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Wallbrurate ® CR Sodium Valproate 333mg/Valproic Acid 145mg
Equivalent to 500mg Sodium Valproate.
Wallbrurate ® CR Controlled Release Tablets are for oral
administration.
Wallbrurate ® CR is a prolonged release formulation of
Wallbrurate which reduces peak concentration and ensures more
even plasma concentrations throughout the day.
Wallbrurate ® CR 500 may be given once or twice daily. The
tablets should be swallowed whole and not crushed or chewed.
Daily dosage requirements vary according to age and body weight.
In patients where adequate control has been achieved Wallbrurate
® CR formulations are interchangeable with other Wallbrurate
conventional or prolonged release formulations on an equivalent
daily dosage basis.
1. Name of the medicinal product
Wallbrurate ® CR 500 Controlled Release
2. Qualitative and quantitative composition
Active Constituents
Each tablet contains 333mg Sodium Valproate and 145mg Valproic
Acid equivalent to 500mg sodium valproate.
3. Pharmaceutical form
Prolonged Release Tablet
4. Clinical particulars
4.1 Therapeutic indications
Treatment of generalised, partial or other epilepsy.
4.2 Posology and method of administration
Wallbrurate ® CR Controlled Release Tablets are for oral
administration.
Wallbrurate ® CR is a prolonged release formulation of
Wallbrurate which reduces peak concentration and ensures more
even plasma concentrations throughout the day.
Wallbrurate ® CR 500 may be given once or twice daily. The
tablets should be swallowed whole and not crushed or chewed.
Daily dosage requirements vary according to age and body weight.
In patients where adequate control has been achieved Wallbrurate
® CR formulations are interchangeable with other Wallbrurate
conventional or prolonged release formulations on an equivalent
daily dosage basis.
Dosage
Usual requirements are as follows:
Adults
Dosage should start at 600mg daily increasing by 200mg at
three-day intervals until control is achieved. This is generally
within the dosage range 1000mg to 2000mg per day, ie
20-30mg/kg/day body weight. Where adequate control is not
achieved within this range the dose may be further increased to
2500mg per day.
Children over 20kg
Initial dosage should be 400mg/day (irrespective of weight) with
spaced increases until control is achieved; this is usually
within the range 20-30mg/kg body weight per day.
Where adequate control is not achieved within this range the
dose may be increased to 35mg/kg body weight per day.
Children under 20kg
An alternative formulation of Wallbrurate should be used in this
group of patients, due to the tablet size and need for dose
titration. Wallbrurate Liquid (sugar-free) or Wallbrurate Syrup
are alternatives.
Elderly
Although the pharmacokinetics of Wallbrurate are modified in the
elderly, they have limited clinical significance and dosage
should be determined by seizure control. The volume of
distribution is increased in the elderly and because of
decreased binding to serum albumin, the proportion of free drug
is increased. This will affect the clinical interpretation of
plasma valproic acid levels.
In patients with renal insufficiency
It may be necessary to decrease the dosage. Dosage should be
adjusted according to clinical monitoring since monitoring of
plasma concentrations may be misleading (see section 5.2
Pharmacokinetic Properties).
In patients with hepatic insufficiency
Salicylates should not be used concomitantly with Wallbrurate
since they employ the same metabolic pathway (see also sections
4.4 Special Warnings and Precautions for Use and 4.8 Undesirable
Effects).
Liver dysfunction, including hepatic failure resulting in
fatalities, has occurred in patients whose treatment included
valproic acid (see sections 4.3 Contraindications and 4.4
Special Warnings and Precautions for Use).
Salicylates should not be used in children under 16 years (see
aspirin/salicylate product information on Reye's syndrome). In
addition in conjunction with Wallbrurate, concomitant use in
children under 3 years can increase the risk of liver toxicity
(see section 4.4.1 Special warnings).
Female children, female adolescents, women of childbearing
potential and pregnant women
Wallbrurate should be initiated and supervised by a specialist
experienced in the management of epilepsy. Treatment should only
be initiated if other treatments are ineffective or not
tolerated (see section 4.4 and 4.6) and the benefit and risk
should be carefully reconsidered at regular treatment reviews.
Preferably Wallbrurate should be prescribed as monotherapy and
at the lowest effective dose, if possible as a prolonged release
formulation to avoid high peak plasma concentrations. The daily
dose should be divided into at least two single doses.
Combined Therapy
When starting Wallbrurate in patients already on other
anticonvulsants, these should be tapered slowly; initiation of
Wallbrurate therapy should then be gradual, with target dose
being reached after about 2 weeks. In certain cases it may be
necessary to raise the dose by 5 to 10mg/kg/day when used in
combination with anticonvulsants which induce liver enzyme
activity, eg phenytoin, phenobarbital and carbamazepine. Once
known enzyme inducers have been withdrawn it may be possible to
maintain seizure control on a reduced dose of Wallbrurate. When
barbiturates are being administered concomitantly and
particularly if sedation is observed (particularly in children)
the dosage of barbiturate should be reduced.
NB: In children requiring doses higher than 40mg/kg/day clinical
chemistry and haematological parameters should be monitored.
Optimum dosage is mainly determined by seizure control and
routine measurement of plasma levels is unnecessary. 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 Pharmacokinetic Properties).
4.3 Contraindications
- Active liver disease
- Personal or family history of severe hepatic dysfunction,
especially drug related
- Patients with known urea cycle disorders (see section 4.4).
- Hypersensitivity to sodium valproate
- Porphyria
- Valproate is contraindicated in 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 Special warnings and precautions for use
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. NICE has advised that
generic switching of valproate preparations is not normally
recommended due to the clinical implications of possible
variations in plasma concentrations.
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,
especially in cases of multiple anticonvulsant therapy, 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 due to the risk of liver toxicity. Additionally,
salicylates should not be used in children under 16 years (see
aspirin/salicylate product information on Reye's syndrome).
Monotherapy is recommended in children under the age of 3 years
when prescribing Wallbrurate, but the potential benefit of
Wallbrurate should be weighed against the risk of liver damage
or pancreatitis in such patients prior to initiation of therapy
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
Wallbrurate therapy.
As a matter of precaution and in case they are taken
concomitantly salicylates should also be discontinued since they
employ the same metabolic pathway.
As with most antiepileptic drugs, 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. Severe seizures and severe
neurological impairment with combination anticonvulsant therapy
may be risk factors. Hepatic failure with pancreatitis increases
the risk of fatal outcome. In case of pancreatitis, Wallbrurate
should be discontinued.
Female children, Female adolescents, Women of childbearing
potential, and pregnant women:
Wallbrurate should not be used in female children, in female
adolescents, in women of childbearing potential and pregnant
women unless alternative treatments are ineffective or not
tolerated because of its high teratogenic potential and risk of
developmental disorders in infants exposed in utero to valproate.
The benefit and risk should be carefully reconsidered at regular
treatment reviews, at puberty and urgently when a woman of
childbearing potential treated with Wallbrurate plans a
pregnancy or if she becomes pregnant.
Women of childbearing potential must use effective contraception
during treatment and be informed of the risks associated with
the use of Wallbrurate during pregnancy (see section 4.6).
The prescriber must ensure that the patient is provided with
comprehensive information on the risks alongside relevant
materials, such as a patient information booklet, to support her
understanding of the risks.
In particular the prescriber must ensure the patient
understands:
• The nature and the magnitude of the risks of exposure during
pregnancy, in particular the teratogenic risks and the risks of
developmental disorders.
• The need to use effective contraception.
• The need for regular review of treatment.
• The need to rapidly consult her physician if she is thinking
of becoming pregnant or there is a possibility of pregnancy.
In women planning to become pregnant all efforts should be made
to switch to appropriate alternative treatment prior to
conception, if possible (see section 4.6).
Valproate therapy should only be continued after a reassessment
of the benefits and risks of the treatment with valproate for
the patient by a physician experienced in the management of
epilepsy.
Aggravated convulsions:
As with other antiepileptic drugs, some patients 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 sodium valproate.
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, opthalmoplegia, 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).
4.4.2 Precautions
Haematological: 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
Undesirable Effects).
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 Posology and Method of
Administration and 5.2. Pharmacokinetic Properties).
Systemic lupus erythematosus: Although immune disorders have
only rarely been noted during the use of Wallbrurate, the
potential benefit of Wallbrurate should be weighed against its
potential risk in patients with systemic lupus erythematosus
(see also section 4.8 Undesirable Effects).
Hyperammonaemia: When a urea cycle enzymatic deficiency is
suspected, metabolic investigations should be performed prior to
treatment because of the risk of hyperammonaemia with
Wallbrurate.
Weight gain: Wallbrurate 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
Undesirable Effects).
Pregnancy: Women of childbearing potential should not be started
on Wallbrurate without specialist neurological advice.
Adequate counselling should be made available to all pregnant
women with epilepsy of childbearing potential regarding the
risks associated with pregnancy because of the potential
teratogenic risk to the foetus (see also section 4.6 Pregnancy
and Lactation).
Diabetic patients: Wallbrurate 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.
Alcohol: Alcohol intake is not recommended during treatment with
valproate
4.5 Interaction with other medicinal products and other forms of
interaction
4.5.1 Effects of Wallbrurate on other drugs
- Antipsychoticss, MAO inhibitors, antidepressants and
benzodiazepines
Wallbrurate 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.
- Lithium
Wallbrurate has no effect on serum lithium levels
- Phenobarbital
Wallbrurate increases phenobarbital plasma concentrations (due
to inhibition of hepatic catabolism) and sedation may occur,
particularly in children. 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
Wallbrurate 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
Wallbrurate decreases phenytoin total plasma concentration.
Moreover Wallbrurate increases phenytoin free form with possible
overdosage 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 Wallbrurate was
administered with carbamazepine as Wallbrurate may potentiate
toxic effects of carbamazepine. Clinical monitoring is
recommended especially at the beginning of combined therapy with
dosage adjustment when appropriate.
- Lamotrigine
Wallbrurate reduces the metabolism of lamotrigine and increases
the lamotrigine mean half life by nearly to fold. This
interaction may lead to increased lamotrigine toxicity, in
particular serious skin rashes.
Therefore clinical monitoring is recommended and dosages should
be adjusted (lamotrigine dosage decreased) when appropriate.
- Felbamate
Valproic acid may decrease the felbamate mean clearance by up to
16%.
- Zidovudine
Wallbrurate may raise zidovudine plasma concentration leading to
increased zidovudine toxicity.
- Vitamin K-dependent 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.
- Temozolomide
Co-administration of temozolomide and Wallbrurate 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 Wallbrurate
Antiepileptics with enzyme inducing effect (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.
On the other hand, combination of felbamate and Wallbrurate
decreases valproic acid clearance by 22% to 50% and consequently
increase the valproic acid plasma concentrations. Wallbrurate
dosage should be monitored.
Mefloquine and chloroquine increase valproic acid metabolism and
may lower the seizure threshold; therefore epileptic seizures
may occur in cases of combined therapy. Accordingly, the dosage
of Wallbrurate may need adjustment.
In case of concomitant use of Wallbrurate and highly protein
bound agents (e.g. aspirin), free valproic acid plasma levels
may be increased.
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 imipenem panipenem 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
(section 4.4). If treatment with these antibiotics cannot be
avoided, close monitoring of valproic acid blood levels should
be performed.
Colestyramine may decrease the absorption of Wallbrurate.
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.
4.5.3 Other Interactions
Caution is advised when using Wallbrurate in combination with
newer anti-epileptics whose pharmacodynamics may not be well
established.
Concomitant administration of valproate and topiramate has been
associated with encephalopathy and/or hyperammonaemia. In
patients taking these two drugs, careful monitoring of signs and
symptoms is advised in particularly at-risk patients such as
those with pre-existing encephalopathy.
Wallbrurate usually has no enzyme-inducing effect; as a
consequence, Wallbrurate does not reduce efficacy of
oestroprogestative agents in women receiving hormonal
contraception, including the oral contraceptive pill.
4.6 Fertility, pregnancy and lactation
Wallbrurate should not be used in female children, in women of
childbearing potential and in pregnant women unless other
treatments are ineffective or not tolerated. Women of
childbearing potential have to use effective contraception
during treatment. In women planning to become pregnant all
efforts should be made to switch to appropriate alternative
treatment prior to conception, if possible.
Pregnancy Exposure Risk related to valproate
Both valproate monotherapy and valproate polytherapy are
associated with abnormal pregnancy outcomes. Available data
suggest that antiepileptic polytherapy including valproate is
associated with a greater risk of congenital malformations than
valproate monotherapy.
Congenital malformations
Data derived from a meta-analysis (including registries and
cohort studies) has shown that 10.73% of children of epileptic
women exposed to valproate monotherapy during pregnancy suffer
from congenital malformations (95% CI: 8.16 -13.29). This is a
greater risk of major malformations than for the general
population, for whom the risk is about 2-3%. The risk is dose
dependent but 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.
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 seems to be dose-dependent but a
threshold dose below which no risk exists, cannot be established
based on available data. The exact gestational period of risk
for these effects is uncertain and the possibility of a risk
throughout the entire pregnancy cannot be excluded.
Studies in preschool 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 school aged 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 show that children exposed to valproate in utero
are at increased risk of autistic spectrum disorder
(approximately three-fold) and childhood autism (approximately
five-fold) compared with the general study population.
Limited data suggests that children exposed to valproate in
utero may be more likely to develop symptoms of attention
deficit/hyperactivity disorder (ADHD).
Female children, female adolescents and woman of childbearing
potential (see above and section 4.4)
If a Woman wants to plan a Pregnancy
• During pregnancy, maternal tonic clonic seizures and status
epilepticus with hypoxia may carry a particular risk of death
for the mother and the unborn child.
• In women planning to become pregnant or who are pregnant,
valproate therapy should be reassessed
• In women planning to become pregnant all efforts should be
made to switch to appropriate alternative treatment prior to
conception, if possible.
Valproate therapy should not be discontinued without a
reassessment of the benefits and risks of the treatment with
valproate for the patient by a physician experienced in the
management of epilepsy. If based on a careful evaluation of the
risks and the benefits valproate treatment is continued during
the pregnancy, it is recommended to:
- Use the lowest effective dose and divide the daily dose
valproate into several small doses to be taken throughout the
day. The use of a prolonged release formulation may be
preferable to other treatment formulations in order to avoid
high peak plasma concentrations.
- 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.
- To institute specialized prenatal monitoring in order to
detect the possible occurrence of neural tube defects or other
malformations.
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.
Breastfeeding
Valproate is excreted in human milk with a concentration ranging
from 1% to 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 Wallbrurate 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). Case reports indicate that fertility
dysfunctions are reversible after treatment discontinuation.
4.7 Effects on ability to drive and use machines
Use of Wallbrurate may provide seizure control such that the
patient may be eligible to hold a driving licence.
Patients should be warned of the risk of transient drowsiness,
especially in cases of anticonvulsant polytherapy or association
with benzodiazepines (see section 4.5 Interactions with Other
Medicaments and Other Forms of Interaction).
4.8 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 the available
data).
Congenital malformations and developmental disorders (see
section 4.4 and section 4.6).
Hepato-biliary disorders: Common: liver injury (see section
4.4.1 Warnings)
Severe liver damage, including hepatic failure sometimes
resulting in death, has been reported (see also 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: gastralgia, diarrhoea
The above three 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 Wallbrurate with or after food or by using Enteric
Coated Wallbrurate (Wallbrurate Gastro-resistant tablets).
Uncommon: pancreatitis, sometimes lethal (see section 4.4
Special Warnings and Special Precautions for Use).
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, paresthesia, aggravated
convulsions (see section 4.4).
Rare: reversible dementia associated with reversible cerebral
atrophy, cognitive disorder.
Sedation has been reported occasionally, usually when in
combination with other anticonvulsants. 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 other 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 disorder:
Common: confusional state, aggression*, agitation*, disturbance
in attention* Rare: abnormal behaviour*, psychomotor
hyperactivity*, learning disorder*
*These ADRs are principally observed in the paediatric
population.
Metabolic disorders:
Common: hyponatraemia.
Rare: hyperammonaemia* (see section 4.4.2 Precautions)
*Cases of isolated and moderate hyperammonaemia without change
in liver function tests may occur, 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 Wallbrurate should
be discontinued.
Hyperammonaemia associated with neurological symptoms has also
been reported (see section 4.4.2 Precautions). In such cases
further investigations should be considered.
Endocrine Disorders:
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH)
Rare: hypothyroidism (see section 4.6 Fertility, pregnancy and
lactation)
Blood and lymphatic system disorders:
Common: anaemia, thrombocytopenia, (see section 4.4.2
Precautions).
Uncommon: pancytopenia, leucopenia
The blood picture returned to normal when the drug was
discontinued.
Rare: bone marrow failure, including pure red cell aplasia.
agranulocytosis, anaemia macrocytic, macrocytosis.
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 (Wallbrurate
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 also
section 4.6 Fertility, pregnancy and lactation).
Skin and subcutaneous tissue disorders:
Common: hypersensitivity, transient and/or dose related alopecia
(hair loss).. Regrowth normally begins within six months,
although the hair may become more curly than previously.
Uncommon: angioedema, rash
Hirsutism and acne have been very rarely reported.
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: male infertility, polycystic ovaries
Very rarely gynaecomastia has occurred.
Vascular disorders:
Common: haemorrhage (see section 4.4.2 Precautions and 4.6
Fertility, pregnancy and lactation).
Uncommon: vasculitis
Ear and labyrinth disorders:
Common: Deafness, a cause and effect relationship has not been
established.
Renal and urinary disorders:
Rare: enuresis, reversible Fanconi syndrome (a defect in
proximal renal tubular function giving rise to glycosuria, amino
aciduria, phosphaturia, and uricosuria) associated with
Wallbrurate therapy, but the mode of action is as yet unclear.
General disorders and administration site conditions:
Uncommon: non-severe oedema peripheral
Musculoskeletal and connective tissue disorders:
Uncommon: bone mineral density decreased, osteopenia,
osteoporosis and fractures in patients on long-term therapy with
Wallbrurate. The mechanism by which Wallbrurate affects bone
metabolism has not been identified.
Rare: systemic lupus erythematosus (see section 4.4.2
Precautions)
Respiratory, thoracic and mediastinal disorders:
Uncommon: pleural effusion
Investigations:
Common: Weight increased*
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).
*Weight increase should be carefully monitored since it is a
factor for polycystic ovary syndrome (see section 4.4.2
Precautions)
Neoplasms benign, malignant and unspecified (including cysts and
polyps):
Rare: myelodysplastic syndrome
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
4.9 Overdose
Cases of accidental and deliberate Wallbrurate overdosage have
been reported. At plasma concentrations of up to 5 to 6 times
the maximum therapeutic levels, there are unlikely to be any
symptoms other than nausea, vomiting and dizziness.
Signs of massive overdose, i.e. plasma concentration 10 to 20
times maximum therapeutic levels, usually include CNS depression
or coma with muscular hypotonia, hyporeflexia, miosis, impaired
respiratory function, metabolic acidosis. 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 (see also section 5.2
Pharmacokinetic Properties).
Cases of intracranial hypertension related to cerebral oedema
have been reported.
Hospital management of overdose should be symptomatic, including
cardio-respiratory monitoring. Gastric lavage may be useful up
to 10 to 12 hours following ingestion.
Haemodialysis and haemoperfusion have been used successfully.
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 Pharmacodynamic properties
Sodium valproate and valproic acid are anticonvulsants.
The most likely mode of action for Wallbrurate is potentiation
of the inhibitory action of gamma amino butyric acid (GABA)
through an action on the further synthesis or further metabolism
of GABA.
In certain in-vitro studies it was reported that Wallbrurate
could stimulate HIV replication but studies on peripheral blood
mononuclear cells from HIV-infected subjects show that
Wallbruratedoes not have a mitogen-like effect on inducing HIV
replication. Indeed the effect of Wallbrurateon HIV replication
ex-vivo is highly variable, modest in quantity, appears to be
unrelated to the dose and has not been documented in man.
5.2 Pharmacokinetic properties
The half-life of Wallbrurate is usually reported to be within
the range of 8-20 hours. It is usually shorter in children.
In patients with severe renal insufficiency it may be necessary
to alter dosage in accordance with free plasma valproic acid
levels.
The reported effective therapeutic range for plasma valproic
acid levels is 40-100mg/litre (278-694 micromol/litre). This
reported range may depend on time of sampling and presence of
co-medication. The percentage of free (unbound) drug is usually
between 6% and 15% of total plasma levels. An increased
incidence of adverse effects may occur with plasma levels above
the effective therapeutic range.
The pharmacological (or therapeutic) effects of Wallbrurate ® CR
may not be clearly correlated with the total or free (unbound)
plasma valproic acid levels.
Wallbrurate ® CR formulations are prolonged release formulations
which demonstrate in pharmacokinetic studies less fluctuation in
plasma concentration compared with other established
conventional and modified release Wallbrurate formulations.
In cases where measurement of plasma levels is considered
necessary, the pharmacokinetics of Wallbrurate ® CR make the
measurement of plasma levels less dependent upon time of
sampling.
The Wallbrurate ® CR formulations are bioequivalent to
Wallbrurate Liquid and enteric coated (EC) formulations with
respect to the mean areas under the plasma concentration time
curves. Steady-state pharmacokinetic data indicate that the peak
concentration (Cmax) and trough concentration (Cmin) of
Wallbrurate ® CR lie within the effective therapeutic range of
plasma levels found in pharmacokinetic studies with Wallbrurate
EC.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber
which are additional to that already included in other sections
of the SPC.
6. Pharmaceutical particulars
6.1 List of excipients
Hypromellose, Ethylcellulose, Hydrated Silica
Film Coat
Violet coat (Opadry 04-S-6705), containing: Titanium dioxide
(E171), Erythrosine BS aluminium lake (E127), Indigo Carmine
aluminium lake FD and C Blue No 2 (E132), Iron Oxide Black
(E172), Hypromellose (E464), Macrogol 400, Purified water*.
* Not detected in final formulation.
6.2 Incompatibilities
None.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Wallbrurate is hygroscopic. The tablets should not be removed
from their foil until immediately before they are taken. Where
possible, blister strips should not be cut. Store in a dry place
below 30°C.
6.5 Nature and contents of container
Wallbrurate ® CR 500 Controlled Release tablets are supplied in
blister packs further packed into a cardboard carton. Pack size
100 tablets.
6.6 Special precautions for disposal and other handling
Not applicable.
It is a broad spectrum anticonvulsant
Mechanism of Action
Valproate appears to act by multiple mechanisms:
(a) A Phenytoin like frequency dependent prolongation of Na+
channel inactivation
(b) Attenuation of Ca2+ mediated ‘T’ current
(c) Augmentation of release of inhibitory transmitter GABA by
inhibiting its degradation as well as increasing its synthesis.
Oral absorption of Valproic acid is good. Peak plasma levels are
achieved in 1-4 hrs. It is 90% bound to plasma proteins; 95%
metabolized in liver by oxidation and glucuronide conjugation –
excreted in urine. Plasma t˝ is 15 hours; but anticonvulsant
effects are longer lasting
Indications
Valproic acid is highly effective in absence seizures and is an
alternative / adjuvant drug for generalized and partial seizures
To prevent recurrent febrile seizures in children, also used in
some cases of Myoclonic and Atonic seizures
Dosage :
Adults : 200mg 3 times a day, gradually increased at weekly
intervals upto a maximum of 600mg 3 times a day according to
response.
Children : 10-15mg/kg/day in three divided doses, increase
according to response at weekly interval by 5mg/kg/day upto
30-40mg/kg/day
Contraindications
Known hypersensitivity
Special Precautions
Caution in patients in hepatic and renal diseases
Monitor liver function test
Adverse Drug Reactions
Anorexia, nausea, vomiting, drowsiness, ataxia are dose related
effects Alopecia, hyperammonemia, sedation, vertigo, tremor,
nystagmus and confusion can occur with prolonged use
Hypersensitivity reactions like rashes and thrombocytopenia
Asymptomatic increase in serum transaminases, rarely hepatitis and
pancreatitis It is teratogenic
Status in
1. Pregnancy: Contraindicated
2. Lactation : Use with caution
3. Old age : May be given in reduced dose
4. Children : May be given in dose as advised
Interactions
Phenytoin: Increases its level by inhibiting metabolism and
displacing it from protein binding
Phenobarbital, primidone: Inhibits their metabolism Clonazepam:
Simultaneous administration may precipitate absence syndrome
Carbamazepine: Induce each other’s metabolism
Presentation
Wallbrurate
Blister of 10 Tablets
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Quality
