Suspension is to be mixed with a beverage, only water is to be used.
6.3 |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical particulars - Shelf life | Shelf life
Unopened: 6 months
In-use shelf life: 90 days after first opening.
6.4 |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Amber glass bottle containing 100 ml of suspension.
The bottle is fitted with a white, polypropylene, round child-resistant, tamper-evident screw cap containing a LDPE foam liner.
The filled and sealed bottle is packed into a carton along with a bottle adaptor and two graduated oral dispensers (1 x 1 ml oral dispenser and 1 x 10 ml oral dispenser) for dispensing and administration of the suspension.
6.6 |
Denzapine 50mg/ml Oral Suspension | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Denzapine 50mg/ml Oral Suspension | Marketing authorisation holder | Britannia Pharmaceuticals Limited
200 Longwater Avenue
Green Park
Reading
Berkshire
RG2 6GP
UK
8. Marketing authorisation number(s)
PL 04483/0071
9. |
Denzapine 50mg/ml Oral Suspension | Date of first authorisation/renewal of the authorisation | 30 January 2012
10. |
Depakote 250mg Tablets | Introduction | This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.1. |
Depakote 250mg Tablets | Name of the medicinal product | Depakote 250 mg Tablets
2. |
Depakote 250mg Tablets | Qualitative and quantitative composition | Containing 269.10 mg of valproate semisodium* per tablet (equivalent to 250 mg of valproic acid).
*Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. It is also known as divalproex sodium (USAN).
Excipient(s) with known effect:
Sodium 19.96 mg (see section 4.4).
For the full list of excipients, see section 6.1.
3. |
Depakote 250mg Tablets | Pharmaceutical form | Gastro-resistant tablet
Oval, orange gastro-resistant tablets.
4. |
Depakote 250mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated.
For the continuation of treatment after manic episode could be considered in patients who have responded to Depakote for acute mania.
4.2 |
Depakote 250mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The daily dosage should be established according to age and body weight. The wide variation in individual sensitivity to Depakote should also be considered.
Dosage
Manic episodes in bipolar disorder:
Adults
The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750 mg in 2 – 3 divided doses. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The mean daily dose usually ranges between 1000 – 2000 mg valproate. Patients receiving daily doses higher than 45 mg/kg/day body weight should be carefully monitored.
Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.
Elderly
Although the pharmacokinetics of valproate are modified in the elderly, they have limited clinical significance and dosage should be determined on the basis of clinical response.
Paediatric population
The efficacy of Depakote in children below 18 years of age in the treatment of manic episodes of bipolar disorder has not been established. With respect to safety information in children see section 4.8.
Renal impairment
It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. Valproate is dialysable (see section 4.9). Dosing should be modified according to clinical monitoring of the patient (see section 4.4).
Hepatic impairment
Salicylates should not be used concomitantly with valproate since they employ the same metabolic pathway (see sections 4.4 and 4.8).
Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 and 4.4).
Salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome). In addition, in conjunction with valproate, concomitant use in children under 3 years of age can increase the risk of liver toxicity (see section 4.4.1).
Female children and women of childbearing potential
Valproate must be initiated and supervised by a specialist experienced in the management of bipolar disorder. Valproate should not be used in female children or women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.3, 4.4 and 4.6).
Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (see sections 4.3 and 4.4). The benefit and risk should be carefully reconsidered at regular treatment reviews (see section 4.4).
Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).
Combined therapy (see section 4.5)
When starting Depakote in patients, already on anti-convulsants, these should be tapered slowly; if clinically possible; initiation of Depakote therapy should then be gradual, with target dose being reached after about 2 weeks. Faster titration may be permissible if plasma level monitoring is available. In certain cases, it may be necessary to raise the dose by 5 – 10 mg/kg/day when used in combination with anti-convulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain control on a reduced dose of Depakote. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.
When using Depakote with other psychotropics, a reduced dose may be required (see section 4.5.1).
Optimum dosage is mainly determined by control. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2).
Method of administration
For oral administration. The tablets should be swallowed whole with a drink of water, and not crushed or chewed.
4.3 |
Depakote 250mg Tablets | Clinical particulars - Contraindications | Contraindications
Depakote is contraindicated in the following situations:
• In pregnancy (see sections 4.4 and 4.6).
• In women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.4 and 4.6).
• Hypersensitivity to valproate semisodium or any other excipients listed in section 6.1.
• Active liver disease, or personal or family history of severe hepatic dysfunction, especially drug related.
• Patients with known urea cycle disorders (see section 4.4).
• Porphyria.
• Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).
4.4 |
Depakote 250mg Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
To ensure the correct medication is prescribed for the patient's condition, care must be taken not to confuse Depakote with Epilim or sodium valproate. Patients with bipolar disorder and epilepsy are distinct populations. These differences are reflected in the patient information leaflets which clearly indicate specific indications for these differing medications.
Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.
4.4.1 Special Warnings
Liver dysfunction:
Conditions of occurrence:
Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.
The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome).
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2 – 12 weeks.
Suggestive signs:
Clinical symptoms are essential for early diagnosis. In particular, the following conditions which may precede jaundice should be taken into consideration, especially in patients at risk (see above: 'Conditions of occurrence'):
- non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.
- in patients with epilepsy, recurrence of seizures
These are an indication for immediate withdrawal of the drug.
Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Detection:
Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.
Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.
Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of treatment.
As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
Increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.
More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
Pancreatitis:
Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase). Young children are at particular risk; this risk decreases with increasing age. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate should be discontinued.
Female children, women of childbearing potential and pregnant women:
Pregnancy Prevention Programme
Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neuro-developmental disorders (see section 4.6).
Depakote is contraindicated in the following situations:
• In pregnancy (see sections 4.3 and 4.6).
• In women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).
Conditions of Pregnancy Prevention Programme:
The prescriber must ensure that:
• Individual circumstances should be evaluated in each case. Involving the patient in the discussion to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.
• The potential for pregnancy is assessed for all female patients.
• The patient has understood and acknowledged the risks of congenital malformations and neuro-developmental disorders including the magnitude of these risks for children exposed to valproate in utero.
• The patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.
• The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (for further details please refer to subsection contraception of this boxed warning), without interruption during the entire duration of treatment with valproate.
• The patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of bipolar disorder.
• The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception and before contraception is discontinued.
• The patient understands the need to urgently consult her physician in case of pregnancy.
• The patient has received the Patient Guide.
• The patient has acknowledged that she has understood the hazards and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Female children
The prescriber must ensure that:
• The parents/caregivers of female children understand the need to contact the specialist once the female child using valproate experiences menarche.
• The parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neuro-developmental disorders including the magnitude of these risks for children exposed to valproate in utero.
In patients who have experienced menarche, the prescribing specialist must annually reassess the need for valproate therapy and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention programme should be discussed. Every effort should be made by the specialist to switch female children to alternative treatment before they reach adulthood.
Pregnancy test
Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of childbearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a healthcare provider, to rule out unintended use in pregnancy.
Contraception
Women of childbearing potential who are prescribed valproate must use effective contraception without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case when choosing the contraception method, involving the patient in the discussion to guarantee her engagement and compliance with the chosen measures. Even if she has amenorrhea, she must follow all the advice on effective contraception.
Oestrogen-containing products
Concomitant use with oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (mood control) when initiating or discontinuing oestrogen-containing products.
On the opposite, valproate does not reduce efficacy of hormonal contraceptives.
Annual treatment reviews by a specialist
The specialist should review at least annually whether valproate is the most suitable treatment for the patient. The specialist should discuss the Annual Risk Acknowledgement Form at initiation and during each annual review and ensure that the patient has understood its content.
Pregnancy planning
If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.
In case of pregnancy
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative treatment options. The patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy (see section 4.6).
Pharmacists must ensure that:
• The Patient Card is provided with every valproate dispensation and that patients understand its content.
• Patients are advised not to stop valproate medication and to immediately contact a specialist in case of planned or suspected pregnancy.
Educational materials
In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorisation Holder has provided educational materials to reinforce the warnings, provide guidance regarding use of valproate in women of childbearing potential and provide details of the Pregnancy Prevention Programme. A Patient Guide and Patient Card should be provided to all women of childbearing potential using valproate.
An Annual Risk Acknowledgement Form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.
Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a specialist experienced in the management of bipolar disorder.
Aggravated convulsions:
As with other anti-epileptic drugs, some patients with epilepsy may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see section 4.8).
Suicidal ideation and behaviour:
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known, and the available data does not exclude the possibility of an increased risk for valproate semisodium.
Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Carbapenem agents:
The concomitant use of valproate and carbapenem agents is not recommended.
Patients with known or suspected mitochondrial disease:
Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).
Excipients with known effect
Sodium: This medicinal product contains 19.96 mg sodium per tablet, equivalent to 0.10% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Sunset yellow FCF (E110): This colourant (azo dye) may cause allergic reactions including asthma in some people. You are more likely to have an allergy if you are also allergic to aspirin.
4.4.2 Precautions
Haematological tests:
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8).
Renal insufficiency:
In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 and 5.2).
Patients with systemic lupus erythematosus:
Although immune disorders have only rarely been noted during the use of valproate, the potential benefit of valproate should be weighed against its potential risk in patients with systemic lupus erythematosus (see also section 4.8).
Urea cycle disorders:
When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate (see section 4.3).
Weight gain:
Valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8).
Diabetic patients:
Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.
Carnitine palmitoyltransferase (CPT) type II deficiency:
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomylosis when taking valproate.
Alcohol:
Alcohol intake is not recommended during treatment with valproate.
4.5 |
Depakote 250mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
4.5.1 Effects of Depakote on other drugs
- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines
Valproate may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.
- Clozapine and haloperidol
No significant interaction was observed when clozapine and haloperidol were administered concurrently with valproate.
- Lithium
Co-administration of valproate and lithium does not appear to affect the steady state kinetics of lithium. Valproate has no effect on serum lithium levels.
- Olanzapine
Valproic acid may decrease the olanzapine plasma concentration.
- Phenobarbital
Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
- Primidone
Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
- Phenytoin
Valproate decreases phenytoin total plasma concentration. Moreover, valproate increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
- Carbamazepine
Clinical toxicity has been reported when valproate was administered with carbamazepine as valproate may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
- Lamotrigine
Valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended, and dosage should be adjusted (lamotrigine dosage decreased) when appropriate.
- Felbamate
Valproic acid may decrease the felbamate mean clearance by up to 16%.
- Rufinamide
Valproic acid may lead to an increase in plasma levels of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
- Propofol
Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.
- Zidovudine
Valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
- Nimodipine
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
- Temozolomide
Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
4.5.2 Effects of other drugs on Depakote
- Anti-epileptics
Anti-epileptics with enzyme inducing effects (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
On the other hand, combination of felbamate and valproate decreases valproic acid clearance by 22 – 50% and consequently increase the valproic acid plasma concentrations. Valproate dosage should be monitored.
- Anti-malarial agents
Mefloquine and chloroquine increase valproic acid metabolism. Accordingly, the dosage of valproate may need adjustment.
- Highly protein bound agents
In case of concomitant use of valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.
- Vitamin K-dependent factor anticoagulants
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
- Cimetidine or erythromycin
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
- Carbapenem antibiotics (such as panipenem, imipenem and meropenem)
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60 – 100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level should be performed.
- Rifampicin
Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
- Protease inhibitors
Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.
- Cholestyramine
Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
- Oestrogen-containing products, including oestrogen-containing hormonal contraceptives
Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
- Metamizole
Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (mood control) and consider monitoring valproate serum levels as appropriate.
4.5.3 Other interactions
- Newer anti-epileptics (including topiramate and acetazolamide)
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
- Quetiapine
Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
4.6 |
Depakote 250mg Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
• Valproate is contraindicated as treatment for bipolar disorder during pregnancy.
• Valproate is contraindicated for use in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.3 and 4.4).
Teratogenicity and developmental effects
Pregnancy exposure risk related to valproate
Both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neuro-developmental disorders in both valproate monotherapy and polytherapy compared to the population not exposed to valproate.
Valproate was shown to cross the placental barrier in both animal species and humans (see section 5.2).
In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).
Congenital malformations
A meta-analysis (including registries and cohort studies) showed that approximately 11% of children of women with epilepsy exposed to valproate monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations in the general population (approximately 2 – 3%).
The risk of major congenital malformations in children after in utero exposure to anti-epileptic drug polytherapy including valproate is higher than that of anti-epileptic drug polytherapy not including valproate.
This risk is dose-dependent in valproate monotherapy, and available data suggests it is dose-dependent in valproate polytherapy. However, a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to valproate may also result in hearing impairment or deafness due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases did not recover.
In utero exposure to valproate may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
Neuro-developmental disorders
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk of neuro-developmental disorders (including that of autism) seems to be dose-dependent when valproate is used in monotherapy, but a threshold dose below which no risk exists cannot be established based on available data. When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neuro-developmental disorders in the offspring were also significantly increased as compared with those in children from the general population or born to untreated women with epilepsy.
The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
When valproate is administered in monotherapy, studies in children exposed in utero to valproate show that up to 30 – 40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Intelligence quotient (IQ) measured in children (age 6) with a history of valproate exposure in utero was on average 7 – 10 points lower than those children exposed to other anti-epileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long-term outcomes.
Available data from a population-based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.
Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.
Female children and woman of childbearing potential (see above and section 4.4)
Oestrogen-containing products
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4 and 4.5).
If a woman plans a pregnancy
If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.
Pregnant women
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy (see sections 4.3 and 4.4). If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.
All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Risk in the neonate
• Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
• Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.
• Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
• Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Breast-feeding
Valproate is excreted in human milk with a concentration ranging from 1 – 10% of maternal serum levels. Haematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from valproate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8).
Valproate administration may also impair fertility in men (see section 4.8). Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility was unknown.
4.7 |
Depakote 250mg Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Patients should be warned of the risk of transient drowsiness, especially in cases of polytherapy or association with benzodiazepines (see section 4.5).
4.8 |
Depakote 250mg Tablets | Clinical particulars - Undesirable effects | Undesirable effects
The following CIOMS frequency rating is used, when applicable: Very common (≥ 1/10); common (≥ 1/100 to < 1/ 10); uncommon (≥ 1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).
The following adverse events have been described from experience of sodium valproate in epilepsy; no other adverse event that could be specifically associated with the use of Depakote in the treatment of manic episodes have been identified.
Congenital malformations and developmental disorders: (see sections 4.4 and 4.6).
Hepatobiliary disorders:
Common: liver injury (see section 4.4.1)
Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment and may be transient (see section 4.4.1).
Gastrointestinal disorders:
Very common: nausea
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea
The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Depakote with or after food.
Uncommon: pancreatitis, sometimes lethal (see section 4.4)
Nervous system disorders:
Very common: tremor
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus
Uncommon: coma*, encephalopathy*, lethargy* (see below), reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions (see section 4.4)
Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder
Sedation has been reported occasionally. In monotherapy it occurred early in treatment on rare occasions and is usually transient.
*Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of anti-convulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Psychiatric disorders:
Common: confusional state, hallucinations, aggression, agitation, disturbance in attention
Rare: abnormal behaviour, psychomotor hyperactivity, learning disorder
Metabolism and nutrition disorders:
Common: hyponatraemia, weight increased*
*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4).
Rare: hyperammonaemia* (see section 4.4.2), obesity
*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, but they are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur valproate should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2). In such cases further investigations should be considered.
Endocrine disorders:
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase)
Rare: hypothyroidism (see section 4.6)
Blood and lymphatic system disorders:
Common: anaemia, thrombocytopenia (see section 4.4.2)
Uncommon: pancytopenia, leucopenia
Rare: bone marrow failure, including red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis
The blood picture returned to normal when the drug was discontinued.
Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see section 4.6).
Skin and subcutaneous tissue disorders:
Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.
Uncommon: angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome
Reproductive system and breast disorders:
Common: dysmenorrhea
Uncommon: amenorrhea
Rare: polycystic ovaries, male infertility (see section 4.6)
Very rarely gynaecomastia has occurred.
Vascular disorders:
Common: haemorrhage (see sections 4.4.2 and 4.6)
Uncommon: vasculitis
Eye disorders:
Rare: diplopia
Ear and labyrinth disorders:
Common: deafness, a cause-and-effect relationship has not been established.
Renal and urinary disorders:
Common: urinary incontinence
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy, but the mode of action is as yet unclear.
General disorders and administration site conditions:
Uncommon: hypothermia, non-severe peripheral oedema
Musculoskeletal and connective tissue disorders:
Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproate. The mechanism by which valproate affects bone metabolism has not been identified.
Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4.2)
Respiratory, thoracic and mediastinal disorders:
Uncommon: pleural effusion
Investigations:
Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged) (see sections 4.4 and 4.6)
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Rare: myelodysplastic syndrome
Paediatric population
The safety profile of valproate in the paediatric population is comparable to adults, but some ADRs are more severe or principally observed in the paediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of 3 years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see section 4.4). Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are principally observed in the paediatric population. Based on a limited number of post-marketing cases, Fanconi Syndrome, enuresis and gingival hyperplasia have been reported more frequently in paediatric patients than in adult patients.
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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Depakote 250mg Tablets | Clinical particulars - Overdose | Overdose
Symptoms
Signs of acute massive overdose, i.e. plasma concentration 10 – 20 times maximum therapeutic levels, usually include CNS depression, or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory functions and metabolic acidosis, hypotension and circulatory collapse/shock. A favourable outcome is usual. However, some deaths have occurred following massive overdose.
Symptoms may however be variable, and seizures have been reported in the presence of very high plasma levels in patients with epilepsy. Cases of intracranial hypertension related to cerebral oedema have been reported.
The presence of sodium content in the Depakote formulations may lead to hypernatraemia when taken in overdose.
Management
Hospital management of overdose should be symptomatic, including cardio-respirato-gastric monitoring. Gastric lavage may be useful up to 10 – 12 hours following ingestion.
Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.
In cases of massive overdose, haemodialysis and haemoperfusion have been used successfully.
5. Pharmacological properties
5.1 |
Depakote 250mg Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Following oral administration of Depakote, the absolute bioavailability of valproic acid approaches 100%. Mean terminal half-life is about 14 hours, steady state conditions usually being achieved within 3 – 4 days. Peak plasma concentrations are achieved within 3 – 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption.
Distribution
Plasma protein binding of Depakote ranges from 85 – 94% over plasma drug concentrations of 40 – 100 µg/ml. It is concentration-dependent, and the free fraction increases non-linearly with plasma drug concentration.
Placental transfer (see section 4.6)
Valproate crosses the placental barrier in animal species and in humans:
• In animal species, valproate crosses the placenta to a similar extent as in humans.
• In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Metabolism
Depakote is extensively metabolised in the liver with less than 3% of an administered dose excreted unchanged in the urine. Principal metabolites found in urine are those originating from β-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose). Plasma clearance ranges from 0.4 – 0.6 L/h and is independent of hepatic blood flow.
The major pathway of valproate biotransformation is glucuronidation (~ 40%), mainly via UGT1A6, UGT1A9, and UGT2B7.
Interaction with oestrogen-containing products
Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction.
Special populations
In elderly patients and those with liver cirrhosis (including alcoholic), acute hepatitis or renal failure the elimination of valproic acid is reduced. Reduction in intrinsic clearance and protein binding are reported. Thus, monitoring of total concentrations may be misleading and dosage adjustment may need to be considered according to clinical response.
Haemodialysis reduces serum valproic acid concentrations by about 20%.
5.3 |
Depakote 250mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Valproate was neither mutagenic in bacteria, nor in the mouse lymphoma assay in vitro and did not induce DNA repair in primary rat hepatocyte cultures. In vivo, however, contradictory results were obtained at teratogenic doses depending on the route of administration. After oral administration, the predominant route of administration in humans, valproate did not induce chromosome aberrations in rat bone marrow or dominant lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand-breaks and chromosomal damage in rodents. In addition, increased sister-chromatid exchanges in patients with epilepsy exposed to valproate as compared to untreated healthy subjects have been reported in published studies. However, conflicting results were obtained when comparing data in patients with epilepsy treated with valproate with those in untreated patients with epilepsy. The clinical relevance of these DNA/chromosome findings is unknown.
Non-clinical data reveal no special hazard for humans based on conventional carcinogenicity studies.
Reproductive and developmental toxicity
Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits.
Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
Behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. Some behavioural changes have also been observed in the second generation and those were less pronounced in the third generation of mice following acute in utero exposure of the first generation to teratogenic valproate doses. The underlying mechanisms and the clinical relevance of these findings are unknown.
Testicular toxicity
In sub-chronic/chronic toxicity studies, testicular degeneration/atrophy or spermatogenesis abnormalities and a decrease in testes weight were reported in adult rats and dogs after oral administration starting at doses of 465 mg/kg/day and 150 mg/kg/day, respectively. The safety margin based on plasma concentrations is unknown, however body-surface-area comparisons indicate that there may be no safety margin.
In juvenile (sexually immature) and young adult rats (pubertal), a significant dose-related reduction in testes weight was observed at 240 mg/kg/day following i.v. and i.p. administration with no apparent histopathological changes. However, testicular atrophy was observed in the young adult rat at an i.v. dose of 480 mg/kg/day. Despite the absence of apparent histopathology changes, the testicular weight reductions were considered part of a dose-related spectrum leading to testicular atrophy. There is no safety margin for the effect on testicular weight.
There is a limited number of published papers which report findings in juvenile animals consistent with those reported in the GLP adult and juvenile studies, with respect to testicular weights. Reductions in testicular weights are associated with adverse effects on the adult male reproductive tract in animal studies and impaired fertility in adult patients (see section 4.6).
The toxicological significance of the testicular findings in juvenile animals has not been evaluated and hence the relevance to human testicular development, particularly in the paediatric population, is unknown.
6. |
Depakote 250mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Silicone dioxide
Starch pre-gelatinised
Povidone
Titanium dioxide (E171)
Hypromellose
Polyethylene glycol 6000
Methacrylic acid-ethyl acrylate copolymer (1:1)
Triethyl citrate
Sunset yellow aluminium lake (E110)
Vanillin
6.2 |
Depakote 250mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Depakote 250mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Depakote 250mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
None.
6.5 |
Depakote 250mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Aluminium/aluminium blister packs containing 30, 60 or 90 tablets.
Not all pack sizes may be marketed
6.6 |
Depakote 250mg Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements
7. |
Depakote 250mg Tablets | Marketing authorisation holder | Aventis Pharma Limited
410 Thames Valley Park Drive
Reading
Berkshire
RG6 1PT
UK
Trading as:
Sanofi
410 Thames Valley Park Drive
Reading
Berkshire
RG6 1PT
UK
8. Marketing authorisation number(s)
PL 04425/0199
9. |
Depakote 250mg Tablets | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 21 December 2000
Date of latest renewal: 1 June 2009
10. |
Depakote 250mg Tablets | Date of revision of the text | 15/08/2022
LEGAL STATUS
POM |
Depakote 500mg Tablets | Introduction | This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. |
Depakote 500mg Tablets | Name of the medicinal product | Depakote 500 mg Tablets
2. |
Depakote 500mg Tablets | Qualitative and quantitative composition | Containing 538.20 mg of valproate semisodium* per tablet (equivalent to 500 mg of valproic acid).
*Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. It is also known as divalproex sodium (USAN).
Excipient(s) with known effect:
Sodium 39.93 mg (see section 4.4).
For the full list of excipients, see section 6.1.
3. |
Depakote 500mg Tablets | Pharmaceutical form | Gastro-resistant tablet
Oval, lilac pink gastro-resistant tablets.
4. |
Depakote 500mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated.
For the continuation of treatment after manic episode could be considered in patients who have responded to Depakote for acute mania.
4.2 |
Depakote 500mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The daily dosage should be established according to age and body weight. The wide variation in individual sensitivity to Depakote should also be considered.
Dosage
Manic episodes in bipolar disorder:
Adults
The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750 mg in 2 – 3 divided doses. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The mean daily dose usually ranges between 1000 – 2000 mg valproate. Patients receiving daily doses higher than 45 mg/kg/day body weight should be carefully monitored.
Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.
Elderly
Although the pharmacokinetics of valproate are modified in the elderly, they have limited clinical significance and dosage should be determined on the basis of clinical response.
Paediatric population
The efficacy of Depakote in children below 18 years of age in the treatment of manic episodes of bipolar disorder has not been established. With respect to safety information in children see section 4.8.
Renal impairment
It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. Valproate is dialysable (see section 4.9). Dosing should be modified according to clinical monitoring of the patient (see section 4.4).
Hepatic impairment
Salicylates should not be used concomitantly with valproate since they employ the same metabolic pathway (see sections 4.4 and 4.8).
Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 and 4.4).
Salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome). In addition, in conjunction with valproate, concomitant use in children under 3 years of age can increase the risk of liver toxicity (see section 4.4.1).
Female children and women of childbearing potential
Valproate must be initiated and supervised by a specialist experienced in the management of bipolar disorder. Valproate should not be used in female children or women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.3, 4.4 and 4.6).
Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (see sections 4.3 and 4.4). The benefits and risks should be carefully reconsidered at regular treatment reviews (see section 4.4).
Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).
Combined therapy (see section 4.5)
When starting Depakote in patients already on anticonvulsants, these should be tapered slowly; if clinically possible; initiation of Depakote therapy should then be gradual, with target dose being reached after about 2 weeks. Faster titration may be permissible if plasma level monitoring is available. In certain cases, it may be necessary to raise the dose by 5 – 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain control on a reduced dose of Depakote. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.
When using Depakote with other psychotropics, a reduced dose may be required (see section 4.5.1).
Optimum dosage is mainly determined by control. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2).
Method of administration
For oral administration. The tablets should be swallowed whole with a drink of water, and not crushed or chewed.
4.3 |
Depakote 500mg Tablets | Clinical particulars - Contraindications | Contraindications
Depakote is contraindicated in the following situations:
• In pregnancy (see sections 4.4 and 4.6).
• In women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.4 and 4.6).
• Hypersensitivity to valproate semisodium or any other excipients listed in section 6.1.
• Active liver disease, or personal or family history of severe hepatic dysfunction, especially drug related.
• Patients with known urea cycle disorders (see section 4.4).
• Porphyria.
• Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).
4.4 |
Depakote 500mg Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
To ensure the correct medication is prescribed for the patient's condition, care must be taken not to confuse Depakote with Epilim or sodium valproate. Patients with bipolar disorder and epilepsy are distinct populations. These differences are reflected in the patient information leaflets which clearly indicate specific indications for these differing medications.
Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.
4.4.1 Special Warnings
Liver dysfunction:
Conditions of occurrence:
Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.
The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome).
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2 – 12 weeks.
Suggestive signs:
Clinical symptoms are essential for early diagnosis. In particular, the following conditions which may precede jaundice should be taken into consideration, especially in patients at risk (see above: 'Conditions of occurrence'):
- non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.
- in patients with epilepsy, recurrence of seizures
These are an indication for immediate withdrawal of the drug.
Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Detection:
Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.
Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.
Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of treatment.
As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
Increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.
More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
Pancreatitis:
Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase). Young children are at particular risk; this risk decreases with increasing age. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate should be discontinued.
Female children, women of childbearing potential and pregnant women:
Pregnancy Prevention Programme
Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neuro-developmental disorders (see section 4.6).
Depakote is contraindicated in the following situations:
• In pregnancy (see sections 4.3 and 4.6).
• In women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).
Conditions of Pregnancy Prevention Programme:
The prescriber must ensure that:
• Individual circumstances should be evaluated in each case. Involving the patient in the discussion to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.
• The potential for pregnancy is assessed for all female patients.
• The patient has understood and acknowledged the risks of congenital malformations and neuro-developmental disorders including the magnitude of these risks for children exposed to valproate in utero.
• The patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.
• The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (for further details please refer to subsection contraception of this boxed warning), without interruption during the entire duration of treatment with valproate.
• The patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of bipolar disorder.
• The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception and before contraception is discontinued.
• The patient understands the need to urgently consult her physician in case of pregnancy.
• The patient has received the Patient Guide.
• The patient has acknowledged that she has understood the hazards and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Female children
The prescriber must ensure that:
• The parents/caregivers of female children understand the need to contact the specialist once the female child using valproate experiences menarche.
• The parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neuro-developmental disorders including the magnitude of these risks for children exposed to valproate in utero.
In patients who have experienced menarche, the prescribing specialist must annually reassess the need for valproate therapy and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention programme should be discussed. Every effort should be made by the specialist to switch female children to alternative treatment before they reach adulthood.
Pregnancy test
Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of childbearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a healthcare provider, to rule out unintended use in pregnancy.
Contraception
Women of childbearing potential who are prescribed valproate must use effective contraception without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case when choosing the contraception method, involving the patient in the discussion to guarantee her engagement and compliance with the chosen measures. Even if she has amenorrhea, she must follow all the advice on effective contraception.
Oestrogen-containing products
Concomitant use with oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (mood control) when initiating or discontinuing oestrogen-containing products.
On the opposite, valproate does not reduce efficacy of hormonal contraceptives.
Annual treatment reviews by a specialist
The specialist should review at least annually whether valproate is the most suitable treatment for the patient. The specialist should discuss the Annual Risk Acknowledgement Form at initiation and during each annual review and ensure that the patient has understood its content.
Pregnancy planning
If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.
In case of pregnancy
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative treatment options. The patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy (see section 4.6).
Pharmacists must ensure that:
• The Patient Card is provided with every valproate dispensation and that patients understand its content.
• Patients are advised not to stop valproate medication and to immediately contact a specialist in case of planned or suspected pregnancy.
Educational materials
In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorisation Holder has provided educational materials to reinforce the warnings, provide guidance regarding use of valproate in women of childbearing potential and provide details of the Pregnancy Prevention Programme. A Patient Guide and Patient Card should be provided to all women of childbearing potential using valproate.
An Annual Risk Acknowledgement Form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.
Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a specialist experienced in the management of bipolar disorder.
Aggravated convulsions:
As with other anti-epileptic drugs, some patients with epilepsy may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see section 4.8).
Suicidal ideation and behaviour:
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known, and the available data does not exclude the possibility of an increased risk for valproate semisodium.
Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Carbapenem agents:
The concomitant use of valproate and carbapenem agents is not recommended.
Patients with known or suspected mitochondrial disease:
Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).
Excipients with known effect
Sodium: This medicinal product contains 39.93 mg sodium per tablet, equivalent to 2.00% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Ponceau 4R (E124): This colourant (azo dye) may cause allergic reactions including asthma in some people. You are more likely to have an allergy if you are also allergic to aspirin.
4.4.2 Precautions
Haematological tests:
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8)
Renal insufficiency:
In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 and 5.2).
Patients with systemic lupus erythematosus:
Although immune disorders have only rarely been noted during the use of valproate, the potential benefit of valproate should be weighed against its potential risk in patients with systemic lupus erythematosus (see section 4.8).
Urea cycle disorders:
When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate (see section 4.3).
Weight gain:
Valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8).
Diabetic patients:
Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.
Carnitine palmitoyltransferase (CPT) type II deficiency:
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomylosis when taking valproate.
Alcohol:
Alcohol intake is not recommended during treatment with valproate.
4.5 |
Depakote 500mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
4.5.1 Effects of Depakote on other drugs
- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines
Valproate may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.
- Clozapine and haloperidol
No significant interaction was observed when clozapine and haloperidol were administered concurrently with valproate.
- Lithium
Co-administration of valproate and lithium does not appear to affect the steady state kinetics of lithium. Valproate has no effect on serum lithium levels.
- Olanzapine
Valproic acid may decrease the olanzapine plasma concentration.
- Phenobarbital
Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
- Primidone
Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
- Phenytoin
Valproate decreases phenytoin total plasma concentration. Moreover, valproate increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
- Carbamazepine
Clinical toxicity has been reported when valproate was administered with carbamazepine as valproate may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
- Lamotrigine
Valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended, and dosage should be adjusted (lamotrigine dosage decreased) when appropriate.
- Felbamate
Valproic acid may decrease the felbamate mean clearance by up to 16%.
- Rufinamide
Valproic acid may lead to an increase in plasma levels of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
- Propofol
Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.
- Zidovudine
Valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
- Nimodipine
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
- Temozolomide
Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
4.5.2 Effects of other drugs on Depakote
- Anti-epileptics
Antiepileptics with enzyme inducing effects (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
On the other hand, combination of felbamate and valproate decreases valproic acid clearance by 22 – 50% and consequently increase the valproic acid plasma concentrations. Valproate dosage should be monitored.
- Anti-malarial agents
Mefloquine and chloroquine increase valproic acid metabolism. Accordingly, the dosage of valproate may need adjustment.
- Highly protein bound agents
In case of concomitant use of valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.
- Vitamin K-dependent factor anticoagulants
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
- Cimetidine or erythromycin
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
- Carbapenem antibiotics (such as panipenem, imipenem and meropenem)
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60 – 100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level should be performed.
- Rifampicin
Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
- Protease inhibitors
Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.
- Cholestyramine
Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
- Oestrogen-containing products, including oestrogen-containing hormonal contraceptives
Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuoronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
- Metamizole
Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (mood control) and consider monitoring valproate serum levels as appropriate.
4.5.3 Other interactions
- Newer anti-epileptics (including topiramate and acetazolamide)
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
- Quetiapine
Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
4.6 |
Depakote 500mg Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
• Valproate is contraindicated as treatment for bipolar disorder during pregnancy.
• Valproate is contraindicated for use in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.3 and 4.4).
Teratogenicity and developmental effects
Pregnancy exposure risk related to valproate
Both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neuro-developmental disorders in both valproate monotherapy and polytherapy compared to the population not exposed to valproate.
Valproate was shown to cross the placental barrier both in animal species and in humans (see section 5.2).
In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).
Congenital malformations
A meta-analysis (including registries and cohort studies) showed that approximately 11% of children of women with epilepsy exposed to valproate monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations in the general population (approximately 2 – 3%).
The risk of major congenital malformations in children after in utero exposure to anti-epileptic drug polytherapy including valproate is higher than that of anti-epileptic drug polytherapy not including valproate.
This risk is dose-dependent in valproate monotherapy, and available data suggests it is dose-dependent in valproate polytherapy. However, a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to valproate may also result in hearing impairment or deafness due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases did not recover.
In utero exposure to valproate may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
Neuro-developmental disorders
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk of neuro-developmental disorders (including that of autism) seems to be dose-dependent when valproate is used in monotherapy, but a threshold dose below which no risk exists cannot be established based on available data. When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neuro-developmental disorders in the offspring were also significantly increased as compared with those in children from the general population or born to untreated women with epilepsy.
The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
When valproate is administered in monotherapy, studies in children exposed in utero to valproate show that up to 30 – 40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Intelligence quotient (IQ) measured in children (age 6) with a history of valproate exposure in utero was on average 7 – 10 points lower than those children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long-term outcomes.
Available data from a population-based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.
Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.
Female children and woman of childbearing potential (see above and section 4.4).
Oestrogen-containing products
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4 and 4.5).
If a woman plans a pregnancy
If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.
Pregnant women
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy (see sections 4.3 and 4.4). If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.
All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Risk in the neonate
• Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
• Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.
• Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
• Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Breast-feeding
Valproate is excreted in human milk with a concentration ranging from 1 – 10% of maternal serum levels. Haematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from valproate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8).
Valproate administration may also impair fertility in men (see section 4.8). Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility was unknown.
4.7 |
Depakote 500mg Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Patients should be warned of the risk of transient drowsiness, especially in cases of polytherapy or association with benzodiazepines (see section 4.5).
4.8 |
Depakote 500mg Tablets | Clinical particulars - Undesirable effects | Undesirable effects
The following CIOMS frequency rating is used, when applicable: Very common (≥ 1/10); common (≥ 1/100 to < 1/ 10); uncommon (≥ 1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).
The following adverse events have been described from experience of sodium valproate in epilepsy; no other adverse event that could be specifically associated with the use of Depakote in the treatment of manic episodes have been identified.
Congenital malformations and developmental disorders: (see sections 4.4 and 4.6).
Hepatobiliary disorders:
Common: liver injury (see section 4.4.1)
Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment and may be transient (see section 4.4.1).
Gastrointestinal disorders:
Very common: nausea
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea
The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Depakote with or after food.
Uncommon: pancreatitis, sometimes lethal (see section 4.4)
Nervous system disorders:
Very common: tremor
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus
Uncommon: coma*, encephalopathy*, lethargy* (see below), reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions (see section 4.4)
Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder
Sedation has been reported occasionally. In monotherapy it occurred early in treatment on rare occasions and is usually transient.
*Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Psychiatric disorders:
Common: confusional state, hallucinations, aggression, agitation, disturbance in attention
Rare: abnormal behaviour, psychomotor hyperactivity, learning disorder
Metabolism and nutrition disorders:
Common: hyponatraemia, weight increased*
*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4).
Rare: hyperammonaemia* (see section 4.4.2), obesity
*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, but they are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur valproate should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2). In such cases further investigations should be considered.
Endocrine disorders:
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase)
Rare: hypothyroidism (see section 4.6)
Blood and lymphatic system disorders:
Common: anaemia, thrombocytopenia (see section 4.4.2)
Uncommon: pancytopenia, leucopenia
Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis
The blood picture returned to normal when the drug was discontinued.
Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see section 4.6).
Skin and subcutaneous tissue disorders:
Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.
Uncommon: angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth).
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome
Reproductive system and breast disorders:
Common: dysmenorrhea
Uncommon: amenorrhea
Rare: polycystic ovaries, male infertility (see section 4.6)
Very rarely gynaecomastia has occurred.
Vascular disorders:
Common: haemorrhage (see sections 4.4.2 and 4.6)
Uncommon: vasculitis
Eye disorders:
Rare: diplopia
Ear and labyrinth disorders:
Common: deafness, a cause-and-effect relationship has not been established.
Renal and urinary disorders:
Common: urinary incontinence
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy, but the mode of action is as yet unclear.
General disorders and administration site conditions:
Uncommon: hypothermia, non-severe peripheral oedema
Musculoskeletal and connective tissue disorders:
Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproate. The mechanism by which valproate affects bone metabolism has not been identified.
Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4.2)
Respiratory, thoracic and mediastinal disorders:
Uncommon: pleural effusion
Investigations:
Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged) (see sections 4.4 and 4.6)
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Rare: myelodysplastic syndrome
Paediatric population
The safety profile of valproate in the paediatric population is comparable to adults, but some ADRs are more severe or principally observed in the paediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of 3 years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see section 4.4). Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are principally observed in the paediatric population. Based on a limited number of post-marketing cases, Fanconi Syndrome, enuresis and gingival hyperplasia have been reported more frequently in paediatric patients than in adult patients.
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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Depakote 500mg Tablets | Clinical particulars - Overdose | Overdose
Symptoms
Signs of acute massive overdose, i.e. plasma concentration 10 – 20 times maximum therapeutic levels, usually include CNS depression, or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory functions and metabolic acidosis, hypotension and circulatory collapse/shock. A favourable outcome is usual. However, some deaths have occurred following massive overdose.
Symptoms may however be variable, and seizures have been reported in the presence of very high plasma levels in patients with epilepsy. Cases of intracranial hypertension related to cerebral oedema have been reported.
The presence of sodium content in the Depakote formulations may lead to hypernatraemia when taken in overdose.
Management
Hospital management of overdose should be symptomatic, including cardio-respirato-gastric monitoring. Gastric lavage may be useful up to 10 – 12 hours following ingestion.
Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.
In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.
5. Pharmacological properties
5.1 |
Depakote 500mg Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Following oral administration of Depakote, the absolute bioavailability of valproic acid approaches 100%. Mean terminal half-life is about 14 hours, steady state conditions usually being achieved within 3 – 4 days. Peak plasma concentrations are achieved within 3 – 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption.
Distribution
Plasma protein binding of Depakote ranges from 85 – 94% over plasma drug concentrations of 40 – 100 µg/ml. It is concentration-dependent, and the free fraction increases non-linearly with plasma drug concentration.
Placental transfer (see section 4.6)
Valproate crosses the placental barrier in animal species and in humans:
• In animal species, valproate crosses the placenta to a similar extent as in humans.
• In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentrations in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Metabolism
Depakote is extensively metabolised in the liver with less than 3% of an administered dose excreted unchanged in the urine. Principal metabolites found in urine are those originating from β-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose). Plasma clearance ranges from 0.4 – 0.6L/h and is independent of hepatic blood flow.
The major pathway of valproate biotransformation is glucuronidation (~ 40%), mainly via UGT1A6, UGT1A9 and UGT2B7.
Interaction with oestrogen-containing products
Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction.
Special populations
In elderly patients and those with liver cirrhosis (including alcoholic), acute hepatitis or renal failure the elimination of valproic acid is reduced. Reduction in intrinsic clearance and protein binding are reported. Thus, monitoring of total concentrations may be misleading and dosage adjustment may need to be considered according to clinical response.
Haemodialysis reduces serum valproic acid concentrations by about 20%.
5.3 |
Depakote 500mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Valproate was neither mutagenic in bacteria, nor in the mouse lymphoma assay in vitro and did not induce DNA repair in primary rat hepatocyte cultures. In vivo, however, contradictory results were obtained at teratogenic doses depending on the route of administration. After oral administration, the predominant route of administration in humans, valproate did not induce chromosome aberrations in rat bone marrow or dominant lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand-breaks and chromosomal damage in rodents. In addition, increased sister-chromatid exchanges in patients with epilepsy exposed to valproate as compared to untreated healthy subjects have been reported in published studies. However, conflicting results were obtained when comparing data in patients with epilepsy treated with valproate with those in untreated patients with epilepsy. The clinical relevance of these DNA/chromosome findings is unknown.
Non-clinical data reveal no special hazard for humans based on conventional carcinogenicity studies.
Reproductive and developmental toxicity
Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits.
Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
Behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. Some behavioural changes have also been observed in the second generation and those were less pronounced in the third generation of mice following acute in utero exposure of the first generation to teratogenic valproate doses. The underlying mechanisms and the clinical relevance of these findings are unknown.
Testicular toxicity
In sub-chronic/chronic toxicity studies, testicular degeneration/atrophy or spermatogenesis abnormalities and a decrease in testes weight were reported in adult rats and dogs after oral administration starting at doses of 465 mg/kg/day and 150 mg/kg/day, respectively. The safety margin based on plasma concentrations is unknown, however body-surface-area comparisons indicate that there may be no safety margin.
In juvenile (sexually immature) and young adult rats (pubertal), a significant dose-related reduction in testes weight was observed at 240 mg/kg/day following i.v. and i.p. administration with no apparent histopathological changes. However, testicular atrophy was observed in the young adult rat at an i.v. dose of 480 mg/kg/day. Despite the absence of apparent histopathology changes, the testicular weight reductions were considered part of a dose-related spectrum leading to testicular atrophy. There is no safety margin for the effect on testicular weight.
There is a limited number of published papers which report findings in juvenile animals consistent with those reported in the GLP adult and juvenile studies, with respect to testicular weights. Reductions in testicular weights are associated with adverse effects on the adult male reproductive tract in animal studies and impaired fertility in adult patients (see section 4.6).
The toxicological significance of the testicular findings in juvenile animals has not been evaluated and hence the relevance to human testicular development, particularly in the paediatric population, is unknown.
6. |
Depakote 500mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Silicone dioxide
Starch pre-gelatinised
Povidone
Titanium dioxide (E171)
Hypromellose
Polyethylene glycol 6000
Methacrylic acid-ethyl acrylate copolymer (1:1)
Triethyl citrate
Ponceau 4R aluminium lake (E124)
Indigotine aluminium lake (E132)
Vanillin
6.2 |
Depakote 500mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Depakote 500mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Depakote 500mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
None.
6.5 |
Depakote 500mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Aluminium/aluminium blister packs containing 30, 60 or 90 tablets.
Not all pack sizes may be marketed
6.6 |
Depakote 500mg Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements
7. |
Depakote 500mg Tablets | Marketing authorisation holder | Aventis Pharma Limited
410 Thames Valley Park Drive
Reading
Berkshire
RG6 1PT
UK
Trading as:
Sanofi
410 Thames Valley Park Drive
Reading
Berkshire
RG6 1PT
UK
8. Marketing authorisation number(s)
PL 04425/0200
9. |
Depakote 500mg Tablets | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 21 December 2000
Date of latest renewal: 24 March 2009
10. |
Depakote 500mg Tablets | Date of revision of the text | 15/08/2022
LEGAL STATUS
POM |
Depixol 20 mg/ml solution for injection | Name of the medicinal product | Depixol® 20 mg/ml solution for injection
Depixol® Conc. 100 mg/ml solution for injection
2. |
Depixol 20 mg/ml solution for injection | Qualitative and quantitative composition | Depixol Injection:
20 mg/ml flupentixol decanoate in thin vegetable oil.
Depixol Conc. Injection:
100 mg/ml flupentixol decanoate in thin vegetable oil.
For the full list of excipients, see section 6.1
3. |
Depixol 20 mg/ml solution for injection | Pharmaceutical form | Solution for injection.
Depixol Injection:Clear, colourless to slightly yellowish oil, practically free from particles.
Depixol Conc. Injection:Clear, yellowish to yellow oil, practically free from particles.
Oily solution for deep intramuscular injection.
4. |
Depixol 20 mg/ml solution for injection | Clinical particulars - Therapeutic indications | Therapeutic indications
The treatment of schizophrenia and other psychoses.
Use of Depixol should be restricted to those stabilised on oral therapy.
4.2 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
The usual dosage of flupentixol decanoate lies between 50 mg every 4 weeks and 300 mg every 2 weeks, but some patients may require up to 400 mg weekly. The maximum single dose at any one time is 400 mg. For example, 800 mg ever 2 weeks should not be given. Other patients may be adequately maintained on dosages of 20-40 mg flupentixol decanoate every 2-4 weeks. In patients who have not previously received depot antipsychotic, treatment is usually started with a small dose (e.g. 20 mg) to assess tolerability. An interval of at least one week should be allowed before the second injection is given at a dose consistent with the patients' condition.
Depixol Injection 20 mg/ml is not intended for use in patients requiring doses of greater than 60 mg (3 ml) of flupentixol. Injection volumes of 2 – 3 ml should be distributed between two injection sites.
More concentrated solutions of flupentixol decanoate (Depixol Conc Injection or Depixol Low Volume Injection) should be used if doses greater than 3 ml (60 mg) are required.
The injection volumes selected for Depixol Conc Injection or Depixol Low Volume Injection should not exceed 2 ml.
Adequate control of severe psychotic symptoms may take up to 4 to 6 months at high enough dosage. Once stabilised lower maintenance doses may be considered, but must be sufficient to prevent relapse.
Older patients
In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or older patients.
Children
Depixol is not recommended for use in children due to lack of clinical experience.
Patients with reduced renal function
Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).
Patients with reduced hepatic function
Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4). Depixol should be initiated at low doses orally to check for tolerability before switching to the depot formulation.
Method of administration
Route of administration
Deep intramuscular injection into the upper outer buttock or lateral thigh.
Dosage and dosage interval should be adjusted according to the patients' symptoms and response to treatment.
Note: As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.
4.3 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates), coma.
Not recommended for excitable or agitated patients.
4.4 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Caution should be exercised in patients having: liver disease; cardiac disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.
The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation, and opiate and alcohol abuse are overrepresented among fatal cases.
Treatment: Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful.
Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.
Blood dyscrasias, including thrombocytopenia, have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.
As described for other psychotropics flupentixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. The plasma concentrations of the Depixol Injection and Conc. Injection gradually decrease over several weeks which makes gradual dosage tapering unnecessary.
When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.
As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.
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 Depixol and preventive measures undertaken.
Concomitant treatment with other antipsychotics should be avoided (see section 4.5).
Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including flupentixol decanoate.
Long-acting depot antipsychotics should be used with caution in combination with other medicines known to have a myelosuppressive potential, as these cannot rapidly be removed from the body in conditions where this may be required.
Suicide/suicidal thoughts 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 flupentixol 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.
Older people
The elderly require close supervision because they are specially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes.
Cerebrovascular
An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical 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. Flupentixol should be used with caution in patients with risk factors for stroke.
Increased Mortality in Older people with Dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Depixol is not licensed for the treatment of dementia-related behavioural disturbances.
4.5 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
In common with other antipsychotics, flupentixol enhances the response to alcohol the effects of barbiturates and other CNS depressants. Flupentixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.
The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased. Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal effects such as tardive dyskinesia. Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.
Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin. The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and α-blockers (e.g. doxazosin), or methyl-dopa may be enhanced.
Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval.
Co-administration of such drugs should be avoided. Relevant classes include:
• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)
• some antipsychotics (e.g. thioridazine)
• some macrolides (e.g. erythromycin)
• some antihistamines
• some quinolone antibiotics (e.g. moxifloxacin)
The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided.
Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrythmias (see section 4.4).
Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine and similar adrenergic-blocking agents. Antipsychotics may also impair the effect of levodopa, adrenergic drugs and anticonvulsants.
The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.
4.6 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As the safety of this drug during pregnancy has not been established, use during pregnancy, especially the first and last trimesters, should be avoided, unless the expected benefit to the patient outweighs the potential risk to the foetus.
Neonates exposed to antipsychotics (including Depixol) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Animal studies have shown reproductive toxicity (see section 5.3).
Breast-feeding
Flupentixol is excreted into the breast milk. If the use of Depixol is considered essential, nursing mothers should be advised to stop breast-feeding.
Fertility
In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, libido decreased, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may have a negative impact on female and/or male sexual function and fertility.
If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.
In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats (see section 5.3).
4.7 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known. Patients should not drive if they have blurred vision.
4.8 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Undesirable effects | Undesirable effects
Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or early after treatment discontinuation (see section 4.4).
The majority of undesirable effects are dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.
Extrapyramidal reactions may occur, especially in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended.Antiparkinsonian drugs do not alleviate tardive dyskinesia and may aggravate them. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.
Frequencies are taken from the literature and spontaneous reporting. Frequencies are defined as: very common (≤1/10), common (≤1/100 to <1/10), uncommon (≤1/1,000 to <1/100), rare (≤1/10,000 to <1/1,000), very rare (<1/10,000), or not known (can not be estimated from the available data).
Blood and lymphatic system disorders
Rare
Thrombocytopenia, neutropenia, leukopenia, agranulocytosis
Immune system disorders
Rare
Hypersensitivity, anaphylactic reaction.
Endocrine disorder
Rare
Hyperprolactinaemia.
Metabolism and nutrition disorders
Common
Increased appetite, weight increased.
Uncommon
Decreased appetite.
Rare
Hyperglycaemia, glucose tolerance abnormal.
Psychiatric disorders
Common
Insomnia, depression, nervousness, agitation, libido decreased.
Uncommon
Confusional state.
Not known
Suicidal ideation, suicidal Behaviour
Nervous system disorders
Very common
Somnolence, akathisia, hyperkinesia, hypokinesia.
Common
Tremor, dystonia, dizziness, headache, disturbance in attention.
Uncommon to Rare
Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion.
Very Rare
Neuroleptic malignant syndrome.
Eye disorders
Common
Accommodation disorder, vision abnormal.
Uncommon
Oculogyration.
Cardiac disorders
Common
Tachycardia, palpitations.
Rare
Electrocardiogram QT prolonged.
Vascular disorders
Uncommon
Hypotension, hot flush.
Not known
Venous thromboemoblism
Respiratory, thoracic and mediastinal disorders
Common
Dyspnoea.
Gastrointestinal disorders
Very common
Dry mouth.
Common
Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea.
Uncommon
Abdominal pain, nausea, flatulence.
Hepatobiliary disorders
Uncommon
Liver function test abnormal.
Very rare
Jaundice
Skin and subcutaneous tissue disorders
Common
Hyperhidrosis, pruritus.
Uncommon
Rash, photosensitivity reaction, dermatitis.
Musculoskeletal and connective tissue disorder
Common
Myalgia.
Uncommon
Muscle rigidity.
Renal and urinary disorders
common
Micturition disorder, urinary retention.
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see 4.6)
Reproductive system and breast disorders
Uncommon
Ejaculation failure, erectile dysfunction.
Rare
Gynaecomastia, galactorrhoea, amenorrhoea.
General disorders and administration site conditions
Common
Asthenia, fatigue.
Uncommon
Injection site reaction1.
1 For injectable flupentixol presentations.
As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol (see section 4.4).
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown
Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.
Reporting of suspected adverse reactionsReporting 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 |
Depixol 20 mg/ml solution for injection | Clinical particulars - Overdose | Overdose
Overdosage may cause somnolence or even coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper or hypothermia. ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.
Treatment is symptomatic and supportive, with measures aimed at supporting the respiratory and cardiovascular systems. The following specific measures may be employed if required.
- Anticholinergic antiparkinson drugs if extrapyramidal symptoms occur
- Sedation (with benzodiazepines) in the unlikely event of agitation or excitement or convulsions
- Noradrenaline in saline intravenous drip if the patient is in shock. Adrenaline must not be given.
5. Pharmacological properties
5.1 |
Depixol 20 mg/ml solution for injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
After intramuscular injection, the ester is slowly released from the oil depot and is rapidly hydrolysed to release flupentixol. Flupentixol is widely distributed in the body and extensively metabolized in the liver. Peak circulating levels occur around 7 days after administration.
5.3 |
Depixol 20 mg/ml solution for injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Reproductive toxicity
In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Animal reproduction studies in mice, rats and rabbits have not shown evidence of teratogenic effects. Embryotoxic effects in terms of increased post implantation loss/increased absorption rates or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity.
6. |
Depixol 20 mg/ml solution for injection | Pharmaceutical particulars - List of excipients | List of excipients
Thin vegetable oil "Viscoleo" (fractionated coconut oil).
6.2 |
Depixol 20 mg/ml solution for injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
This product may be mixed in the same syringe with other products in the Depixol Injection range. It should not be mixed with any other injection fluids.
6.3 |
Depixol 20 mg/ml solution for injection | Pharmaceutical particulars - Shelf life | Shelf life
Depixol Injection:Ampoules 1 ml and 2 ml : 4 years
Depixol Conc Injection:Ampoule 1 ml : 4 years
6.4 |
Depixol 20 mg/ml solution for injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Keep the ampoules in the outer carton in order to protect from light.
6.5 |
Depixol 20 mg/ml solution for injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Depixol Injection:Ampoules containing 1 ml and 2 ml of 20 mg/ml flupentixol decanoate in thin vegetable oil. Pack size : 10 ampoules per carton.
Depixol Conc Injection:Ampoules containing 1 ml of 100 mg/ml flupentixol decanoate in thin vegetable oil. Pack size : 10 ampoules per carton.
6.6 |
Depixol 20 mg/ml solution for injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Depixol 20 mg/ml solution for injection | Marketing authorisation holder | Lundbeck Limited
Iveco House,
Station Road,
Watford,
Hertfordshire,
WD17 1ET,
UK
8. Marketing authorisation number(s)
Depixol Injection
PL 00458/0007R
Depixol Conc. Injection
PL 00458/0015R
9. |
Depixol 20 mg/ml solution for injection | Date of first authorisation/renewal of the authorisation | Date of First Authorisation in the UK: 28 January 1987
Renewal of the Authorisation: 9 November 2010
10. |
Depixol 20 mg/ml solution for injection | Date of revision of the text | 01/2021
Legal category: POM |
Depixol Conc. 100 mg/ml solution for injection | Name of the medicinal product | Depixol® 20 mg/ml solution for injection
Depixol® Conc. 100 mg/ml solution for injection
2. |
Depixol Conc. 100 mg/ml solution for injection | Qualitative and quantitative composition | Depixol Injection:
20 mg/ml flupentixol decanoate in thin vegetable oil.
Depixol Conc. Injection:
100 mg/ml flupentixol decanoate in thin vegetable oil.
For the full list of excipients, see section 6.1
3. |
Depixol Conc. 100 mg/ml solution for injection | Pharmaceutical form | Solution for injection.
Depixol Injection:Clear, colourless to slightly yellowish oil, practically free from particles.
Depixol Conc. Injection:Clear, yellowish to yellow oil, practically free from particles.
Oily solution for deep intramuscular injection.
4. |
Depixol Conc. 100 mg/ml solution for injection | Clinical particulars - Therapeutic indications | Therapeutic indications
The treatment of schizophrenia and other psychoses.
Use of Depixol should be restricted to those stabilised on oral therapy.
4.2 |
Depixol Conc. 100 mg/ml solution for injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
The usual dosage of flupentixol decanoate lies between 50 mg every 4 weeks and 300 mg every 2 weeks, but some patients may require up to 400 mg weekly. The maximum single dose at any one time is 400 mg. For example, 800 mg ever 2 weeks should not be given. Other patients may be adequately maintained on dosages of 20-40 mg flupentixol decanoate every 2-4 weeks. In patients who have not previously received depot antipsychotic, treatment is usually started with a small dose (e.g. 20 mg) to assess tolerability. An interval of at least one week should be allowed before the second injection is given at a dose consistent with the patients' condition.
Depixol Injection 20 mg/ml is not intended for use in patients requiring doses of greater than 60 mg (3 ml) of flupentixol. Injection volumes of 2 – 3 ml should be distributed between two injection sites.
More concentrated solutions of flupentixol decanoate (Depixol Conc Injection or Depixol Low Volume Injection) should be used if doses greater than 3 ml (60 mg) are required.
The injection volumes selected for Depixol Conc Injection or Depixol Low Volume Injection should not exceed 2 ml.
Adequate control of severe psychotic symptoms may take up to 4 to 6 months at high enough dosage. Once stabilised lower maintenance doses may be considered, but must be sufficient to prevent relapse.
Older patients
In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or older patients.
Children
Depixol is not recommended for use in children due to lack of clinical experience.
Patients with reduced renal function
Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).
Patients with reduced hepatic function
Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4). Depixol should be initiated at low doses orally to check for tolerability before switching to the depot formulation.
Method of administration
Route of administration
Deep intramuscular injection into the upper outer buttock or lateral thigh.
Dosage and dosage interval should be adjusted according to the patients' symptoms and response to treatment.
Note: As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.
4.3 |
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