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Metabolic disorders:
Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, 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 Epilim should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported (see Precautions). In such cases further investigations should be considered.
Blood and lymphatic system disorders:
Frequent occurrence of thrombocytopenia, rare cases of anaemia, leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.
Isolated reduction of fibrinogen or reversible increase in bleeding time have been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication
pending investigations (see Pregnancy and lactation).
Skin and subcutaneous tissue disorders:
Cutaneous reactions such as exanthematous rash rarely occur with valproate. In very rare cases toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported.
Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become more curly than previously. Hirsutism and acne have been vary rarely reported.
Reproductive system and breast disorders:
Amenorrhoea and irregular periods have been reported. Very rarely gynaecomastia has occurred.
Vascular disorders:
The occurrence of vasculitis has occasionally been reported.
Ear disorders:
Hearing loss, either reversible or irreversible has been reported rarely; however a cause and effect relationship has not been established.
Renal and urinary disorders:
There have been isolated reports of a reversible Fanconi's syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy, but the mode of action is as yet unclear.
Immune system disorders:
Allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.
General disorders:
Very rare cases of non-severe peripheral oedema have been reported.
Increasing in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored. (see Special warnings and special precaution for use).
Overdose
Cases of accidental and deliberate valproate 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.
Clinical 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. Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see 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. Deaths have occurred following massive overdose: nevertheless, a favourable outcome is usual.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Sodium valproate is an anticonvulsant.
The most likely mode of action for valproate 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 sodium valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of sodium valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.
Pharmacokinetic properties
The half-life of sodium valproate 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 Epilim Chrono may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.
Epilim Chrono formulations are prolonged release formulations which demonstrate in pharmacokinetic studies less fluctuation in plasma concentration compared with other established conventional and modified release Epilim formulations.
In cases where measurement of plasma levels is considered necessary, the pharmacokinetics of Epilim Chrono make the measurement of plasma levels less dependent upon time of sampling.
The Epilim chrono formulations are bioequivalent to Epilim 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 Epilim Chrono lie within the effective therapeutic range of plasma levels found in pharmacokinetic studies with Epilim EC.
PHARMACEUTICAL PARTICULARS
Incompatibilities: None
Shelf-life : 36 months
Special precautions for storage
Epilim is hygroscopic. The tablets should not be removed from the container until immediately before they are taken. Store in a dry place below 25°C.
Nature and contents of container
HDPE bottle with polyethylene cap. Pack size 30 tablets.
Presentations
Epilim Chrono 500mg Scored . A white coloured, slow released film-coated tablet.
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