COMPOSITION :
Sodium Valproate Syrup 250 mg/5 ml, each 5 ml (a measurement spoonful) contains : Sodium valproate equivalent to Valproic acid 250 mg.
DESCRIPTIONS :
Sodium Valproate contains Sodium valproate (equivalent to Valproic acid) as active ingredient is available in syrup 250 mg/5 ml.
INDICATIONS :
Sodium Valproate may be used as sole or adjunctive therapy in the treatment of partial seizures (both elementary and complex) and absence seizures (petit mal seizures).
DOSAGE AND ADMINISTRATIONS :
Sodium Valproate is administered orally. The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 – 10 mg/kg/day, until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in a divided regimen.
The following table is a guide for the initial daily dose of Sodium Valproate (15 mg/kg/day) :
| Weight | Total daily dose (mg) | Number of measurement spoonful of syrup | |||
| (kg) | (lb) | Dose 1 | Dose 2 | Dose 3 | |
| 10 – 24.9 | 22 – 54.9 | 250 | 0 | 0 | 1 |
| 25 – 39.9 | 55 – 87.9 | 500 | 1 | 0 | 1 |
| 40 – 59.9 | 88 – 131.9 | 750 | 1 | 1 | 1 |
| 60 – 74.9 | 132 – 164.9 | 1000 | 1 | 1 | 2 |
| 75 – 89.9 | 165 – 197.9 | 1250 | 2 | 1 | 2 |
The frequency of adverse effects (particulary elevated liver enzymes) may be dose-related. The benefit of improved seizure control which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse reaction.
A good correlation has not been established between daily dose, serum level and therapeutic effect. However, therapeutic serum levels for most patients will range from 50 – 100 mcg/ml. Occasional patients may be controlled with serum levels lower or higher than this range.
As the Sodium Valproate dosage is titrated upward, blood levels of Phenobarbital and/or Phenytoin may affected.
Gastrointestinal tract irritation : Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
OVERDOSAGES :
- Overdosage with Valproate may result in somnolence, heart block and deep coma. Fatalities have been reported; however, patients have recovered from Valproate levels as high as 2120 mcg/ml.
- In overdose situations, the fraction of drug not bound to protein is high and hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
- Naloxone has been reported to reverse the CNS depressant effects of Valproate overdosage. Because Naloxone could theoretically also reverse the antiepileptic effects of Valproate, it should be used with caution in patients with epilepsy.
CONTRAINDICATIONS :
- Should not be administered to patients with hepatic disease or significant dysfunction.
- Patient with known hypersensitivity to the drug.
- Patient with known urea cycle disorders (see WARNINGS AND PRECAUTIONS).
WARNINGS AND PRECAUTIONS :
Warnings
- Hepatotoxicity :
Hepatic failure resulting in fatalities has occurred in patients receiving Valproic acid. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering Sodium valproate to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Sodium valproate products is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of seizure control should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.
- Pancreatitis :
Cases of life-threatening pancreatitis have been reported in both children and adults receiving Valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with Valproate. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated (see WARNING).
- Urea Cycle Disorders (UCD) :
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of Valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Valproate therapy, evaluation for UCD should be considered in the following patients :
- Those with a history of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine.
- Those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance.
- Those with a family history of UCD or a family history of unexplained infant deaths (particularly males).
- Those with other signs or symptoms of UCD.
Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving Valproate therapy should receive prompt treatment (including discontinuation of Valproate therapy) and be evaluated for underlying urea cycle disorders (see CONTRAINDICATIONS and PRECAUTIONS).
- Suicidal behavior and ideation :
An increase in the risk of suicidal thoughts or behavior in patients taking AEDs for any indication has been reported. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing Valproic acid or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and an increase risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Interaction with Carbapenem antibiotics :
Carbapenem antibiotics (Ertapenem, Imipenem, Meropenem) may reduce serum Valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum Valproic acid concentrations should be monitored frequently after initiating Carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum Valproic acid concentrations drop significantly or seizure control deteriorates (see DRUG INTERACTIONS).
- Somnolence in the elderly :
A significantly higher proportion of Valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence, there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower Valproate clearance and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence and other adverse events. Dose reductions or discontinuation of Valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence (see DOSAGE AND ADMINISTRATIONS).
- Thrombocytopenia :
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia [see PRECAUTIONS]) may be dose-related.
The therapeutic benefit that may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
- Nursing mothers :
Valproate is excreted in breast milk. Concentrations in breast milk have been reported of serum concentrations. It is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when Valproic acid is administered to a nursing woman.
- Usage in pregnancy :
According to published and unpublished reports Valproic acid may produce teratogenic effects, such as neural tube defects (e.g. spina bifida) in the offspring of human females receiving the drug during pregnancy. There are data that suggest an increased incidence of congenital malformations associated with the use of Valproic acid during pregnancy when compared with some other antiepileptic drugs. Therefore, Valproic acid should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of the treatment.
There are multiple reports in the clinical literature that indicate the use of antiepilepsy drugs during pregnancy results in an increased incidence of birth defects in the offspring. Therefore, antiepileptic drugs should be administered to women of childbearing potential only if they are clearly shown to be essential in the management of their disease.
The data described below were gained almost exclusively from women who received Valproate to treat epilepsy. The incidence of neural tube defects in the fetus may be increased in mothers receiving valproate during the first trimester of pregnancy. The United states Centers for Disease Control (CDC) has estimated the risk of Valproic acid exposed women having children with spina bifida to be approximately 1 to 2%.
Other congenital anomalies (e.g. craniofacial defects, cardiovascular malformations and anomalies involving various body systems), compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of these congenital anomalies are not available.
The higher incidence of congenital anomalies in antiepileptic drug-treated women with seizure disorders cannot be regarded as a cause and effects relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; genetic factors or the epileptic condition itself may be more important than drug therapy in contributing to congenital anomalies.
There have been reports of development delay, autism and/or autism spectrum disorder in the offspring of women exposed to Valproic acid during pregnancy.
Patients taking Valproate may develop clotting abnormalities. A patient who had low fibrinogen when taking multiple anticonvulsants including Valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If Valproate is used in pregnancy, the clotting parameters should be monitored carefully.
Hepatic failure, resulting in the death of a newborn and of an infant, has been reported following the use of Valproate during pregnancy.
Test to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving Valproate.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Precautions
- Hepatic dysfunction (see CONTRAINDICATIONS and WARNINGS)
- Pancreatitis (see WARNINGS)
- Hyperammonemia
Hyperammonemia has been reported in association with Valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia (see PRECAUTIONS – Hypothermia). If ammonia is increased, Valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated and such patients should undergo investigation for underlying urea cycle disorders (see CONTRAINDICATIONS and WARNINGS – Urea Cycle Disorders (UCD) and PRECAUTIONS – Hyperammonemia and encephalopathy associated with concomitant Topiramate use).
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of Valproate therapy should be considered.
- Hyperammonemia and encephalopathy associated with concomitant Topiramate use :
Concomitant administration of Topiramate and Valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia (see PRECAUTIONS – Hypothermia). In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if Topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of Topiramate and Valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons (see CONTRAINDICATIONS and WARNINGS – Urea Cycle Disorders and PRECAUTIONS – Hyperammonemia).
- Hypothermia :
Hypothermia, defined as an unintentional drop in body core temperature to < 35ºC (95ºF), has been reported in association with Valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant Topiramate with Valproate after starting Topiramate treatment or after increasing the daily dose of Topiramate (see DRUG INTERACTIONS – Topiramate). Consideration should be given to stopping Valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
- General :
Because of reports of thrombocytopenia (see WARNINGS), inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts, and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Valproic acid be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since Valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of Valproate and concomitant drugs are recommended during the early course of therapy (see DRUG INTERACTIONS).
Valproate is partially eliminated in the urine as a keto-metabolite that may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with Valproate. The clinical significance of these is unknown. There are in vitro studies that suggest Valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving Valproate or when following CMV infected patients clinically.
- Multi-organ hypersensitivity reaction :
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of Valproate therapy in adult and pediatric patients (median time to detection 21 days : Range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepato-renal syndrome, arthralgia and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs not noted here may occur. If this reaction is suspected, Valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
- Information for patients :
- Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.
- Patients and guardians should be informed of the signs and symptoms associated with hyperammonemic encephalopathy (see PRECAUTIONS – Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.
- Since Sodium valproate may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
- Since Sodium valproate has been associated with certain types of birth defects, female patients of child-bearing age considering the use of Sodium valproate should be advised of the risk associated with the use of Valproic acid during pregnancy (see WARNINGS).
- Pediatric use :
Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (see WARNINGS). When Sodium valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound Valproic acid concentrations. The variability in free fraction limits the clinical usefulness of monitoring total serum Valproic acid concentrations. Interpretation of Valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
- Geriatric use :
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see WARNINGS – Somnolence in the elderly). The starting dose should be reduced in these patients and dosage reductions or discontinuation should be considered in patients with excessive somnolence (see DOSAGE AND ADMINISTRATIONS).
DRUG INTERACTIONS :
- Effects of co-administered drugs on Valproate clearance :
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of Valproate. For example, Phenytoin, Carbamazepine and Phenobarbital (or Primidone) can double the clearance of Valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on Valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in Valproate clearance, monitoring of Valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on Valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
- Drugs for which a potentially important interaction has been observed :
Aspirin
Caution should be observed if Valproate and Aspirin are to be co-administered.
Carbapenem antibiotics
A clinically significant reduction in serum Valproic acid concentration has been reported in patients receiving Carbapenem antibiotics (Ertapenem, Imipenem, Meropenem) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum Valproic acid concentrations should be monitored frequently after initiating Carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum Valproic acid concentrations drop significantly or seizure control deteriorates (see WARNINGS AND PRECAUTIONS).
Felbamate
A decrease in Valproate dosage may be necessary when Felbamate therapy is initiated.
Rifampin
Valproate dosage adjustment may be necessary when it is co-administered with Rifampin.
- Drugs for which either no interaction or a likely clinically unimportant interaction has been observed :
Antacids
The co-administration of Valproate with commonly administered antacids (Maalox, Trisogel, and Titralac) did not reveal any effect on the extent of absorption of Valproate.
Chlorpromazine
The administration of Chlorpromazine to schizophrenic patients already receiving Valproate revealed a increase in trough plasma levels of Valproate.
Haloperidol
The administration of Haloperidol to schizophrenic patients already receiving Valproate revealed no significant changes in Valproate trough plasma levels.
Cimetidine and Ranitidine
Cimetidine and Ranitidine do not affect the clearance of Valproate.
- Effects of Valproate on other drugs :
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase and glucuronyltransferases.
The following list provides information about the potential for an influence of Valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.
- Drugs for which a potentially important Valproate interaction has been observed :
Amitriptyline/Nortriptyline
Rare postmarketing reports of concurrent use of Valproate and Amitriptyline resulting in an increased Amitriptyline level have been received. Concurrent use of Valproate and Amitriptyline has rarely been associated with toxicity. Monitoring of Amitriptyline levels should be considered for patients taking Sodium valproate concomitantly with Amitriptyline. Consideration should be given to lowering the dose of Amitriptyline/Nortriptyline in the presence of Valproate.
Carbamazepine/Carbamazepine-10,11-Epoxide
Serum levels of Carbamazepine (CBZ) decreased while that of carbamazepine-10,11-epoxide (CBZ-E) increased by upon co-administration of Valproate and CBZ to epileptic patients.
Clonazepam
The concomitant use of Valproic acid and Clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam
Valproate displaces Diazepam from its plasma albumin binding sites and inhibits its metabolism. Plasma clearance and volume of distribution for free Diazepam were reduced in the presence of Valproate. The elimination half-life of Diazepam remained unchanged upon addition of Valproate.
Ethosuximide
Valproate inhibits the metabolism of Ethosuximide. Patients receiving Valproate and Ethosuximide, especially along with other anticonvulsants, should be monitored for alterationsin serum concentrations of both drugs.
Lamotrigine
The dose of Lamotrigine should be reduced when co-administered with Valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant Lamotrigine and Valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of Phenobarbital. There is evidence for severe CNS depression, with or without significant elevations of Barbiturate or Valproate serum concentrations. All patients receiving concomitant Barbiturate therapy should be closely monitored for neurological toxicity. Serum Barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone
Primidone is metabolized into a Barbiturate and therefore, may also be involved in a similar interaction with Valproate as Phenobarbital.
Phenytoin
Valproate displaces Phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of Valproate and Phenytoin. The dosage of Phenytoin should be adjusted as required by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of Tolbutamide was increased when added to plasma samples taken from patients treated with Valproate. The clinical relevance of this displacement is unknown.
Topiramate
Concomitant administration of Valproic acid and Topiramate has been associated with hyperammonemia with and without encephalopathy (see CONTRAINDICATIONS and WARNINGS – Urea cycle disorders and PRECAUTIONS – Hyperammonemia and encephalopathy associated with concomitant Topiramate use). Concomitant administration of Topiramate with Valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. Blood ammonia levels should be measured in patients with reported onset of hypothermia (see PRECAUTIONS – Hypothermia and hyperammonemia).
Warfarin
In an in vitro study, Valproate increased the unbound fraction of Warfarin. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if Sodium valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of Zidovudine was decreased after administration of Valproate; the half-life of Zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed : Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of Acetaminophen when it was concurrently administered to three epileptic patients.
Clozapine
In psychotic patients, no interaction was observed when Valproate was co-administered with Clozapine.
Lithium
Co-administration of Valproate and Lithium carbonate to normal male volunteers had no effect on the steady-state kinetics of Lithium.
Lorazepam
Concomitant administration of Valproate and Lorazepam in normal male volunteers was accompanied decrease in the plasma clearance of Lorazepam.
Oral contraceptive steroids
Administration of a single-dose of Ethinyloestradiol/Levonorgestrel to women on Valproate therapy did not reveal any pharmacokinetic interaction.
ADVERSE REACTIONS :
- Gastrointestinal : Nausea, vomiting, indigestion, diarrhea, abdominal cramps, constipation, anorexia with some weight loss and increased appetite with weight gain.
- CNS effects : Sedation, tremor, hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, “spots before eyes”, dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, parkinsonism, coma, encephalopathy with or without fever.
- Dermatologic : Hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
- Psychiatric : Emotional upset, depression, psychosis, aggression, hyperactivity, hostility and behavioural deterioration.
- Musculoskeletal : Weakness.
- Hematologic : Thrombocytopenia, petechiae, bruising, hematoma formation, epistaxis, frank hemorrhage, relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis and acute intermittent porphyria.
- Hepatic : Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH, increases in serum bilirubin and abnormal changes in other liver function tests, hepatotoxicity.
- Endocrine : Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, paratoid gland swelling, abnormal thyroid function tests, polycystic ovary disease.
- Pancreatic : Acute pancreatitis including fatalities (see WARNINGS).
- Metabolic : Hyperammonemia, hyponatremia, inappropriate ADH secretion, Fanconi’s syndrome, hyperglycinemia.
- Genitourinary : Enuresis and urinary tract infection.
- Special senses : Hearing loss, ear pain.
- Other : Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever and hypothermia.
- Mania : Chills, neck pain, neck rigidity, hypotension, postural hypotension, vasodilation, fecal incontinence, gastroenteritis, glossitis, arthrosis, agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo, furunculosis, maculopapular rash, seborrhea, conjunctivitis, dry eyes, eye pain, dysuria.
- Migraine : Face edema, dry mouth, stomatitis, cystitis, metrorrhagia and vaginal hemorrhage.
PRESENTATION :
Sodium Valproate Syrup 250 mg/5 ml Box, 1 bottle @ 120 ml Reg. No. GKL1702356437A1
STORAGE :
STORE BELOW 30ºC, PROTECT FROM LIGHT
ON MEDICAL PRESCRIPTION ONLY
Manufactured by :
BERNOFARM
Sidoarjo – Indonesia
