Sodium Valproate & Valproic Acid Tablets SMPC Taj Pharmaceuticals

Sodium Valproate and Valpr oic Acid 500 mg Tablets TajP harma : Uses, Side E ffects, I nteractions, Pict
ures, War nings, Sodium Valproate and Valpr oic Acid D osage & Rx Info | Sodium Valproate and Valproic A cid Use s, Side Effe cts - Antiepile ptic, Sodi um Valpr oate and Valproi c Acid : I ndications, Side E ffects, Warni ngs, Sodi um Valpr oate and Valproi c Acid - Dr ug Infor mation - Taj Phar ma, Sodium Valproate a nd Valproi c Acid dose Taj phar ma ceuticals S odium Valproate and Valproic A cid interactions, Taj Phar maceutical Sodium Valproate and Valpr oic Aci d contraindications, Sodium Valpr oate and Val proic Aci d price, Sodium Valproate and Valpr oic Aci d TajPhar ma Antiepilepti c Tablets SmPC - TajPhar ma Stay connected t o all update d on Sodium Valproate and Valpr oic Aci d Taj Phar mace uticals Taj pharma ceutical s Mumbai. Pa tient I nfor mation Lea flets, SmP C.
Sodium Valproate & Valproic Dosage
acid 500mg Controlled Release Usual requirements are as follows:

Tablets Adults
Dosage should start at 600 mg daily increasing
1. Name of the medicinal by 200 mg at three-day intervals until control is
product achieved. This is generally within the dosage
range 1000 – 2000 mg per day, i.e. 20 – 30
Sodium Valproate & Valproic acid 500mg mg/kg/day body weight. Where adequate control
Controlled Release Tablets TajPharma is not achieved within this range the dose may
be further increased to 2500 mg per day.
2. Qualitative and quantitative
Children over 20 kg
composition
Initial dosage should be 400 mg/day
Each Film Coated Controlled Release Tablet (irrespective of weight) with spaced increases
Contains: until control is achieved; this is usually within
Sodium Valproate BP 333mg the range 20 – 30 mg/kg body weight per day.
Valproic Acid USP 145mg
Excipients q.s. Where adequate control is not achieved within
Colour: Red Oxide of Iron & Titanium Dioxide this range the dose may be increased to 35
USP mg/kg body weight per day.
Children under 20 kg
3. Pharmaceutical form
An alternative formulation of Epilim should be
Controlled Release Tablet used in this group of patients, due to the tablet
size and need for dose titration. Epilim Liquid
4. Clinical particulars (sugar-free) or Epilim Syrup are alternatives.
4.1 Therapeutic indications Elderly
Treatment of generalised, partial or other
epilepsy. Although the pharmacokinetics of Epilimare
modified in the elderly, they have limited
4.2 Posology and method of administration clinical significance and dosage should be
Sodium Valproate &Valproicacid is a determined by seizure control. The volume of
prolonged release formulation of Epilim which distribution is increased in the elderly and
reduces peak concentration and ensures more because of decreased binding to serum albumin,
even plasma concentrations throughout the day. the proportion of free drug is increased. This
Sodium Valproate &Valproicacid 500 may be will affect the clinical interpretation of plasma
given once or twice daily. The tablets should be valproic acid levels.
swallowed whole and not crushed or chewed.
Daily dosage requirements vary according to age In patients with renal insufficiency
and body weight.
It may be necessary to decrease the dosage.
In patients where adequate control has been Dosage should be adjusted according to clinical
achieved Sodium Valproate &Valproicacid monitoring since monitoring of plasma
formulations are interchangeable with other concentrations may be misleading (see section
Epilim conventional or prolonged release 5.2).
formulations on an equivalent daily dosage
In patients with hepatic insufficiency
basis.
Sodium Valproate and Valpr oic Acid 500 mg Tablets TajP harma : Uses, Side E ffects, I nteractions, Pict ures, War nings, Sodium Valproate and Valpr oic Acid D osage & Rx Info | Sodium Valproate and Valproic A cid Use s, Side Effe cts - Antiepile ptic, Sodi um Valpr oate and Valproi c Acid : I ndications, Side E ffects, Warni ngs, Sodi um Valpr oate and Valproi c Acid - Dr ug Infor mation - Taj Phar ma, Sodium Valproate a nd Valproi c Acid dose Taj phar ma ceuticals S odium Valproate and Valproic A cid interactions, Taj Phar maceutical Sodium Valproate and Valpr oic Aci d contraindications, Sodium Valpr oate and Val proic Aci d price, Sodium Valproate and Valpr oic Aci d TajPhar ma Antiepilepti c Tablets SmPC - TajPhar ma Stay connected t o all update d on Sodium Valproate and Valpr oic Aci d Taj Phar mace uticals Taj pharma ceutical s Mumbai. Pa tient I nfor mation Lea flets, SmP C.
Salicylates should not be used concomitantly control on a reduced dose of Epilim. When
with Epilim since they employ the same barbiturates are being administered
metabolic pathway (see sections 4.4 and 4.8). concomitantly and particularly if sedation is
observed (particularly in children) the dosage of
Liver dysfunction, including hepatic failure barbiturate should be reduced.
resulting in fatalities, has occurred in patients
whose treatment included valproic acid (see NB: In children requiring doses higher than 40
sections 4.3 and 4.4). mg/kg/day clinical chemistry and
haematological parameters should be monitored.
Salicylates should not be used in children under
16 years (see aspirin/salicylate product Optimum dosage is mainly determined by
information on Reye's syndrome). In addition in seizure control and routine measurement of
conjunction with Epilim, concomitant use in plasma levels is unnecessary. However, a
children under 3 years can increase the risk of method for measurement of plasma levels is
liver toxicity (see section 4.4.1). available and may be helpful where there is poor
control or side effects are suspected (see section
Female children and women of childbearing 5.2).
potential
Method of administration
Valproate must be initiated and supervised by a
specialist experienced in the management of Sodium Valproate &Valproicacid Controlled
epilepsy. Valproate should not be used in female Release Tablets are for oral administration.
children and women of childbearing potential
In view of the sustained release process and the
unless other treatments are ineffective or not
tolerated (see sections 4.3, 4.4 and 4.6). nature of the excipients in the formula, the inert
matrix of the tablet is not absorbed by the
Valproate is prescribed and dispensed according digestive tract; it is eliminated in the stools after
to the Valproate Pregnancy Prevention the active substances have been released.
Programme (see sections 4.3 and 4.4). The
benefits and risks should be carefully 4.3 Contraindications
Epilim is contraindicated in the following
reconsidered at regular treatment reviews (see
section 4.4). situations:
• In pregnancy unless there is no suitable
Valproate should preferably be prescribed as
alternative treatment (see sections 4.4 and 4.6).
monotherapy and at the lowest effective dose, if
possible as a prolonged release formulation. The • In women of childbearing potential unless the
daily dose should be divided into at least two conditions of the pregnancy prevention
single doses (see section 4.6). programme are fulfilled (see sections 4.4 and
Combined Therapy 4.6).
• Active liver disease.
When starting Epilim in patients already on
other anti-convulsants, these should be tapered • Personal or family history of severe hepatic
slowly; initiation of Epilim therapy should then dysfunction, especially drug related.
be gradual, with target dose being reached after
about 2 weeks. In certain cases it may be • Patients with known urea cycle disorders (see
necessary to raise the dose by 5 – 10 mg/kg/day section 4.4).
when used in combination with anti-convulsants • Hypersensitivity to sodium valproate.
which induce liver enzyme activity, e.g.
phenytoin, phenobarbital and carbamazepine. • Porphyria.
Once known enzyme inducers have been
withdrawn it may be possible to maintain seizure
• Valproate is contraindicated in patients known Monotherapy is recommended in children under

to have mitochondrial disorders caused by the age of 3 years when prescribing Epilim, but
mutations in the nuclear gene encoding the the potential benefit of Epilim should be
mitochondrial enzyme polymerase γ (POLG), weighed against the risk of liver damage or
e.g. Alpers-Huttenlocher Syndrome, and in pancreatitis in such patients prior to initiation of
children under two years of age who are therapy
suspected of having a POLG-related disorder
(see section 4.4). In most cases, such liver damage occurred
during the first 6 months of therapy, the period
4.4 Special warnings and precautions for use of maximum risk being 2 – 12 weeks.
Although there is no specific evidence of sudden
Suggestive signs:
recurrence of underlying symptoms following
withdrawal of valproate, discontinuation should Clinical symptoms are essential for early
normally only be done under the supervision of diagnosis. In particular the following conditions,
a specialist in a gradual manner. This is due to which may precede jaundice, should be taken
the possibility of sudden alterations in plasma into consideration, especially in patients at risk
concentrations giving rise to a recurrence of (see above: 'Conditions of occurrence'):
symptoms. NICE has advised that generic
switching of valproate preparations is not - non-specific symptoms, usually of sudden
normally recommended due to the clinical onset, such as asthenia, malaise, anorexia,
implications of possible variations in plasma lethargy, oedema and drowsiness, which are
concentrations. sometimes associated with repeated vomiting
and abdominal pain.
4.4.1 Special warnings
- in patients with epilepsy, recurrence of
Liver dysfunction: seizures.
Conditions of occurrence: These are an indication for immediate
withdrawal of the drug.
Severe liver damage, including hepatic failure
sometimes resulting in fatalities, has been very Patients (or their family for children) should be
rarely reported. Experience in epilepsy has instructed to report immediately any such signs
indicated that patients most at risk, especially in to a physician should they occur. Investigations
cases of multiple anti-convulsant therapy, are including clinical examination and biological
infants and in particular young children under assessment of liver function should be
the age of 3 years and those with severe seizure undertaken immediately.
disorders, organic brain disease, and (or)
congenital metabolic or degenerative disease Detection:
associated with mental retardation. After the age Liver function should be measured before
of 3 years, the incidence of occurrence is therapy and then periodically monitored during
significantly reduced and progressively the first 6 months of therapy, especially in those
decreases with age. who seem most at risk, and those with a prior
The concomitant use of salicylates should be history of liver disease.
avoided in children under 3 years due to the risk Amongst usual investigations, tests which reflect
of liver toxicity. Additionally, salicylates should protein synthesis, particularly prothrombin rate,
not be used in children under 16 years (see are most relevant.
aspirin/salicylate product information on Reye's
syndrome). Confirmation of an abnormally low prothrombin
rate, particularly in association with other
biological abnormalities (significant decrease in
fibrinogen and coagulation factors; increased Programme:

bilirubin level and raised transaminases) requires The prescriber must ensure that:
cessation of Epilim therapy. • Individual circumstances should be evaluated
As a matter of precaution and in case they are in each case. Involving the patient in the
taken concomitantly salicylates should also be discussion to guarantee her engagement, discuss
discontinued since they employ the same therapeutic options and ensure her understanding
metabolic pathway. of the risks and the measures needed to
minimise the risks.
As with most anti-epileptic drugs, increased • The potential for pregnancy is assessed for all
liver enzymes are common, particularly at the female patients.
beginning of therapy; they are also transient. • The patient has understood and acknowledged
the risks of congenital malformations and
More extensive biological investigations
neurodevelopmental disorders including the
(including prothrombin rate) are recommended
magnitude of these risks for children exposed to
in these patients; a reduction in dosage may be
valproate in utero.
considered when appropriate and tests should be
• The patient understands the need to undergo
repeated as necessary.
pregnancy testing prior to initiation of treatment
Pancreatitis: and during treatment, as needed.
• The patient is counselled regarding
Pancreatitis, which may be severe and result in contraception, and that the patient is capable of
fatalities, has been very rarely reported. Patients complying with the need to use effective
experiencing nausea, vomiting or acute contraception (for further details please refer to
abdominal pain should have a prompt medical subsection contraception of this boxed warning),
evaluation (including measurement of serum without interruption during the entire duration of
amylase).Young children are at particular risk; treatment with valproate.
this risk decreases with increasing age. Severe • The patient understands the need for regular (at
seizures and severe neurological impairment least annual) review of treatment by a specialist
with combination anti-convulsant therapy may experienced in the management of epilepsy.
be risk factors. Hepatic failure with pancreatitis • The patient understands the need to consult her
increases the risk of fatal outcome. In case of physician as soon as she is planning pregnancy
pancreatitis, Epilim should be discontinued. to ensure timely discussion and switching to
Female children, women of childbearing alternative treatment options prior to conception
potential and pregnant women: and before contraception is discontinued.
• The patient understands the need to urgently
Pregnancy Prevention Programme consult her physician in case of pregnancy.
Valproate has a high teratogenic potential and • The patient has received the Patient Guide.
children exposed in utero to valproate have a • The patient has acknowledged that she has
high risk for congenital malformations and understood the hazards and necessary
neurodevelopmental disorders (see section 4.6). precautions associated with valproate use
Epilim is contraindicated in the following (Annual Risk Acknowledgement Form).
situations: These conditions also concern women who are
• In pregnancy unless there is no suitable not currently sexually active unless the
alternative treatment (see sections 4.3 and 4.6). prescriber considers that there are compelling
• In women of childbearing potential unless the reasons to indicate that there is no risk of
conditions of the pregnancy prevention pregnancy.
programme are fulfilled (see sections 4.3 and Female children
4.6). The prescriber must ensure that:
Conditions of Pregnancy Prevention • The parents/caregivers of female children
understand the need to contact the specialist advice on effective contraception.

once the female child using valproate Oestrogen-containing products
experiences menarche. Concomitant use with oestrogen-containing
• The parents/caregivers of female children who products, including oestrogen-containing
have experienced menarche are provided with hormonal contraceptives, may potentially result
comprehensive information about the risks of in decreased valproate efficacy (see section 4.5).
congenital malformations and Prescribers should monitor clinical response
neurodevelopmental disorders including the (seizure control) when initiating, or
magnitude of these risks for children exposed to discontinuing oestrogen-containing products.
valproate in utero. On the opposite, valproate does not reduce
In patients who have experienced menarche, the efficacy of hormonal contraceptives.
prescribing specialist must annually reassess the Annual treatment reviews by a specialist
need for valproate therapy and consider The specialist should review at least annually
alternative treatment options. If valproate is the whether valproate is the most suitable treatment
only suitable treatment, the need for using for the patient. The specialist should discuss the
effective contraception and all other conditions Annual Risk Acknowledgement Form at
of the pregnancy prevention programme should initiation and during each annual review, and
be discussed. Every effort should be made by the ensure that the patient has understood its
specialist to switch female children to alternative content.
treatment before they reach adulthood. Pregnancy planning
Pregnancy test If a woman is planning to become pregnant, a
Pregnancy must be excluded before start of specialist experienced in the management of
treatment with valproate. Treatment with epilepsy must reassess valproate therapy and
valproate must not be initiated in women of consider alternative treatment options. Every
childbearing potential without a negative effort should be made to switch to appropriate
pregnancy test (plasma pregnancy test) result, alternative treatment prior to conception and
confirmed by a healthcare provider, to rule out before contraception is discontinued (see section
unintended use in pregnancy. 4.6). If switching is not possible, the woman
Contraception should receive further counselling regarding the
Women of childbearing potential who are risks of valproate for the unborn child to support
prescribed valproate must use effective her informed decision-making regarding family
contraception without interruption during the planning.
entire duration of treatment with valproate. In case of pregnancy
These patients must be provided with If a woman using valproate becomes pregnant,
comprehensive information on pregnancy she must be immediately referred to a specialist
prevention and should be referred for to re-evaluate treatment with valproate and
contraceptive advice if they are not using consider alternative treatment options. The
effective contraception. At least one effective patients with valproate-exposed pregnancy and
method of contraception (preferably a user their partners should be referred to a specialist
independent form such as an intra-uterine device experienced in prenatal medicine for evaluation
or implant) or two complementary forms of and counselling regarding the exposed
contraception including a barrier method should pregnancy (see section 4.6).
be used. Individual circumstances should be Pharmacists must ensure that:
evaluated in each case when choosing the • The Patient Card is provided with every
contraception method, involving the patient in valproate dispensation and that patients
the discussion to guarantee her engagement and understand its content.
compliance with the chosen measures. Even if • Patients are advised not to stop valproate
she has amenorrhea she must follow all the medication and to immediately contact a
specialist in case of planned or suspected advised to seek medical advice should signs of
pregnancy. suicidal ideation or behaviour emerge.
Educational materials Carbapenem agents:
In order to assist healthcare professionals and
patients in avoiding exposure to valproate during The concomitant use of valproate and
pregnancy, the Marketing Authorisation Holder carbapenem agents is not recommended.
has provided educational materials to reinforce
Patients with known or suspected
the warnings, provide guidance regarding use of
mitochondrial disease:
valproate in women of childbearing potential
and provide details of the Pregnancy Prevention Valproate may trigger or worsen clinical signs of
Programme. A Patient Guide and Patient Card underlying mitochondrial diseases caused by
should be provided to all women of childbearing mutations of mitochondrial DNA as well as the
potential using valproate. nuclear encoded POLG gene. In particular,
An Annual Risk Acknowledgement Form needs valproate-induced acute liver failure and liver-
to be used at time of treatment initiation and related deaths have been reported at a higher rate
during each annual review of valproate in patients with hereditary neurometabolic
treatment by the specialist. syndromes caused by mutations in the gene for
Valproate therapy should only be continued after the mitochondrial enzyme polymerase γ
a reassessment of the benefits and risks of the (POLG), e.g. Alpers-Huttenlocher Syndrome.
treatment with valproate for the patient by a
specialist experienced in the management of POLG-related disorders should be suspected in
epilepsy. patients with a family history or suggestive
symptoms of a POLG-related disorder, including
Aggravated convulsions:
but not limited to unexplained encephalopathy,
As with other anti-epileptic drugs, some patients refractory epilepsy (focal, myoclonic), status
may experience, instead of an improvement, a epilepticus at presentation, developmental
reversible worsening of convulsion frequency delays, psychomotor regression, axonal
and severity (including status epilepticus), or the sensorimotor neuropathy, myopathy cerebellar
onset of new types of convulsions with ataxia, opthalmoplegia, or complicated migraine
valproate. In case of aggravated convulsions, the with occipital aura. POLG mutation testing
patients should be advised to consult their should be performed in accordance with current
physician immediately (see section 4.8). clinical practice for the diagnostic evaluation of
such disorders (see section 4.3).
Suicidal ideation and behaviour:
4.4.2 Precautions
Suicidal ideation and behaviour have been
reported in patients treated with anti-epileptic Haematological tests:
agents in several indications. A meta-analysis of
Blood tests (blood cell count, including platelet
randomised placebo controlled trials of anti-
count, bleeding time and coagulation tests) are
epileptic drugs has also shown a small increased
recommended prior to initiation of therapy or
risk of suicidal ideation and behaviour. The
before surgery, and in case of spontaneous
mechanism of this risk is not known and the
bruising or bleeding (see section 4.8).
available data does not exclude the possibility of
an increased risk for sodium valproate. Renal insufficiency:
Therefore patients should be monitored for signs In patients with renal insufficiency, it may be
of suicidal ideation and behaviours and necessary to decrease dosage. As monitoring of
appropriate treatment should be considered. plasma concentrations may be misleading,
Patients (and caregivers of patients) should be dosage should be adjusted according to clinical
monitoring (see sections 4.2 and 5.2).
Patients with systemic lupus erythematosus: inhibitors, antidepressants and benzodiazepines;

therefore, clinical monitoring is advised and the
Although immune disorders have only rarely dosage of the other psychotropics should be
been noted during the use of Epilim, the adjusted when appropriate.
potential benefit of Epilim should be weighed
against its potential risk in patients with In particular, a clinical study has suggested that
systemic lupus erythematosus (see section 4.8). adding olanzapine to valproate or lithium
therapy may significantly increase the risk of
Urea cycle disorders: certain adverse events associated with
When a urea cycle enzymatic deficiency is olanzapine e.g. neutropenia, tremor, dry mouth,
suspected, metabolic investigations should be increased appetite and weight gain, speech
performed prior to treatment because of the risk disorder and somnolence.
of hyperammonaemia with Epilim (see section - Lithium
4.3).
Epilim has no effect on serum lithium levels.
Weight gain:
- Olanzapine
Epilim very commonly causes weight gain,
which may be marked and progressive. Patients Valproic acid may decrease the olanzapine
should be warned of the risk of weight gain at plasma concentration.
the initiation of therapy and appropriate
- Phenobarbital
strategies should be adopted to minimise it (see
section 4.8). Epilim increases phenobarbital plasma
concentrations (due to inhibition of hepatic
Diabetic patients:
catabolism) and sedation may occur, particularly
Epilim is eliminated mainly through the kidneys, in children. Therefore, clinical monitoring is
partly in the form of ketone bodies; this may recommended throughout the first 15 days of
give false positives in the urine testing of combined treatment with immediate reduction of
possible diabetics. phenobarbital doses if sedation occurs and
determination of phenobarbital plasma levels
Carnitinepalmitoyltransferase (CPT) type II when appropriate.
deficiency:
- Primidone
Patients with an underlying
carnitinepalmitoyltransferase (CPT) type II Epilim increases primidone plasma levels with
deficiency should be warned of the greater risk exacerbation of its adverse effects (such as
of rhabdomyolysis when taking Epilim. sedation); these signs cease with long term
treatment. Clinical monitoring is recommended
Alcohol: especially at the beginning of combined therapy
Alcohol intake is not recommended during with dosage adjustment when appropriate.
treatment with valproate. - Phenytoin
4.5 Interaction with other medicinal products Epilim decreases phenytoin total plasma
and other forms of interaction concentration. Moreover Epilim increases
4.5.1 Effects of Epilim on other drugs phenytoin free form with possible overdose
- Antipsychotics, MAO inhibitors, symptoms (valproic acid displaces phenytoin
antidepressants and benzodiazepines from its plasma protein binding sites and reduces
its hepatic catabolism). Therefore clinical
Epilim may potentiate the effect of other monitoring is recommended; when phenytoin
psychotropics such as antipsychotics, MAO
plasma levels are determined, the free form nimodipine dose should therefore be decreased
should be evaluated. in case of hypotension.
- Carbamazepine - Temozolomide
Clinical toxicity has been reported when Epilim Co-administration of temozolomide and Epilim
was administered with carbamazepine as Epilim may cause a small decrease in the clearance of
may potentiate toxic effects of carbamazepine. temozolomide that is not thought to be clinically
Clinical monitoring is recommended especially relevant.
at the beginning of combined therapy with
dosage adjustment when appropriate. 4.5.2 Effects of other drugs on Epilim
- Lamotrigine - Anti-epileptics
Epilim reduces the metabolism of lamotrigine Anti-epileptics with enzyme inducing effect
and increases the lamotrigine mean half-life by (including phenytoin, phenobarbital,
nearly to fold. This interaction may lead to carbamazepine) decrease valproic acid plasma
increased lamotrigine toxicity, in particular concentrations. Dosages should be adjusted
according to clinical response and blood levels
serious skin rashes. Therefore clinical
in case of combined therapy.
monitoring is recommended and dosages should
be adjusted (lamotrigine dosage decreased) Valproic acid metabolite levels may be
when appropriate. increased in the case of concomitant use with
- Felbamate phenytoin or phenobarbital. Therefore patients
treated with those two drugs should be carefully
Valproic acid may decrease the felbamate mean monitored for signs and symptoms of
clearance by up to 16%. hyperammonaemia.
- Rufinamide On the other hand, combination of felbamate
and Epilim decreases valproic acid clearance by
Valproic acid may lead to an increase in plasma 22% – 50% and consequently increase the
levels of rufinamide. This increase is dependent valproic acid plasma concentrations. Epilim
on concentration of valproic acid. Caution dosage should be monitored.
should be exercised, in particular in children, as
this effect is larger in this population. - Anti-malarial agents
- Propofol Mefloquine and chloroquine increase valproic
acid metabolism and may lower the seizure
Valproic acid may lead to an increased blood threshold; therefore epileptic seizures may occur
level of propofol. When co-administered with in cases of combined therapy. Accordingly, the
valproate, a reduction of the dose of propofol dosage of Epilim may need adjustment.
should be considered.
- Highly protein bound agents
- Zidovudine
In case of concomitant use of Epilim and highly
Epilim may raise zidovudine plasma protein bound agents (e.g. aspirin), free valproic
concentration leading to increased zidovudine acid plasma levels may be increased.
toxicity.
- Vitamin K-dependent factor anticoagulants
- Nimodipine
The anticoagulant effect of warfarin and other
In patients concomitantly treated with sodium
coumarin anticoagulants may be increased
valproate and nimodipine the exposure to following displacement from plasma protein
nimodipine can be increased by 50%. The
binding sites by valproic acid. The prothrombin valproate and potentially decreased valproate
time should be closely monitored. efficacy (see section 4.4). Consider monitoring
of valproate serum levels.
- Cimetidine or erythromycin
On the opposite, valproate has no enzyme
Valproic acid plasma levels may be increased inducing effect; as a consequence, valproate
(as a result of reduced hepatic metabolism) in does not reduce efficacy of oestroprogestative
case of concomitant use with cimetidine or agents in women receiving hormonal
erythromycin. contraception.
- Carbapenem antibiotics (such as
4.5.3 Other interactions
imipenempanipenem and meropenem)
Caution is advised when using Epilim in
Decreases in blood levels of valproic acid have combination with newer anti-epileptics whose
been reported when it is co-administered with pharmacodynamics may not be well established.
carbapenem agents resulting in a 60% – 100%
decrease in valproic acid levels within two days, Concomitant administration of valproate
sometimes associated with convulsions. Due to and topiramate or acetazolamide has been
the rapid onset and the extent of the decrease, associated with encephalopathy and/or
co-administration of carbapenem agents in hyperammonaemia. In patients taking these two
patients stabilised on valproic acid should be drugs, careful monitoring of signs and
avoided (section 4.4). If treatment with these symptoms is advised in particularly at-risk
antibiotics cannot be avoided, close monitoring patients such as those with pre-existing
of valproic acid blood levels should be encephalopathy.
performed.
- Quetiapine
- Rifampicin
Co-administration of Epilim and quetiapine may
Rifampicin may decrease the valproic acid blood increase the risk of neutropenia/leucopenia.
levels resulting in a lack of therapeutic effect.
Therefore, valproate dosage adjustment may be 4.6 Fertility, pregnancy and lactation
necessary when it is co-administered with • Valproate is contraindicated as treatment for
rifampicin. epilepsy during pregnancy unless there is no
suitable alternative to treat epilepsy.
- Protease inhibitors • Valproate is contraindicated for use in women
Protease inhibitors such as lopinavir and of childbearing potential unless the conditions of
ritonavir decrease valproate plasma level when the Pregnancy Prevention Programme are
co-administered. fulfilled (see sections 4.3 and 4.4).
Pregnancy exposure risk related to valproate
- Cholestyramine
Both valproate monotherapy and valproate
Cholestyramine may lead to a decrease in polytherapy are associated with abnormal
plasma level of valproate when co-administered. pregnancy outcomes. Available data suggest that
- Oestrogen-containing products, including anti-epileptic polytherapy including valproate is
oestrogen-containing hormonal contraceptives associated with a greater risk of congenital
malformations than valproate monotherapy.
Oestrogens are inducers of the UDP-
glucuronosyltransferase (UGT) isoforms Teratogenicity and developmental effects
involved in valproate glucuronidation and may Congenital malformations
increase the clearance of valproate, which would
result in decreased serum concentration of Data derived from a meta-analysis (including
registries and cohort studies) has shown that
10.73% of children of epileptic women exposed Available data show that children exposed to
to valproate monotherapy during pregnancy valproate in utero are at increased risk of autistic
suffer from congenital malformations (95% CI: spectrum disorder (approximately three-fold)
8.16 – 13.29). This is a greater risk of major and childhood autism (approximately five-fold)
malformations than for the general population, compared with the general study population.
for whom the risk is about 2 – 3%. The risk is
dose dependent but a threshold dose below Limited data suggests that children exposed to
which no risk exists cannot be established. valproate in utero may be more likely to develop
symptoms of attention deficit/hyperactivity
Available data show an increased incidence of disorder (ADHD).
minor and major malformations. The most
common types of malformations include neural Female children and woman of childbearing
potential (see above and section 4.4)
tube defects, facial dysmorphism, cleft lip and
palate, craniostenosis, cardiac, renal and Oestrogen-containing products
urogenital defects, limb defects (including
bilateral aplasia of the radius), and multiple Oestrogen-containing products, including
anomalies involving various body systems. oestrogen-containing hormonal contraceptives,
may increase the clearance of valproate, which
Developmental disorders would result in decreased serum concentration
Data have shown that exposure to valproate in of valproate and potentially decreased valproate
efficacy (see sections 4.4 and 4.5).
utero can have adverse effects on mental and
physical development of the exposed children. If a woman plans a pregnancy
The risk seems to be dose-dependent but a
threshold dose below which no risk exists, If a woman is planning to become pregnant, a
cannot be established based on available data. specialist experienced in the management of
The exact gestational period of risk for these epilepsy must reassess valproate therapy and
effects is uncertain and the possibility of a risk consider alternative treatment options. Every
throughout the entire pregnancy cannot be effort should be made to switch to appropriate
excluded. alternative treatment prior to conception and
before contraception is discontinued (see section
Studies in preschool children exposed in utero to 4.4). If switching is not possible, the woman
valproate show that up to 30 – 40% experience should receive further counselling regarding the
delays in their early development such as talking risks of valproate for the unborn child to support
and walking later, lower intellectual abilities, her informed decision-making regarding family
poor language skills (speaking and planning.
understanding) and memory problems.
Pregnant women
Intelligence quotient (IQ) measured in school
aged children (age 6) with a history of valproate Valproate as treatment for epilepsy is
exposure in utero was on average 7 – 10 points contraindicated in pregnancy unless there is no
lower than those children exposed to other anti- suitable alternative treatment (see sections 4.3
epileptics. Although the role of confounding and 4.4). If a woman using valproate becomes
factors cannot be excluded, there is evidence in pregnant, she must be immediately referred to a
children exposed to valproate that the risk of specialist to consider alternative treatment
intellectual impairment may be independent options.
from maternal IQ. During pregnancy, maternal tonic clonic
There are limited data on the long term seizures and status epilepticus with hypoxia may
outcomes. carry a particular risk of death for the mother
and the unborn child. If in exceptional
circumstances, despite the known risks of • Cases of hypothyroidism have been reported in
valproate in pregnancy and after careful neonates whose mothers have taken valproate
consideration of alternative treatment, a during pregnancy.
pregnant woman must receive valproate for
epilepsy, it is recommended to: • Withdrawal syndrome (such as, in particular,
agitation, irritability, hyper-excitability,
• Use the lowest effective dose and divide the jitteriness, hyperkinesia, tonicity disorders,
daily dose valproate into several small doses to tremor, convulsions and feeding disorders) may
be taken throughout the day. occur in neonates whose mothers have taken
valproate during the last trimester of their
• The use of a prolonged release formulation pregnancy.
may be preferable to other treatment
formulations in order to avoid high peak plasma Breast-feeding
concentrations (see section 4.2).
Valproate is excreted in human milk with a
All patients with valproate-exposed pregnancy concentration ranging from 1% – 10% of
and their partners should be referred to a maternal serum levels. Haematological disorders
specialist experienced in prenatal medicine for have been shown in breastfed newborns/infants
evaluation and counselling regarding the of treated women (see section 4.8).
exposed pregnancy. Specialised prenatal
monitoring should take place to detect the A decision must be made whether to discontinue
breast-feeding or to discontinue/abstain from
possible occurrence of neural tube defects or
Epilim therapy taking into account the benefit of
other malformations. Folate supplementation
before the pregnancy may decrease the risk of breast feeding for the child and the benefit of
therapy for the woman.
neural tube defects which may occur in all
pregnancies. However the available evidence Fertility
does not suggest it prevents the birth defects or
malformations due to valproate exposure. Amenorrhoea, polycystic ovaries and increased
testosterone levels have been reported in women
Risk in the neonate using valproate (see section 4.8). Valproate
administration may also impair fertility in men
• Cases of haemorrhagic syndrome have been
reported very rarely in neonates whose mothers (see section 4.8). Case reports indicate that
have taken valproate during pregnancy. This fertility dysfunctions are reversible after
treatment discontinuation.
haemorrhagic syndrome is related to
thrombocytopenia, hypofibrinogenemia and/or 4.7 Effects on ability to drive and use
to a decrease in other coagulation factors. machines
Afibrinogenemia has also been reported and Use of Epilim may provide seizure control such
may be fatal. However, this syndrome must be that the patient may be eligible to hold a driving
distinguished from the decrease of the vitamin-K licence.
factors induced by phenobarbital and enzymatic
inducers. Therefore, platelet count, fibrinogen Patients should be warned of the risk of transient
plasma level, coagulation tests and coagulation drowsiness, especially in cases of anti-
factors should be investigated in neonates. convulsantpolytherapy or association with
benzodiazepines (see section 4.5 Interactions
• Cases of hypoglycaemia have been reported in with Other Medicaments and Other Forms of
neonates whose mothers have taken valproate Interaction).
during the third trimester of their pregnancy.
4.8 Undesirable effects
The following CIOMS frequency rating is used,
when applicable: Very common (≥ 1/10);
common (≥ 1/100 to ≤ 1/10); uncommon (≥ treatment on rare occasions and is usually

1/1,000 to ≤ 1/100); rare (≥ 1/10,000 to ≤ transient.
1/1,000); very rare (≤ 1/10,000); not known
(cannot be estimated from the available data). *Rare cases of lethargy occasionally progressing
to stupor, sometimes with associated
Congenital malformations and developmental hallucinations or convulsions have been
disorders: (see sections 4.4 and 4.6). reported. Encephalopathy and coma have very
rarely been observed. These cases have often
Hepatobiliary disorders:
been associated with too high a starting dose or
Common: liver injury (see section 4.4.1) too rapid a dose escalation or concomitant use of
other anti-convulsants, notably phenobarbital or
Severe liver damage, including hepatic failure topiramate. They have usually been reversible
sometimes resulting in death, has been reported on withdrawal of treatment or reduction of
(see sections 4.2, 4.3 and 4.4.1). Increased liver dosage.
enzymes are common, particularly early in
treatment, and may be transient (see section An increase in alertness may occur; this is
4.4.1). generally beneficial but occasionally aggression,
hyperactivity and behavioural deterioration have
Gastrointestinal disorders been reported.
Very common: nausea Psychiatric disorders:
Common: vomiting, gingival disorder (mainly Common: confusional state, hallucinations,
gingival hyperplasia), stomatitis, gastralgia, aggression*, agitation*, disturbance in
diarrhoea attention*
The above adverse events frequently occur at the Rare: abnormal behaviour*, psychomotor
start of treatment, but they usually disappear hyperactivity*, learning disorder*
after a few days without discontinuing treatment.
These problems can usually be overcome by *These ADRs are principally observed in the
taking Epilim with or after food. paediatric population.
Uncommon: pancreatitis, sometimes lethal (see Metabolism and nutrition disorders:
section 4.4) Common: hyponatraemia, weight increased*
Nervous system disorders:
*Weight increase should be carefully monitored
Very common: tremor since it is a factor for polycystic ovary syndrome
(see section 4.4).
Common: extrapyramidal disorder, stupor*,
somnolence, convulsion*, memory impairment, Rare: hyperammonaemia* (see section 4.4.2),
headache, nystagmus obesity
Uncommon: coma*, encephalopathy, lethargy* *Cases of isolated and moderate
(see below), reversible parkinsonism, ataxia, hyperammonaemia without change in liver
paraesthesia, aggravated convulsions (see function tests may occur, are usually transient
section 4.4) and should not cause treatment discontinuation.
However, they may present clinically as
Rare: reversible dementia associated with vomiting, ataxia, and increasing clouding of
reversible cerebral atrophy, cognitive disorder consciousness. Should these symptoms occur
Sedation has been reported occasionally, usually Epilim should be discontinued.
when in combination with other anti-
convulsants. In monotherapy it occurred early in
Hyperammonaemia associated with neurological Reproductive system and breast disorders:

symptoms has also been reported (see section
4.4.2). In such cases further investigations Common: dysmenorrhea
should be considered. Uncommon: amenorrhea
Endocrine disorders: Rare: male infertility, polycystic ovaries
Uncommon: Syndrome of Inappropriate Very rarely gynaecomastia has occurred.
Secretion of ADH (SIADH), hyperandrogenism
(hirsutism, virilism, acne, male pattern alopecia, Vascular disorders:
and/or androgen increase) Common: haemorrhage (see sections 4.4.2 and
Rare: hypothyroidism (see section 4.6) 4.6)
Blood and lymphatic system disorders: Uncommon: vasculitis
Common: anaemia, thrombocytopenia, (see Eye disorders:

section 4.4.2) Rare: diplopia
Uncommon: pancytopenia, leucopenia Ear and labyrinth disorders:
Rare: bone marrow failure, including pure red Common: deafness, a cause and effect
cell aplasia, agranulocytosis, anaemia relationship has not been established.
macrocytic, macrocytosis
Renal and urinary disorders:
The blood picture returned to normal when the
drug was discontinued. Common: urinary incontinence
Isolated findings of a reduction in blood Uncommon: renal failure

fibrinogen and/or an increase in prothrombin Rare: enuresis, tubulointerstitial nephritis,
time have been reported, usually without reversible Fanconi syndrome (a defect in
associated clinical signs and particularly with proximal renal tubular function giving rise to
high doses (Epilim has an inhibitory effect on glycosuria, amino aciduria, phosphaturia, and
the second phase of platelet aggregation). uricosuria) associated with Epilim therapy, but
Spontaneous bruising or bleeding is an the mode of action is as yet unclear.
indication for withdrawal of medication pending
investigations (see section 4.6). General disorders and administration site
conditions:
Skin and subcutaneous tissue disorders:
Uncommon: hypothermia, non-severe peripheral
Common: hypersensitivity, transient and/or dose oedema
related alopecia (hair loss), nail and nail bed
disorders. Regrowth normally begins within six Musculoskeletal and connective tissue disorders:
months, although the hair may become more
Uncommon: bone mineral density decreased,
curly than previously.
osteopenia, osteoporosis and fractures in patients
Uncommon: angioedema, rash, hair disorder on long-term therapy with Epilim. The
(such as abnormal hair texture, hair colour mechanism by which Epilim affects bone
changes, abnormal hair growth) metabolism has not been identified.
Rare: toxic epidermal necrolysis, Stevens- Rare: systemic lupus erythematosus,
Johnson syndrome, erythema multiforme, Drug rhabdomyolysis (see section 4.4.2)
Rash with Eosinophilia and Systemic Symptoms
Respiratory, thoracic and mediastinal disorders:
(DRESS) syndrome
Uncommon: pleural effusion Hospital management of overdose should be

symptomatic, including cardio-respiratory
Investigations: monitoring. Gastric lavage may be useful up to
Rare: coagulation factors decreased (at least 10 – 12 hours following ingestion.
one), abnormal coagulation tests (such as Haemodialysis and haemoperfusion have been
prothrombin time prolonged, activated partial used successfully.
thromboplastin time prolonged, thrombin time
prolonged, INR prolonged) (see sections 4.4 and Naloxone has been successfully used in a few
4.6) isolated cases, sometimes in association with
activated charcoal given orally.
Neoplasms benign, malignant and unspecified
(including cysts and polyps): In case of massive overdose, haemodialysis and
haemoperfusion have been used successfully.
Rare: myelodysplastic syndrome
Reporting of suspected adverse reactions 5. Pharmacological properties
Reporting suspected adverse reactions after 5.1 Pharmacodynamic properties
authorisation of the medicinal product is Sodium valproate and valproic acid are anti-
important. It allows continued monitoring of the convulsants.
benefit/risk balance of the medicinal product.
The most likely mode of action for Epilim is
potentiation of the inhibitory action of gamma
4.9 Overdose amino butyric acid (GABA) through an action
Cases of accidental and deliberate Epilim on the further synthesis or further metabolism of
overdose have been reported. At plasma GABA.
concentrations of up to 5 – 6 times the maximum
In certain in-vitro studies it was reported that
therapeutic levels, there are unlikely to be any
Epilim could stimulate HIV replication but
symptoms other than nausea, vomiting and
studies on peripheral blood mononuclear cells
dizziness.
from HIV-infected subjects show that
Signs of acute massive overdose, i.e. plasma Epilimdoes not have a mitogen-like effect on
concentration 10 – 20 times maximum inducing HIV replication. Indeed the effect of
therapeutic levels, usually include CNS Epilim on HIV replication ex-vivo is highly
depression or coma with muscular hypotonia, variable, modest in quantity, appears to be
hyporeflexia, miosis, impaired respiratory unrelated to the dose and has not been
function, metabolic acidosis, hypotension and documented in man.
circulatory collapse/shock. A favourable
5.2 Pharmacokinetic properties
outcome is usual, however some deaths have
In patients with severe renal insufficiency it may
occurred following massive overdose.
be necessary to alter dosage in accordance with
Symptoms may however be variable and free plasma valproic acid levels.
seizures have been reported in the presence of
The reported effective therapeutic range for
very high plasma levels (see also section 5.2
plasma valproic acid levels is 40 – 100 mg/litre
Pharmacokinetic Properties). Cases of
(278 – 694 micromol/litre). This reported range
intracranial hypertension related to cerebral
may depend on time of sampling and presence
oedema have been reported.
of co-medication. The percentage of free
The presence of sodium content in the Epilim (unbound) drug is usually between 6% and 15%
formulations may lead to hypernatraemia when of total plasma levels. An increased incidence of
taken in overdose. adverse effects may occur with plasma levels
above the effective therapeutic range.
The pharmacological (or therapeutic) effects of 6.1 List of excipients

Sodium Valproate &Valproicacid may not be Hypromellose, Ethylcellulose, Hydrated Silica,
clearly correlated with the total or free Violet coat, containing: titanium dioxide,
(unbound) plasma valproic acid levels. erythrosine BS aluminium lake, indigo carmine
aluminium lake FD and C, iron oxide black,
Metabolism hypromellose, macrogol 400, purified water*.
The major pathway of valproate
6.2 Incompatibilities
biotransformation is glucuronidation (~40%), None.
mainly via UGT1A6, UGT1A9, and UGT2B7.
6.3 Shelf life
The half-life of Epilim is usually reported to be 36 months.
within the range of 8 – 20 hours. It is usually
shorter in children. 6.4 Special precautions for storage
Epilim is hygroscopic. The tablets should not be
Interaction with oestrogen-containing products
removed from their foil until immediately before
Inter-individual variability has been noted. they are taken. Where possible, blister strips
There are insufficient data to establish a robust should not be cut. Store in a dry place below
PK-PD relationship resulting from this PK 30°C.
interaction.
6.5 Nature and contents of container
Sodium Valproate &Valproicacid formulations Sodium Valproate &Valproicacid 500
are prolonged release formulations which Controlled Release tablets are supplied in blister
demonstrate in pharmacokinetic studies less packs.
fluctuation in plasma concentration compared
Pack size: 7, 14, 28, 30, 50, 100 and 500
with other established conventional and Controlled Release tablets.
modified release Epilim formulations.
Not all pack sizes may be marketed.
In cases where measurement of plasma levels is
considered necessary, the pharmacokinetics of 6.6 Special precautions for disposal and other
Sodium Valproate &Valproicacid make the handling
measurement of plasma levels less dependent Not applicable.
upon time of sampling.
7. Manufactured In India By:
The Sodium Valproate &Valproicacid TAJ PHARMACEUTICALS LTD.
formulations are bioequivalent to Epilim Liquid Mumbai, India
and enteric coated (EC) formulations with
Unit No. 214.Old Bake House,
respect to the mean areas under the plasma
concentration time curves. Steady-state Maharashtra chambers of Commerce Lane,
pharmacokinetic data indicate that the peak Fort, Mumbai - 400001
concentration (Cmax) and trough concentration at:Gujarat, INDIA.
(Cmin) of Sodium Valproate &Valproicacid lie Customer Service and Product Inquiries:
within the effective therapeutic range of plasma 1-800-TRY-FIRST (1-800-222-434 & 1-800-
levels found in pharmacokinetic studies with 222-825)
Epilim EC.
Monday through Saturday 9:00 a.m. to 7:00 p.m.
5.3 Preclinical safety data EST
There are no preclinical data of relevance to the E-mail: tajgroup@tajpharma.com
prescriber which are additional to that already
included in other sections of the SPC.
6. Pharmaceutical particulars

Sodium Valproate & Valproic Acid Tablets SMPC Taj Pharmaceuticals

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Sodium Valproate and Valpr oic Acid 500 mg Tablets TajP harma : Uses, Side E ffects, I nteractions, Pict

Sodium Valproate & Valproic Dosage

acid 500mg Controlled Release Usual requirements are as follows:

• Valproate is contraindicated in patients known Monotherapy is recommended in children under

fibrinogen and coagulation factors; increased Programme:

understand the need to contact the specialist advice on effective contraception.

Patients with systemic lupus erythematosus: inhibitors, antidepressants and benzodiazepines;

common (≥ 1/100 to ≤ 1/10); uncommon (≥ treatment on rare occasions and is usually

Hyperammonaemia associated with neurological Reproductive system and breast disorders:

Blood and lymphatic system disorders: Uncommon: vasculitis

Common: anaemia, thrombocytopenia, (see Eye disorders:

Isolated findings of a reduction in blood Uncommon: renal failure

Uncommon: pleural effusion Hospital management of overdose should be

The pharmacological (or therapeutic) effects of 6.1 List of excipients

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