Valporil/ Valporil CR/ Dixval in Seizure Disorders, Bipolar disorder and migraine attacksWhat is a seizure?Any involuntary behavior that occurs abnormally may represent a seizure. Seizures are classified into several categories.
Generalized (Grand Mal) Seizures - This is the most common form of seizure in small animals. The entire body is involved in stiffness and possibly stiffness/contraction cycles (tonic/clonic action). The animal loses consciousness and may urinate or defecate.Partial Seizures - This form of seizure originates from some specific area in the brain and thus involves the activity of a specific region of the body. Partial seizures may "generalize" to involve the whole body.Psychomotor Seizures - This type of seizure is predominantly behavioral with the animal involuntarily howling, snapping, circling, etc. The abnormal behavior may be followed by a generalized seizure.Seizures (neurological events) are often difficult to tell from fainting spells (cardiovascular events). Classically, true seizures are preceded by an aura, or special feeling associated with a coming seizure. As animals cannot speak, we usually do not notice any changes associated with the aura. The seizure is typically followed by a post-ictal period during which the animal appears disoriented, even blind. This period may last only a few minutes or may last several hours. Fainting animals are usually up and normal within seconds of the spell.
*** Post-Ictal Disorientation Is The Hallmark Of The Seizure ***
Causes of seizures and diagnostics:
Seizures may be caused by situations within the brain (such as trauma or infection) or by situations centered outside the brain (such as low blood sugar, circulating metabolic toxins, or external poisons). The first step is to rule out situations centered outside the brain, easily done with a blood test. An ophthalmic exam may also be performed as the retina may show signs of a brain infection. If these tests are negative, the next step is determined by the age of the pet.
Animals Less Than Age One Year - seizures are usually caused by infections of the brain. Analysis of cerebrospinal fluid, obtained by a tap under anesthesia, would be important.
Animals Between Ages 1 And 5 - In these animals, usually no cause can be found and the term "epilepsy," which simply means "seizure disorder," is applied. If seizures are occurring frequently enough, medication is used to suppress them. Schnauzers, Basset hounds, Collies, and Cocker spaniels have 2-3 times as much epilepsy as other breeds.
Animals More Than Age Five Years - In this group, seizures are usually caused by a tumor growing off the skull and pressing on the brain (a “meningioma”). Most such tumors are operable if found early. A CAT scan or MRI would be the next step. Special referral is necessary for this type of imaging. For patients where surgery is not an option, corticosteroids may be used to reduce swelling in the brain. Treatment to suppress seizures may also be needed (see below).
Epilepsy is the name given to seizure disorders for which no cause can be found. It is not a unique disease in and of itself.
There are two kinds of seizure disorders:
1] An isolated, non-recurrent attack, such as may occur during a febrile illness or after head trauma
2] Epilepsy – a recurrent, paroxysmal disorder of cerebral function characterized by sudden, brief attacks of altered consciousness, motor activity, sensory phenomena, or inappropriate behavior caused by excessive discharge of cerebral neurons.
If given a sufficient stimulus (eg, convulsant drugs, hypoxia, hypoglycemia), even the normal brain can discharge excessively, producing a seizure. In epileptics, seizures are rarely precipitated by exogenous factors, such as sound, light, and touch.
Auras are sensory or psychic manifestations that immediately precede complex partial or generalized tonic-clonic seizures and represent seizure onset.
A postictal state may follow a seizure (most commonly a generalized seizure) and is characterized by deep sleep, headache, confusion, and muscle soreness.
Simple partial seizures consist of motor, sensory, or psychomotor phenomena without loss of consciousness. The specific phenomenon reflects the affected area of the brain. In jacksonian seizures, focal motor symptoms begin in one hand and then "march" up the extremity. Other focal attacks can first affect the face area, then spread down the body to involve an arm and sometimes a leg. Some partial motor seizures begin with raising the arm and turning the head toward the moving part. Some proceed to generalized convulsions.
In complex partial seizures, the patient loses contact with the surroundings for 1 to 2 min. At first, the patient may stare, perform automatic purposeless movements, utter unintelligible sounds without understanding what is said, and resist aid. Mental confusion continues another 1 or 2 min after motor components of the attack subside. These seizures may develop at any age, and structural pathology (eg, mesial temporal sclerosis, low-grade astrocytomas) should be ruled out. Complex partial seizures most commonly originate in the temporal lobe but may originate in any lobe of the brain.
Complex partial seizures are not characterized by unprovoked aggressive behavior. However, if restrained during a complex partial seizure, a patient may lash out at the person restraining him, as may a patient in a postictal confused state after a generalized seizure. Between seizures, patients with temporal lobe epilepsy have a higher incidence of psychiatric disorders than does the general population; 33% may have psychologic difficulties, and 10% may have symptoms of schizophreniform or depressive psychoses.
Generalized seizures cause loss of consciousness and motor function from the onset. Such attacks often have a genetic or metabolic cause. They may be primarily generalized (bilateral cerebral cortical involvement at onset) or secondarily generalized (local cortical onset with subsequent bilateral spread). Types of generalized seizures include infantile spasms and absence, tonic-clonic, atonic, and myoclonic seizures.
Infantile spasms are primarily generalized seizures characterized by sudden flexion of the arms, forward flexion of the trunk, and extension of the legs. Seizures last a few seconds and are repeated many times a day. They occur only in the first 3 yr of life and then are replaced by other types of seizures. Developmental abnormalities are usually apparent.
Absence seizures (formerly called petit mal) consist of brief, primarily generalized attacks manifested by a 10- to 30-sec loss of consciousness and eyelid fluttering at a rate of 3/sec, with or without loss of axial muscle tone. Affected patients do not fall or convulse; they abruptly stop activity and resume it just as abruptly after the seizure, with no postictal symptoms or even knowledge that an attack has occurred. Absence seizures are genetic and occur predominantly in children. Without treatment, such seizures are likely to occur many times a day. Seizures often occur when the patient is sitting quietly and can be precipitated by hyperventilation. They rarely occur during exercise.
Generalized tonic-clonic seizures typically begin with an outcry; they continue with loss of consciousness and falling, followed by tonic, then clonic contractions of the muscles of the extremities, trunk, and head. Urinary and fecal incontinence may occur. Seizures usually last 1 to 2 min. Secondarily generalized tonic-clonic seizures begin with a simple partial or complex partial seizure.
Atonic seizures are brief, primarily generalized seizures in children. They are characterized by complete loss of muscle tone and consciousness. The child falls or pitches to the ground, so that seizures pose the risk of serious trauma, particularly head injury.
Myoclonic seizures are brief, lightning-like jerks of a limb, several limbs, or the trunk. They may be repetitive, leading to a tonic-clonic seizure. There is no loss of consciousness.
Febrile seizures are associated with fever without evidence of intracranial infection. They affect about 4% of children between the ages of 3 mo and 5 yr. Benign febrile seizures are brief, solitary, and generalized tonic-clonic in form; complicated febrile seizures are either focal, last > 15 min, or recur >= 2 times in < 24 h. Overall, the occurrence of febrile seizures is associated with a 2% incidence of subsequent epilepsy; the incidence of epilepsy and the risk of recurrent febrile seizures are much greater among children with complicated febrile seizures, preexisting neurologic abnormalities, onset before age 1 yr, or a family history of epilepsy.
In status epilepticus, seizures follow one another with no intervening periods of normal neurologic function. Generalized convulsive status epilepticus may be fatal. It may result from too-rapid withdrawal of anticonvulsants. Confusion may be the only manifestation of complex partial or absence status epilepticus, and an EEG may be needed to diagnose seizure activity.
An Epilepsia partialis continuum is a rare form of focal (usually hand or face) motor seizures that recur at intervals of a few seconds or minutes for days to years at a time. In adults, it is usually due to a structural lesion, such as a stroke. In children, it is usually due to a focal cerebral cortical inflammatory process (Rasmussen's encephalitis), possibly caused by a chronic viral infection or autoimmune processes.
TreatmentGeneral principles: Treatment aims primarily to control seizures. A causative disorder may need to be treated as well.
A normal life should be encouraged. Exercise is recommended; even such sports as swimming and horseback riding can be permitted with proper safeguards. Most state licensing agencies permit automobile driving after seizures have stopped for1 yr. Social activities should be encouraged. Alcohol intake should be minimized. Cocaine and several other illicit drugs can trigger seizures.
Family members must be taught a commonsense attitude toward the patient. Overprotection should be replaced with sympathetic support that lessens feelings of inferiority and self-consciousness and other emotional handicaps; prevention of invalidism should be emphasized. Institutional care is rarely advisable and should be reserved for severely retarded patients and for patients with seizures so frequent and violent despite drug therapy that they cannot be cared for elsewhere.
During a seizure, injury should be prevented. Protecting the tongue should not be attempted because teeth may be damaged. Inserting a finger to straighten the tongue is dangerous and unnecessary. Clothing around the neck should be loosened, and a pillow placed under the head. The patient should be rolled onto his side to prevent aspiration. A responsible fellow worker may be trained to give emergency aid if the patient agrees.
Causative or precipitating factors should be eliminated. Progressive structural lesions of the brain (eg, tumors, abscesses) should be sought and promptly treated. After definitive treatment of structural lesions, continued medical treatment (eg, anticonvulsants) is usually necessary. Other physical disorders (eg, systemic infections, endocrine abnormalities) should be corrected.Head injuries with skull fractures, intracranial hemorrhages, focal neurologic deficits, or amnesia cause posttraumatic epilepsy in 25 to 75% of cases. Prophylactic treatment with anticonvulsant drugs after the head injury reduces the probability of early posttraumatic seizures during the first few weeks after the injury but does not prevent the development of permanent posttraumatic epilepsy months or years later.
Drug therapy: No single drug controls all types of seizures, and different drugs are required for different patients. Patients rarely require several drugs. The drug of choice for the particular type of epilepsy is started at relatively low dose and increased over about 1 wk to the standard therapeutic dose. After about 1 wk at this dose, blood levels are measured to determine whether the effective therapeutic level has been reached. If seizures continue, the daily dose is increased by small increments. If toxic blood levels or toxic symptoms develop before seizures are controlled, a second anticonvulsant is added, again guarding against toxicity. Interaction between drugs can interfere with their rate of metabolic degradation. The initial, failed anticonvulsant is then withdrawn gradually. Once seizures are controlled, the drug should be continued without interruption until at least 1 yr is seizure-free. At that time, discontinuing the drug should be considered, because about 2/3 of such patients remain seizure-free without drugs. Static encephalopathy and structural brain lesions increase the risk of relapse off medication. Patients whose attacks were initially difficult to control, those who failed a drug-free trial, and those with important social reasons for avoiding seizures should be treated indefinitely.
Once the drug response is known, blood levels are less useful to follow than the clinical course. Some patients have toxic symptoms at low levels; others tolerate high levels without symptoms.
For generalized tonic-clonic seizures, phenytoin, carbamazepine, or valproate is the drug of choice. For adults, phenytoin can be given in divided doses or at bedtime. If seizures continue, the dose can be increased cautiously to 500 mg/day with blood level monitoring. At a higher dose, dividing the daily dose may reduce toxic symptoms.
For partial seizures, treatment begins with carbamazepine, phenytoin, or valproate. If seizures persist despite high doses of these drugs, gabapentin, lamotrigine, or topiramate may be added. For absence seizures, ethosuximide orally is preferred. Valproate and clonazepam orally are effective, but tolerance to clonazepam often develops. Acetazolamide is reserved for refractory cases.
Atonic seizures, myoclonic seizures, and infantile spasms are difficult to treat. Valproate is preferred, followed, if unsuccessful, by clonazepam. Ethosuximide is sometimes effective, as is acetazolamide (in dosages as for absence seizures). Phenytoin has limited effectiveness. For infantile spasms, corticosteroids for 8 to 10 wk are often effective. The optimal corticosteroid regimen is controversial. ACTH 20 to 60 U/day IM may be used. A ketogenic diet may help but is difficult to maintain. Carbamazepine may make patients with primary generalized epilepsy and multiple seizure types worse.
Status epilepticus can be terminated by giving diazepam 10 to 20 mg (for adults) IV or up to 2 doses (if necessary) of lorazepam 4 mg IV. For children, IV diazepam up to 0.3 mg/kg or lorazepam up to 0.1 mg/kg is given. For adults, phenytoin 1.5 g IV may be given to prevent recurrence. Fosphenytoin, a water-soluble product, is an alternative that in equivalent doses reduces the incidence of hypotension and phlebitis. Anesthetic IV doses of phenobarbital, lorazepam, or pentobarbital may be necessary in refractory cases; in such instances, intubation and O2 therapy are required to prevent hypoxemia.In acute generalized tonic-clonic seizures due to febrile illnesses, ingestion of alcohol or other toxins, or acute metabolic disturbance, the causative condition must be treated as well as the seizures. Status epilepticus should be treated at once. If only one seizure has occurred, phenytoin should be given in full dosage for 7 to 10 days; afterward, a decision concerning long-term therapy must be made. After a first seizure, 1/3 of patients have recurrent attacks, followed by chronic epilepsy. Anticonvulsants are of little value in preventing alcohol withdrawal seizures.
Benign febrile convulsions do not require treatment because of the favorable prognosis compared with the potential toxic effects of anticonvulsants in a young child. For patients with complicated febrile seizures or other risk factors for recurrence ,recurrence rates for febrile seizures can be reduced by continuous prophylactic treatment with phenobarbital 5 to 10 mg/kg/day. However, no evidence suggests that such treatment of complicated febrile seizures prevents the development of recurrent nonfebrile seizures (epilepsy). Furthermore, phenobarbital given chronically to children measurably reduces their learning capacity.Adverse effects: All anticonvulsants may cause an allergic scarlatiniform or morbilliform rash.
Patients receiving carbamazepine should have a CBC once a month for the first year of therapy. If the WBC or RBC count decreases significantly, the drug should be discontinued immediately. Patients receiving valproate should have liver function tests every 3 mo for 1 yr; if serum transaminases or ammonia levels increase significantly (to > 2 times the upper limit of normal), the drug should be discontinued. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.
When an overdose reaction occurs, the amount of drug is reduced until the reaction subsides. When more serious acute poisoning occurs, the patient is given ipecac syrup or, if obtunded, is lavaged. After emesis or lavage activated charcoal activated charcoal is administered, followed by a saline cathartic (eg, magnesium citrate). The suspect drug should be discontinued, and a new anticonvulsant started simultaneously.
Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retardation, developmental delay, abnormal facies, digital hypoplasia) occurs in 4% of the children of epileptic women who take anticonvulsants during pregnancy. Among commonly used drugs, carbamazepine appears to be the least teratogenic, but only slightly so; valproate may be the most teratogenic. Yet, because uncontrolled generalized seizures during pregnancy lead to fetal injury and death, continued treatment with anticonvulsants is generally advisable
Surgical therapy: About 10 to 20% of patients have seizures that are refractory to medical treatment. Most patients whose seizures originate from a local area of abnormal brain function improve markedly when the epileptic focus is resected. Some are completely cured. Because extensive monitoring and skilled medical-surgical teamwork are required, these patients are best managed in specialized centers.Vagus nerve stimulation: Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device reduces the number of partial seizures by one third. After the device is programmed, patients can activate it with a magnet when they sense a seizure is imminent. Vagus nerve stimulation is used as an adjunct to an anticonvulsant. Adverse effects include a deepening of the voice during stimulation, cough, and hoarseness. Complications are minimal. Duration of effectiveness is not well established.Sodium Valproate/ Valproic Acid (Valporil / Valporil CR) & Divalproex sodium (Dixval)Valproic acid, valproate sodium, and divalproex belong to the group of medicines called anticonvulsants. They are used to control certain types of seizures in the treatment of epilepsy. Valproic acid, valproate sodium, and divalproex may be used alone or with other seizure medicine. Divalproex is also used to treat the manic phase of bipolar disorder (manic-depressive illness), and to help prevent migraine headaches.
Divalproex and valproate sodium form valproic acid in the body and gets converted to valproate ions. Therefore, the following information applies to all of these medicines.About Sodium Valproate:This belongs to the group of medicines known as antiepileptics.
Sodium Valproate controls the convulsions (fits or seizures) in some forms of epilepsy by reducing the activity in the brain.
Sodium valproate is also helpful in preventing absence seizures (where people appear to 'switch off' for short periods of time).
Sodium valproate is available in enteric-coated tablet, crushable tablet. It is also available as a controlled release preparation, which means sodium valproate is released slowly over the day to give an even effect.
VALPORIL/ VALPORIL CR & DIXVAL IN EPILEPSY
The brain works by sending lots of messages. It manages the number of messages it sends and where it sends them.
Sometimes extra messages are sent which do not go down the normal routes. This can upset the normal function of the brain and can cause an epileptic seizure. A person is said to have epilepsy when they have repeated seizures.
Sodium valproate belongs to a class of medicines called Anti-Epileptics. It can stop these extra messages in the brain. In this way it makes epileptic seizures less likely
What is sodium valproate for?
This form of sodium valproate is used in all types of epilepsy.
Getting Valporil CR to work for you
Valporil (Sodium valproate) is available as 200 mg gastro-resistant tablets, 200 mg controlled release tablets 300 mg controlled -release tablets, 500 mg controlled -release tablets
People who take Valporil / Valporil CR the right way can often get control of their seizures. For the best results, you need to take Valporil CR every day. It is a good idea
Dosage: Valproate sodium, like lithium, is all about blood levels. However none of the PI sheets seemed all that concerned with blood levels. Dosage was good enough, with blood levels just getting a mention.
Everyone recommends starting at 600mg a day divided into two doses, ramping up by 200mg every three days until your symptoms were under control or you hit 2000 to 2500mg a day (based on weight, allowing 30mg/kg/day). Although you just might want to check those blood levels to see if you hit that sweet spot between 45 and 125.
Well, at least that's somewhat saner than the US recommendations for valproates. But unless you're really spazing out, I think you can wait a week between increases. And you can get blood levels done to see how you're doing at 600, 800, 1000mg. And with a half-life of 8-12 hours taking it three times a day would probably work better. I haven't found any studies on valproate sodium and TID dosing, just Divalproex sodium, but people taking Divalproex sodium three times a day seem to complain about some of the side effects less.
Days to Reach a Steady State:
Valproate sodium's non-linear. You can't pin down a hard number on it. I haven't found a number for it in any study. Based on the usual formula of 6 * half-life, approximately three days.
When you're fully saturated with the medication and less prone to peaks and valleys of effects. You still might have peaks of effect after taking many meds, but with a lot of the meds you'll have fewer valleys after this point. In theory anyway.
How long it takes to Work: In theory you should start feeling results once you're in the therapeutic range of your blood levels. So for epilepsy that's generally in the neighborhood of 50-100, and for bipolar it's a wider range of 40-150. Getting to that blood level is between you and your liver. Once there it's up to your brain if it's going to respond to a valproate or not. So unlike most anticonvulsants where you feel something in a matter of days, or there's a definite dosage where we can write, "here is where you should notice effect or not," it's just not like that with the valproates. So once you're there, here's a study with PET scans indicating 2-6 weeks to start feeling something.
Half-Life & Average Time to Clear Out of Your System: 8-12 hours. You should thus step down the dosage by however much you increased it a day every two to three days.
Like any anticonvulsant, if you've been taking valproate sodium for more than a couple months and you've reached the therapeutic blood levels, you just can't stop cold turkey if you're not at the therapeutic dosage for another anticonvulsant that is known to work for you, otherwise you risk partial onset or absence seizures to tonic-clonic grand mals, even if you've never had a seizure disorder before! The risk is worse if you're taking a lithium variant, and/or any antidepressant, especially bupropion. Anyone with a history of a seizure disorder who needs to stop taking an anticonvulsant cold turkey needs to be discussing that with two neurologists and not getting your information from some stupid web site. Get off your computer and start making appointments!
If you've worked your way up to a particular dosage, it's usually best to spend this many days at the next lowest dosage before going down the next lowest dosage before that and so forth. This is the least sucky way to avoid problems when stopping any psychiatric medication. Presuming you have the option of slowly tapering off them.What is divalproex (Dixval)?
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis (2-propylpentanoate). Divalproex sodium occurs as a white powder with a characteristic odor.
Dixval tablets are for oral administration. Dixval tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.
Difference between divalproex and sodium valproate/valproic acid
The molar relation of sodium valproate: valproic acid is 2.3:1 in Valporil/ Valporil CR, while in Dixval it is in the ratio of 1:1
This may not make a difference as far as it’s therapeutic benefits are considered, as it is the valproate ion, which is the active moiety.
Here is a letter from Dr. Phelps to a reader downloaded from the net:
"Forms of the active ingredient, the valproate ion (you could think of that as V-) Sodium valproate (V. Na; dissolving into V- and Na+ when it hits the fluids in the stomach) Valproic acid (V. H); dissolving into V- and H+ when it hits the fluids in the stomach)
Combinations of the two
a) "Divalproex sodium" (Dixval), which is a 1:1 mixture
b) A mixture of 2.3:1 mixture of sodium valproate and valproic acid (Valporil / Valporil CR).
Now, does it make any difference? I'm not aware of any literature comparing the two mixtures (1:1 versus 2.3:1). From what I know so far, always open to learning more, it shouldn't make any difference in the effectiveness of the medications, because all of these forms end up yielding the valproate ion, which is the active form of the medication. The difference is said to be, as I understand it, that the combinations are better in terms of side effects than the Sodium Valproate version. The latter causes little more stomach irritation and thus nausea.
So if your friend is not having stomach problems with the current one, and there's no other reason to look at switching, I don't think there would be any improvement to be had from switching.
Thanks. Dr. Phelps
CLINICAL PHARMACOLOGY
Pharmacodynamics
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Dixval (divalproex sodium) products and Valporil (valproic acid) deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment.
For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.
Co-administration of
oral valproate products with food and substitution formulations should cause no clinical problems in the management of patients with epilepsy. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.Distribution
Protein Binding:
The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mg/mL to 18.5% at 130 mg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See PRECAUTIONS, Drug Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution:
Valproate concentrations in
cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).Metabolism:
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial b-oxidation is the other major metabolic pathway, typically accounting for over 40% o f the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age:
Neonates - Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.
Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage
should be reduced in the elderlyEffect of Disease:
Liver Disease – Liver
disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease - A slight
reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance <>hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.Plasma Levels and Clinical Effect
The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mg/mL to 18.5% at 130 mg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemia c patients, and in patients with hepatic and renal diseases.
Epilepsy:
The
therapeutic range in epilepsy is commonly considered to be 50 to 100 mg/mL of total valproate, although some patients may b e controlled with lower or higher plasma concentrations.Mania:
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mg/mL
Indications and usage
Mania
Dixval (divalproex sodium) is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgement, aggressiveness, and possible hostility.
The efficacy of divalproex sodium was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania .
The safety and effectiveness of divalproex sodium for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use divalproex sodium for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
EpilepsyDivalproex sodium is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
MigraineDivalproex sodium is indicated for prophylaxis of migraine headaches. There is no evidence that Divalproex sodium is useful in the acute treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, Divalproex sodium should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment.
DOSAGE AND ADMINISTRATIONManiaDivalproex sodium tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Divalproex sodium treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of Divalproex sodium in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Divalproex sodium, the safety of Divalproex sodium in long-term use is supported by data from record reviews involving approximately 360 patients treated with Divalproex sodium for greater than 3 months.Epilepsy
Divalproex sodium tablets are administered orally. Divalproex sodium is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Divalproex sodium dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected
Complex Partial Seizures: For adults and children 10 years of age or older.
Monotherapy (Initial Therapy): Divalproex sodium has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mg/mL). No recomme n-dation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mg/mL in females and 135 mg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibil ity of a greater incidence of adverse reactions.
Conversion to Monotherapy: Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100mg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Divalproex sodium therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.Adjunctive Therapy: Divalproex sodium may be added to the patient’s increased by 5 to 10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mg/mL). No recommendation regarding the safety of valproate fo r use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of
adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to Divalproex sodium, no adjustment of carbamazepine or phenytoin dosage was needed However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy .Simple and Complex Absence Seizures: The recommended initial
dose is 15 mg/kg/day, increasing at one week intervals by 5 to 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 divided doses.
A good
correlation has not been established between daily dose,
serum concentrations, and
therapeutic effect. However,
therapeutic valproate
serum concentrations for most patients with
absence seizures is considered to
range from 50 to 100 mg/mL. Some
patient s may be controlled with lower or higher
serum concentrations.
As the Divalproex sodium
dosage is titrated upward,
blood concentrations of phenobarbital and/or
phenytoin may be affected.
Antiepilepsy drugs should not be abruptly discontinued 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
epileptic patients previously receiving valproic acid (Valporil) therapy, Divalproex sodium tablets should be initiated at the same daily
dose and dosing schedule. After the
patient is stabilized on Divalproex sodium tablets, a dosing
schedule of two or three times a day may be elected in selected patients.
MigraineDivalproex sodium tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.
General Dosing Advice:Dosing in Elderly Patients - Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these 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. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response . Dose-Related Adverse Events - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ³110mg/mL (females) or ³135 mg/mL (males). The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.G.I. Irritation - Patients who
experience G.I.
irritation may
benefit from
administration of the
drug with
food or by slowly building up the
dose from an
initial low level.
SIDE EFFECTS
Mania
The
incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled
clinical trials of divalproex sodium in the treatment of
manic episodes associated with
bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment.
In clinical trials, the rates of
premature termination due to
intolerance were not statistically different between placebo, divalproex sodium, and
lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to
intolerance in the placebo, divalproex sodium, and
lithium carbonate groups, respectively.
The following adverse events occurred at an equal or greater incidence for
placebo than for divalproex sodium:
back pain, headache, constipation, diarrhea, tremor, and pharyngitis. The following additional adverse events were reported by greater than 1% but not more than 5% of the 89-divalproex sodium-treated patients in controlled
clinical trials. Body as a Whole: Chest pain, chills, chills and fever, fever,
neck pain,
neck rigidity.
Cardiovascular System: Hypertension, hypotension, palpitations,
postural hypotension, tachycardia, vasodilation.
Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis,
periodontal abscess.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Edema,
peripheral edema.
Musculoskeletal System: Arthralgia, arthrosis,
leg cramps, twitching.Nervous System: Abnormal dreams,
abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia,
thinking abnormalities, vertigo.
Respiratory System: Dyspnea, rhinitis.
Skin and Appendages: Alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.Urogenital System: Dysmenorrhoea, dysuria,
urinary incontinence
MigraineBased on two placebo-controlled clinical trials and their long term extension, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to divalproex sodium in the placebo-controlled trials,17% discontinued for intolerance. This is compared to a
rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse events reported as the primary reason for discontinuation by ³1% of 248 divalproex sodium -treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Those adverse events reported for patients in the placebo-controlled trials where the
incidence rate in the divalproex sodium -treated
group was greater than 5% and was greater than that for
placebo patients.
The following adverse events occurred in at least 5% of divalproex sodium -treated patients and at an equal or greater
incidence for
placebo than for divalproex sodium
flu syndrome and pharyngitis.
The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treated patients in the controlled
clinical trials:
Body as a Whole: Chest pain, chills, face edema,
fever and malaise.
Cardiovascular System: Vasodilatation.
Digestive System: Anorexia, constipation, dry mouth, flatulence,
gastrointestinal disorder (unspecified), and stomatitis
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema,
SGOT increase, and
SGPT increase.
Musculoskeletal System: Leg cramps and myalgia.
Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia,
speech disorder, thinking abnormalities, and vertigo.
Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus and rash.
Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
EpilepsyBased on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the
primary reason for discontinuation in the divalproex sodium -treated patients (6%), compared to 1% of placebo-treated patients
Other Patient Populations
Adverse events that have been reported with all
dosage forms of valproate from
epilepsy trials,
spontaneous reports, and other sources are listed below by
body system.
Gastrointestinal: The most commonly reported
side effects at the initiation of
therapy are nausea, vomiting, and indigestion. These effects are usually
transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps, and
constipation have been reported. Both
anorexia with some
weight loss and increased
appetite with
weight gain have also been reported. The
administration of delayed-release divalproex
sodium may result in reduction of
gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon
reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and
parkinsonism have been reported with the use of valproate. Rare cases of
coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital.
In rare instances encephalopathy with or without
fever has developed shortly after the introduction of valproate
monotherapy without
evidence of
hepatic dysfunction or inappropriately high
plasma valproate levels. Although
recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying
urea cycle disorders Several reports have noted
reversible cerebral
atrophy and
dementia in association with valproate therapy.
Dermatologic: Transient
hair loss,
skin rash, photosensitivity, generalized pruritus,
erythema multiforme, and Stevens-Johnson syndrome. Rare cases of
toxic epidermal
necrolysis have been reported including a
fatal case in a 6 month old
infant taking valproate and several other
concomitant medications.
An additional
case of
toxic epidermal
necrosis resulting in
death was reported in a 35 year old
patient with
AIDS taking several
concomitant medications and with a
history of
multiple cutaneous drug reactions. Serious
skin reactions have been reported with
concomitant administration of
lamotrigine and valproate.
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.
Musculoskeletal: Weakness.Hematologic: Thrombocytopenia and
inhibition of the secondary
phase of
platelet aggregation may be reflected in altered
bleeding time, petechiae, bruising,
hematoma formation, epistaxis, and
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 (eg,
SGOT and SGPT) and
LDH are frequent and appear to be dose-related. Occasionally, laboratory
test results include increases in
serum bilirubin and
abnormal changes in other
liver function tests. These results may reflect potentially serious hepatotoxicity.
Endocrine: Irregular menses,
secondary amenorrhea,
breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal
thyroid function testsThere have been rare
spontaneous reports of
polycystic ovary disease. A cause and
effect relationship has not been established.Pancreatic: Acute
pancreatitis including fatalities.
Metabolic: Hyperammonemia, hyponatremia, and inappropriate
ADH secretion.There have been rare reports of Fanconi’s
syndrome occurring chiefly in children.Decreased
carnitine concentrations have been reported although the clinical relevance is undetermined.Hyperglycinemia has occurred and was associated with a
fatal outcome in a patient with preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and
urinary tract infection.
Special Senses: Hearing loss, either
reversible or irreversible, has been reported; however, a
cause and
effect relationship has not been established. Ear
pain has also been reported.
Other: Allergic reaction, anaphylaxis,
edema of the extremities,
lupus erythematosus,
bone pain,
cough increased, pneumonia,
otitis media, bradycardia,
cutaneous vasculitis, fever, and hypothermia.
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 - A study involving the co-administration of
aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to
pediatric patients (n=6) revealed a decrease in
protein binding and an
inhibition of
metabolism of valproate. Valproate free
fraction was increased 4-fold in the presence of
aspirin compared to valproate alone. The b-oxidation
pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic
acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Felbamate - A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with
epilepsy (n=10) revealed an increase in
mean valproate peak
concentration by 35% (from 86 to 115 mg/mL) compared to valproate alone. Increasing the felbamate
dose to 2400 mg/day increased the
mean valproate peak
concentration to 133 mg/mL (another 16% increase). A decrease in valproate
dosage may be necessary when felbamate
therapy is initiated.
Meropenem - Subtherapeutic valproic
acid levels have been reported when meropenem was coadministered.
Rifampin - A study involving the
administration of a single
dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with
rifampin (600 mg) revealed a 40% increase in the
oral clearance of valproate. 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 - A study involving the co-administration of valproate 500
mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160
mEq doses) did not reveal any
effect on the extent of
absorption of valproate.
Chlorpromazine - A study involving the
administration of 100 to 300 mg/day of
chlorpromazine to schizophrenic patients already receiving valproate (200
mg BID) revealed a 15% increase in
trough plasma levels of valproate.
Haloperidol - A study involving the
administration of 6 to 10 mg/day of
haloperidol to schizophrenic patients already receiving valproate (200 mg BID) 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 glucuronosyltransferases.
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 - Administration of a single
oral 50 mg
dose of amitriptyline to 15
normal volunteers (10 males and 5 females) who received valproate (500
mg BID) resulted in a 21% decrease in
plasma clearance of amitriptyline and a 34% decrease in the net
clearance of 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 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 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% 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. Co-administration of valproate (1500
mg daily) increased the free
fraction of
diazepam (10 mg) by 90% in
healthy volunteers (n=6). Plasma
clearance and
volume of
distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination
half-life of
diazepam remained unchanged upon
addition of valproate.
Ethosuximide - Valproate inhibits the
metabolism of ethosuximide. Administration of a single
ethosuximide dose of 500
mg with valproate (800 to 1600 mg/day) to
healthy volunteers (n=6) was accompanied by a 25% increase in elimination
half-life of
ethosuximide and a 15% decrease in its total
clearance as compared to
ethosuximide alone. Patients receiving valproate and ethosux-imide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine -
In a steady-state study involving 10
healthy volunteers, the
elimination half-life of
lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). 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. See
lamotrigine package insert for details on
lamotrigine dosing with
concomitant valproate administration.
Phenobarbital - Valproate was found to inhibit the
metabolism of phenobarbital. Co-administration of valproate (250
mg BID for 14 days) with
phenobarbital to
normal subjects (n=6) resulted in a 50% increase in
half-life and a 30% decrease in
plasma clearance of
phenobarbital (60
mg single-dose). The
fraction of phenobarbital
dose excreted unchanged increased by 50% in presence of valproate.
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, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin - Valproate displaces
phenytoin from its
plasma albumin binding sites and inhibits its
hepatic metabolism. Co-administration of valproate (400
mg TID) with
phenytoin (250 mg) in
normal volunteers (n=7) was associated with a 60% increase in the free
fraction of phenytoin. Total
plasma clearance and
apparent volume of
distribution of
phenytoin increased 30% in the presence of valproate. Both the
clearance and
apparent volume of
distribution of free phenytoin were reduced by 25%.
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 from 20% to 50% when added to
plasma samples taken from patients treated with valproate. The
clinical relevance of this displacement is unknown.
Warfarin -
In an in vitro study, valproate increased the unbound
fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if divalproex sodium
therapy is instituted in patients taking anticoagulants.
Zidovudine -
In six patients who were
seropositive for HIV, the clearance of
zidovudine (100
mg q8h) was decreased by 38% after
administration of valproate (250 or 500
mg q8h); 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 (n=11), no interaction was observed when valproate was co-administered with clozapine.
Lithium - Co-administration of valproate (500
mg BID) and
lithium carbonate (300
mg TID) to
normal male volunteers (n=16) had no
effect on the steady-state
kinetics of lithium.
Lorazepam - Concomitant
administration of valproate (500
mg BID) and
lorazepam (1
mg BID) in
normal male volunteers (n=9) was accompanied by a 17% decrease in the
plasma clearance of lorazepam.
Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 mg)/levonorgestrel (250 mg) to 6 women on valproate (200
mg BID)
therapy for 2 months did not reveal any pharmacokinetic interaction
CONTRAINDICATIONS
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE
OR SIGNIFICANT HEPATIC DYSFUNCTION.
Divalproex
sodium is contraindicated in patients with known hypersensitivity to the drug.Divalproex
sodium is contraindicated in patients with known
urea cycle disorders.
PATIENT INFORMATIONImportant Information for Women Who Could Become Pregnant
About the Use of
Valporil/Dixval Tablets
Please read this leaflet carefully before you
take Valporil/Dixval tablets. This leaflet provides a summary of important information about taking Valporil/Dixval to women who could become pregnant. If you have any questions or concerns, or want more information about
Valporil/Dixval, contact your
doctor.
Information For Women Who Could Become Pregnant
Valporil/Dixval can be obtained only by
prescription from your doctor. The decision to use
Valporil/Dixval is one that you and your
doctor should make together, taking into account your individual needs and
medical condition.
Before using
Valporil/Dixval, women who can become
pregnant should consider the fact that Valporil/Dixval has been associated with
birth defects, in particular, with
spina bifida and other defects related to
failure of the
spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking
Valporil/Dixval in the first 12 weeks of
pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The
incidence in the general
population is 0.1 to 0.2%.
For further information, e-mail to
Mr. Mukesh Vankani or
Mr. Deepak Shah B. Pharma. MBA at
reliancehealthcare@yahoo.co.in
