Valpros Pedia Special Precautions

General: Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.
Hepatic/Biliary/Pancreatic: Hepatotoxicity (see Warnings): Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, fatal 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 done 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.
To decrease the potential risk of liver toxicity, concomitant use of salicylates and sodium valproate should be avoided in children <3 years old. In addition, salicylates should not be used in children <16 years old (see aspirin/salicylate product information on Reye's syndrome).
In patients > 2 years old who are clinically suspected of having a hereditary mitochondrial disease, sodium valproate should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with sodium valproate for the development of acute liver injury with regular clinical assessments and liver function testing. POLG mutation screening should be performed in accordance with current clinical practice.
Sodium valproate should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed despite discontinuation of the drug.
Pancreatitis: see Warnings.
Endocrine/Metabolic: Urea Cycle Disorders: The use of sodium valproate in patients with known urea cycle disorders is contraindicated. Hyperammonaemic encephalopathy, sometimes fatal, has been reported following initiation of valproate in patients with urea cycle disorders (a group of uncommon genetic abnormalities) particularly ornithine transcarbamylase deficiency. Prior to initiation of sodium valproate, evaluation for urea cycle disorder 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 signs and symptoms of urea cycle disorders [e.g., cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), protein avoidance]; those with a family history of urea cycle disorders or a family history of unexplained infant deaths (particularly males); those with other signs or symptoms of urea cycle disorders.
Discontinue sodium valproate and initiate prompt treatment in patients receiving sodium valproate who develop symptoms of unexplained hyperammonemic encephalopathy.
Hyperammonemia: Hyperammonemia, which may be present in the absence of abnormal liver function tests, can occur in patients during valproate therapy. Hyperammonemia may occasionally present clinically, with or without lethargy or coma, as vomiting, ataxia, increasing clouding of consciousness, and hypothermia. Should these symptoms occur, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for the treatment of hyperammonemia should be initiated (see Urea Cycle Disorders as previously mentioned).
Asymptomatic elevations of serum ammonia are more common and when present, require dose monitoring of serum ammonia levels. If elevation persists, discontinuation of sodium valproate should be considered.
Ornithine Transcarbamylase (OTC) Deficiency: Valproate may precipitate hyperammonemia symptoms in females with pre-existing OTC deficiency. As the symptoms may include seizures, any female with valproate-associated hyperammonemia should be evaluated for OTC deficiency. Investigations should include measurement of plasma amino acids and the immediate cessation of valproate should result in clinical improvement.
Concomitant Topiramate Use: Concomitant use of sodium valproate with topiramate has been shown to produce hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. This adverse event is not due to 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 increased risk for hyperammonemia with or without encephalopathy.
Hypothermia: Hypothermia, an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with sodium valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with sodium valproate after starting topiramate treatment or after increasing the daily dose of topiramate. Hypothermia may be manifested by a variety of clinical abnormalities such as lethargy, confusion, coma, and significant alterations in other major organ systems (i.e., cardiovascular and respiratory). Consideration should be given to discontinuing valproate therapy in patents who develop hypothermia. Examination of blood ammonia levels should be included in the clinical management and assessment of patient.
Diabetes and Sucrose or Fructose Intolerance: Sodium valproate (Valpros Pedia) syrup contains sucrose (which may be harmful to the teeth) and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
When prescribing to diabetic patients, the sucrose content should be taken into account (see Dosage & Administration).
Weight Gain: Sodium valproate very commonly causes weight gain, which may be marked and progressive. Patients should be cautioned on the risk of weight gain at the initiation of therapy and appropriate measures should be made to minimize it.
Central Nervous System (CNS): Brain Atrophy: There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy with neurological symptoms, in children, adults, and the elderly, receiving valproate therapy. In some cases, symptoms disappeared after valproate discontinuation but patients recovered with permanent sequelae. The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be discontinued in the presence of suspected or apparent signs of brain atrophy.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including sodium valproate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence of worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing sodium valproate or any other AED must balance this risk with the risk of untreated illness. Should 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.
Hematologic: The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Blood tests (e.g., blood cell count, including platelet count, bleeding time and coagulation tests) are recommended before initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of sodium valproate dose or withdrawal of therapy.
Musculoskeletal: Although immune disorders have only been rarely noted during the use of sodium valproate, the potential benefit should be weighed against its potential risk in patients with systemic lupus erythematosus.
Dermatologic and Hypersensitivity: Multi-organ Hypersensitivity Reaction: Although there have been rare reports of multi-organ hypersensitivity reactions associated with valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40 days), many of these cases resulted in hospitalization and even death.
Signs and symptoms of this disorder were diverse; however, patients typically 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), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs may occur. If this reaction is suspected, sodium valproate should be discontinued and an alternative treatment should be started.
Serious Skin Reactions: Serious skin reactions (e.g., Stevens-Johnson syndrome and Toxic Epidermal necrolysis) have been reported with concomitant lamotrigine and sodium valproate use.
Effects on Ability to Drive and/or Operate Machines: Since valproate may produce CNS depression, especially when combined with another CNS depressant such as alcohol, patients should be warned that sodium valproate may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle).
Use in Children (< 18 years old): The safety and efficacy of sodium valproate should be weighed against the risk of liver damage or pancreatitis in pediatric patients prior to initiation of therapy (see Warnings).
The safety and efficacy of valproate for acute manic episodes in patients <18 years old with bipolar disorder have not been established.
Use in the Elderly (≥65 years old): The safety and efficacy of sodium valproate in elderly patients with epilepsy has not been evaluated in clinical trials. Exercise caution in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions, and limited experience in this population (see Dosage & Administration).
A case review study showed that the higher percentage of patients >65 years old reported accidental injury, infection, pain, somnolence, and tremor.
The safety and efficacy of sodium valproate for the prevention of migration headaches in elderly patients >65 years old have not been established. Its safety and efficacy in elderly patients with epilepsy and mania has not been established. Because of limited experience with sodium valproate in this population, caution is advised.