INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo CONVULEX®
SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

CONVULEX®

Convulex®Syrup
Convulex®150 Capsules
Convulex®300 Capsules
Convulex®500 Capsules

COMPOSITION:
Convulex® Syrup: One mL contains 50 mg sodium valproate. 
        Preservatives: methylhydroxybenzoate 0,1% m/v
  propylhydroxybenzoate 0,04% m/v
Convulex® 150: valproic acid (per capsule) 150 mg
Convulex® 300: valproic acid (per capsule) 300 mg
Convulex® 500: valproic acid (per capsule) 500 mg

PHARMACOLOGICAL CLASSIFICATION
A2.5 Anticonvulsants, including anti-epileptics.

PHARMACOLOGICAL ACTION
The anti-convulsant action of both valproic acid and sodium valproate may be related to increased levels of gamma-aminobutyric acid (GABA) in the brain by inhibiting aminobutyrate aminotransferase. GABA inhibits pre- and post-synaptic discharges.

INDICATIONS
Convulex® is indicated for generalized seizures as well as for partial (focal) seizures, including complex partial seizures evolving to generalized seizures.

CONTRA-INDICATIONS
Known hypersensitivity to valproic acid or sodium valproate. Hepatic and pancreatic dysfunction. Use of Convulex® during pregnancy: See Special precautions: Women of childbearing age.
Special caution is required in the following cases:
- Bone marrow abnormalities
- Haemorrhagic diathesis
- Renal dysfunction
- Congenital enzyme defects
- Severe epileptic seizure types
- Mentally retarded children
- Organic cerebral lesions
- Children younger than 3 years (as they are especially predisposed for hepatic damage - see SIDE EFFECTS AND SPECIAL PRECAUTIONS)

WARNINGS
Convulex® may cause hepatic dysfunction including fatal hepatic failure. This usually occurs during the first 6 months of treatment and children are at greater risk. This may be preceded by non-specific symptoms such as loss of seizure control, malaise, weakness and lethargy. If clinical symptoms of hepatic damage (recurrent epigastric complaints, anorexia, vomiting, fatigue, asthenia, icterus, ascites, hepatic encephalopathy) occur, treatment must be discontinued under the supervision of the physician. Severe hepatic damage, occurring during the first 6 months of treatment and independent of the dosage level, has been reported on very rare occasions.
Sudden discontinuation of valproic acid may lead to an increase in seizure frequency.

DOSAGE AND DIRECTIONS FOR USE
The dosage (starting with a low initial dose) is determined by the physician, and should not be arbitrarily altered or exceeded. The total daily dose should be administered in divided dosages. Convulex® capsules should be taken whole, with some liquid, during or after meals.
Adults:
The initial dose is 600 mg per day in divided doses, increasing by 150 mg per day to a maintenance dosage of 1000-1600 mg per day (approx. 3-5 capsules of 300 mg each or 2-3 capsules of 500 mg each). If adequate control is not achieved after 2 weeks, further increases to a maximum of 2 600 mg per day may be necessary.
Children:
Children weighing less than 20 kg may be given 15-20 mg per kg per day. In severe cases, the dosage can be increased at one-week intervals by 5-10 mg per kg daily to 40 mg per kg per day, but in these cases the plasma valproate concentration of the patient must be monitored. Should the daily dose exceed 100 mg (e.g. 2 mL of Convulex® Syrup), it should be administered in divided doses.
Children weighing more than 20 kg may be given 450 mg daily in divided doses (e.g. 3 x 1 capsule Convulex® 150 mg), gradually increasing to establish control, usually at a level of 20-30 mg per kg per day.
Dosage in patients being treated with other anticonvulsant drugs should be gradually reduced concurrently with the increase of Convulex® dosage.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Side-effects occur in rare cases and are most frequently seen when plasma levels exceed 100 mg/L or when Convulex® is used in combination therapy.
The most commonly reported side-effects relate to the gastro-intestinal system. Nausea, vomiting and anorexia may occur at the beginning of therapy, but usually disappear with dose adaptation and administration together with, or after meals. Increased appetite and weight gain, gastralgia, gastrospasms, diarrhea and constipation have also been reported.
Rare side-effects include sedation, vertigo, headache, depressive state, aggression, involuntary movements, hyperactivity, tonic spasms, ataxia, oedema, impaired coordination, tremor, dysmenorrhea, galactorrhea, gynaecomastia, asterixis, dysarthria, hearing loss, nystagmus and diplopia. In isolated cases, states of confusion, stupor and coma were observed a few days after therapeutic plasma levels were reached. In these cases, a paradoxical effect in patients with previous psychic disorders was suspected.
Hematological changes reported with valproic acid include thrombocytopenia, inhibition of platelet aggregation, reversible prolongation of bleeding time, red cell hypoplasia, leucopenia, neutropenia, lymphocytosis, hypofibrinogenemia and in extremely rare cases anemia and bone marrow depression. Hyperammonemia, increase in serum glycine levels and decrease in carnitine levels have also been reported.
Patients should be monitored for platelet functions before and during Convulex® therapy and before elective surgery. Caution is required in surgical or dental interventions, because of a possible increase in bleeding tendency. Convulex® should be withdrawn under the supervision of the physician if patients develop spontaneous bruising or bleeding. Allergic skin reactions occur very rarely. Individual cases of petechial bleeding, tendency to develop hematoma, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and transient alopecia with regrowth of curly hair, have been reported. The occurrence of a Reye-like syndrome was also described.
Very rare cases of acute pancreatitis have also been reported.
Special precautions
Patients experiencing abdominal pain, symptoms of organic damage or hemorrhagic disorders should have serum amylase and lipase checked. At the first indication of pancreatitis, treatment must be stopped under the supervision of the physician.
Liver function tests, coagulation parameters and determination of serum amylase and lipase should be carried out before starting therapy and also at 2-monthly intervals during the first 6 months of therapy. Thereafter, the aforementioned tests should be carried out when the dosage is increased. Convulex® should be discontinued if one of the following occurs: hypofibrinogenemia, coagulation disorders, increase in transaminases to their triple value, increases in alkaline phosphatase or serum bilirubin, symptoms or signs of toxic hepatitis. If only transaminases are slightly increased, the dosage should be reduced and liver function as well as coagulation parameters should also be monitored. Renal function and serum ammonia levels should be monitored at regular intervals. Valproic acid should be used with caution if systemic lupus erythematosus is suspected.
Women of childbearing age:
Convulex® has been associated with teratogenicity when given to women in the first trimester of pregnancy. Its use should be avoided in pregnant women and women likely to become pregnant, unless its continued use is considered essential by the prescribing physician. Women who have been exposed to Convulex® in the first trimester of pregnancy should be informed of the risk, and offered prenatal counselling.
Concomitant medication:
Valproic acid displaces phenytoin, phenobarbitone and diazepam from plasma protein binding, which leads to an increase in free levels of these substances. The metabolism of diazepam is inhibited by valproic acid. Serum levels of primidone are increased. The effect of ethosuximide is potentiated. Phenytoin, phenobarbitone and primidone lead to increased clearance and reduced plasma levels of valproic acid. In rare cases concomitant administration of clonazepam may induce absence status. In cases of combination therapy with other anticonvulsants, careful determination of blood levels is essential. Concomitant use of felbamate leads to increased plasma levels of valproic acid. Concomitant administration of lamotrigine increases the elimination half-life of that substance.
Caution must be exercised when administering naloxone, since this drug could theoretically also reverse the anti-epileptic effects of Convulex® (also see below under KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT). Caution is recommended when administering Convulex® with other medicines liable to interfere with blood coagulation, such as aspirin, heparin and warfarin. Salicylates replace valproic acid from its serum albumin binding sites and affect its metabolism, which may result in toxic concentrations of valproic acid, which is clinically relevant, especially in children. Concomitant administration of hepatotoxic drugs may potentiate the possible adverse effects of valproic acid in the liver.
Convulex® does not induce liver enzymes and there have been no reports of loss of efficacy of oral contraceptive agents.
Convulex® may potentiate the effect of monoamine oxidase inhibitors (MAOI) and therefore the dosage of such medicine must be lowered when used together with valproic acid.
Both sodium valproate and valproic acid may enhance the effects of central nervous system depressants (including alcohol), and may reduce the patient's ability to drive vehicles or operate machinery.
Effects of valproic acid on laboratory parameters:
Valproic acid is partially eliminated in the urine as a keto-metabolite which may lead to a false positive result of the urine ketone test in diabetic patients. Depending on the plasma concentration, valproic acid may lead to a displacement of thyroid hormones from their protein binding sites, and to their more rapid metabolism, so that thyroid function tests may incorrectly lead to a suspicion of hypothyroidism.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Acute overdosage may lead to coma, accompanied by areflexia and central respiratory depression. Treatment should include induced vomiting, administration of activated charcoal, gastric lavage, assisted ventilation, forced diuresis and other supportive measures. Naloxone has been reported to reverse the CNS-depressant effects of overdosage (also see SIDE-EFFECTS AND SPECIAL PRECAUTIONS, under Special precautions, Concomitant medication).

IDENTIFICATION
Convulex® Syrup: Sugar-free, clear, colourless to slightly yellow syrup, with a peach / raspberry odour and taste
Convulex® 150: Old-rose coloured, enteric-coated, oval, soft gelatine capsule with black imprint "150"
Content of capsule: clear, colourless to slightly yellow liquid.
Convulex®300: Old-rose coloured, enteric-coated, oval, soft gelatine capsule with black imprint "300"
Content of capsule: clear, colourless to slightly yellow liquid.
Convulex®500: Old-rose coloured, enteric-coated, oval, soft gelatine capsule with
black imprint "500"
Content of capsule: clear, colourless to slightly yellow liquid.

PRESENTATION
Convulex® Syrup: 100 mL amber glass bottles
Convulex® 150: Securitainers or blister packs containing 100 capsules
Convulex® 300: Securitainers or blister packs containing 100 capsules
Convulex® 500: Securitainers or blister packs containing 100 capsules

STORAGE INSTRUCTIONS
Store below 25°C, protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
Convulex® Syrup         W/2.5/390
Convulex® 150 Capsules         R/2.5/218
Convulex® 300 Capsules         R/2.5/219
Convulex® 500 Capsules         W/2.5/20

NAME AND BUSINESS ADDRESS OF APPLICANT
Byk Madaus (Pty.) Ltd., 2nd Road (cnr. 16th Road), Randjespark, MIDRAND

DATE OF PUBLICATION OF THIS PACKAGE INSERT
6 October 1989

        CON PI 02/01/04

Updated on this site: December 2001

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