Topiramate is a new drug that has shown promise in the treatment of epilepsy. Since preliminary evaluation has been encouraging, double-blind, placebo-controlled trials were established in an effort to better define the effectiveness, safety and appropriate dose range of topiramate for refractory partial epilepsy. The objective of this study was to evaluate a medium-to-high dose range consisting of daily dosages of 600, 800, and 1,000 mg of topiramate.

A total of 190 patients with epilepsy, aged from 18 to 68, were enrolled in the study. Over 90% of the patients had a history of complex partial seizures, and over 60% also had secondary generalized seizures. Patients were randomly assigned to one of four groups: placebo (47 patients), 600 (48 patients), 800 (48 patients), or 1,000 (47 patients) mg topiramate (Topamax) per day.

During the 18-week treatment period, the rate of reduction in average monthly seizure rates was 1% for placebo, 41% for 600 mg/day and 800 mg/day topiramate, and 38% for 1,000 mg/day topiramate. Patients who experienced a 50% or greater reduction in the frequency of seizures included 9% of those in the placebo group, 44% in the 600 mg/day topiramate group, 40% in the 800 mg/day topiramate group, and 38% in the 1,000 mg/day topiramate group. While none of the patients in the placebo group experienced improvement of 75% to 100% in the frequency of seizures, 20% of the patients given topiramate were improved to this extent. Topiramate therapy was discontinued in 16% of patients because of side effects, the most common of which were dizziness, headache, fatigue and confusion.

The results of this study indicate that topiramate is highly effective and generally well tolerated in the treatment of refractory partial epilepsy. Dosages of topiramate greater than 600 mg/day do not appear to result in significantly greater effectiveness and may result in more side effects. However, individuals who are able to tolerate higher dosages may receive additional benefit. The investigators suggest that future studies should be aimed at better characterization of the adverse effects of topiramate. Evaluations of the safety and effectiveness of smaller doses and smaller dosage increments are also indicated.

1. Would topiramate be effective in the treatment of other forms of epilepsy, or only refractory partial epilepsy?

The primary studies that have been completed and were submitted to the U.S. FDA for approval were conducted in patients with refractory partial epilepsy. Open-label studies of this medication included patients who had other types of epilepsy and anecdotal experience suggests the drug may be effective in other seizure types. There are currently ongoing studies looking at other seizure types such as generalized epilepsies and the Lennox-Gastaut Syndrome. The Lennox-Gastaut syndrome is a severe form of epilepsy typically seen in childhood and is considered one of the most difficult epileptic syndromes to treat. Results of these studies may be presented at national meetings in the next year or two.

2. Is topiramate synthetic or derived from a natural substance? How was it discovered?

Topiramate is a synthetic compound developed by the Johnson & Johnson Pharmaceutical Research Institute. Its effectiveness in epilepsy was discovered through the collaborative program of the National Institutes for Health Epilepsy Branch. The Epilepsy Branch program allows corporations to submit compounds that might be effective in epilepsy to be evaluated in a series of animal tests and compared to standard antiepileptic drugs. This program has screened thousands of compounds over the last two decades. Topiramate was one of the compounds found to be highly effective in animal models and so was moved on to testing in humans with epilepsy.

3. Are there any trials planned to compare the efficacy and safety of topiramate with other similar drugs?

Most experts in the field feel that such trials are definitely necessary in order to compare the efficacy and tolerability of these medications. Unfortunately, these comparative trials require large numbers of patients, a tremendous effort to organize, and are extremely costly. It is my understanding that several companies have preliminary plans for such comparative trials. At the present time I am not involved in any of these trials and do not believe that any comparative trials are ongoing in the United States.

4. What is known about the long-term effects of topiramate (Topamax)?

In the database submitted to the FDA consisting of approximately 3,000 patients, there did not seem to be any consistent abnormalities of the function of the liver or bone marrow as seen with some other medications. Some patients at the University of Cincinnati Epilepsy Treatment Center have been on the medication for over eight years without significant problems.

5. Has its safety in children been evaluated?

Trials evaluating topiramate’s safety and effectiveness in children are currently underway. Preliminary data are encouraging; however, we must wait for the final results of these efficacy and safety trials in order to fully determine its role in the treatment of children.

Answer. My experience with valproate [Depakote] has been in adults, in which population it is very well-tolerated and rarely the cause of any significant cognitive problems; it can sometimes cause drowsiness, but this is usually mild and dose-related. You may be interested in a Swiss study by Despland [ref: Schweiz Rundsch Med Prax Oct 1994] that reviewed the literature on valproate use in epilepsy from 1976 to 1994 (the drug has been used in Switzerland since 1967). This author found valproate “to be a remarkably safe and effective antiepileptic drug…in children and adults.”

It is associated with fewer neurologic side effects than other major antiepileptic drugs, and “…had minimal impact on cognitive function and was associated with fewer cognitive and behavioral problems than phenytoin [Dilantin] and phenobarbital.”

Side effects of valproate can include weight gain, mild GI effects, tremor, and hair loss, but these may respond to dosage adjustment or other measures. Keep in mind, also, that seizures themselves often leave childen feeling helpless, scared, and “different” from other kids, so that the valproate may, indeed, be an important ally in your daughter’s quality of life. I would suggest, in any case, that you discuss the question of long-term effects on learning and creativity with your daughter’s physician.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Carbamazepine). A white or almost white crystalline powder. It exhibits polymorphism. Very slightly soluble in water; sparingly soluble in alcohol and in acetone; freely soluble in dichloromethane. Store in airtight containers.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Carbamazepine). A white or off-white powder. Practically insoluble in water; soluble in alcohol and in acetone. Store in airtight containers.

Incompatibility. Carbamazepine suspension should be mixed with an equal volume of diluent before nasogastric use as undiluted suspension is adsorbed onto PVC nasogastric tubes.

The FDA have received a report of a patient who passed an orange rubbery mass in his faeces the day after taking a carbamazepine suspension (Tegretol; Novartis, USA) followed immediately by chlorpromazine solution (Thorazine; GSK, USA). Subsequent testing showed that mixing the same carbamazepine suspension with a thioridazine hydrochloride solution (Mellaril; Novartis, USA) also resulted in the precipitation of a rubbery orange mass.

Stability. FDA studies indicate that carbamazepine tablets could lose up to one-third of their effectiveness if stored in humid conditions. This appears to be due to formation of a dihydrate form which leads to hardening of the tablet and poor dissolution and absorption. As the dihydrate has also been detected after storage under ambient conditions some suggest that storage with silica gel sachets may be necessary to avoid physical deterioration of carbamazepine tablets.

Adverse Effects

Fairly common adverse effects of carbamazepine, particularly in the initial stages of therapy, include dizziness, drowsiness, and ataxia. Gastrointestinal disturbances, such as nausea and vomiting, and mild skin reactions are also common. These effects may be minimised by starting therapy with a low dose. Drowsiness and disturbances of cerebellar and oculomotor function (with ataxia, nystagmus, and diplopia) are also symptoms of excessive plasma concentrations of carbamazepine, and may disappear spontaneously with continued treatment or at reduced or divided dosage. Although rare, generalised erythematous rashes can be severe and treatment may have to be withdrawn. Photosensitivity reactions, urticaria, alopecia, exfoliative dermatitis, toxic epidermal necrolysis, erythema multi-forme and Stevens-Johnson syndrome, and SLE (but see below) have also been reported. Transient leucopenia is common and usually resolves with continued therapy; however, rarer blood disorders reported include agranulocytosis, aplastic anaemia, eosinophilia, persistent leucopenia, leucocytosis, thrombocytopenia, and purpura. Lymphadenopathy, splenomegaly, pneumonitis, abnormalities of liver and kidney function, hepatitis, and cholestatic jaundice have occurred. Some or all of these symptoms as well as fever and rashes may represent a generalised hyper-sensitivity reaction to carbamazepine. Gastrointestinal symptoms reported to be less common include dry mouth, abdominal pain, anorexia, and diarrhoea or constipation. Hyponatraemia, and sometimes oedema, have occurred. Other adverse effects reported include paraesthesia, headache, arrhythmias and heart block, heart failure, impotence, male infertility, gynaecomastia, galactorrhoea, and dystonias and dyskinesias with asterixis. Rectal use has resulted in local irritation. Overdosage may be manifested by many of the adverse effects listed above, especially those on the CNS, and may result in stupor, coma, convulsions, respiratory depression, and death.

In rare cases, carbamazepine has been reported to exacerbate seizures in patients suffering from mixed-type epilepsy — see Precautions, below. Congenital malformations have been reported in infants born to women given carbamazepine during pregnancy.

Effects on the blood. Occasional reports of fatal haematological reactions associated with carbamazepine led the manufacturers to recommend extensive blood monitoring during therapy. However, because of the rarity of such reactions these recommendations were questioned and the manufacturers subsequently modified their guidelines (see Precautions, below). Case reports and studies of carbamazepine’s haematological effects have been reviewed. The incidence of haematological reactions to carbamazepine has been estimated to range between 1:10 800 and 1:38 000 per year while one group reported the rate of bone marrow suppression to be between 1:10 000 and 1:50 000 cases. The incidence of aplastic anaemia has been calculated to be 1:200 000 per year. Another investigator indicated that 2.2 deaths per million exposures were associated with aplastic anaemia and agranulocytosis. However, of 27 reports of aplastic anaemia (16 fatal) associated with carbamazepine many were found to have had co-incidental disease or were receiving multiple-drug therapy. Benign or clinically insignificant leucopenia has occurred, usually during the first 3 months of treatment, in about 12% of children and 7% of adults but in most patients this resolved despite continuation of therapy. Mild transient thrombocytopenia has occurred in about 2% of patients; transient eosinophilia has also occurred.

The reviewers suggested that all patients should have blood and platelet counts before treatment. Patients with low white cell and neutrophil counts were at risk of developing leucopenia and should be monitored every 2 weeks for the first 1 to 3 months. If counts fell further the dose should be reduced or treatment stopped. It should be noted that the BNF doubts the practical value of routine monitoring: in particular, aplastic anaemia, agranulocytosis, and thrombocytopenia have a rapid onset and are best monitored by instructing the patient to report warning symptoms (see Precautions, below).

For a discussion of the effects of antiepileptics, including carbamazepine, on serum folate, see Folic Acid Deficiency, under Phenytoin.

Effects on bone. For the effects of antiepileptics including carbamazepine on bone and on calcium and vitamin D metabolism, see under Phenytoin.

Effects on electrolytes. There have been reports of hyponatraemia or water intoxication in patients receiving carbamazepine. One review states that although hyponatraemia occurs in 10 to 15% of patients taking carbamazepine, it is seldom symptomatic or severe enough to cause fluid retention. However, care should be taken to distinguish the confusion, dizziness, nausea and headache of water intoxication from the central and gastrointestinal effects of the drug. The mechanism is uncertain; although some studies suggest an increase in secretion of antidiuretic hormone in subjects given carbamazepine, others indicate the reverse, and the fact that the hyponatraemic effects of carbamazepine can be partly reversed by demeclocycline is cited as evidence for an effect on the kidney, either directly upon the distal tubule or by increasing sensitivity to the effects of antidiuretic hormone. Risk factors for developing carbamazepine-induced hyponatraemia include age of over 40 years, use of sodium-depleting drugs, and low pre-treatment plasma-sodium concentrations; it is unclear whether this adverse effect is dose-related.

Effects on the endocrine system. Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction — see under Interactions of Levothyroxine. For mention of the effects of antiepileptics on sexual function in male epileptic patients, see under Phenytoin.

Effects on the eyes. On rare occasions lenticular opacities have been associated with carbamazepine. Retinotoxicity associated with long-term carbamazepine use has been reported in 2 patients. After stopping the drug visual function and retinal morphological changes improved. A review of the effect of antiepileptics on the eyes noted that despite reports of colour vision disturbances and impaired contrast sensitivity associated with carbamazepine therapy, studies in healthy subjects had shown conflicting results.

Effects on the heart. A review of reports of cardiac effects associated with carbamazepine revealed that patients could be divided into 2 distinct groups based on their symptoms. One group consisted mainly of young patients with non life-threatening sinus tachycardia after carbamazepine overdosage while the other group was composed of older female patients with potentially life-threatening bradycardia or AV block associated with therapeutic or modestly raised blood concentrations of carbamazepine. However, there has been a report of fatal syncope, probably due to ventricular asystole, in a 20-year-old patient. Carbamazepine should be avoided in patients who develop conduction abnormalities, or who have conditions such as myotonic dystrophy in which conduction abnormalities are likely. Elevation of ventricular and atrial stimulation thresholds was reported in a 59-year-old man with a permanent dual-chamber pacemaker, 5 days after starting carbamazepine for mania. For a report of carbamazepine producing fatal eosinophilic myocarditis, see under Hypersensitivity, below.

Effects on the immune system. There have been reports of hypogammaglobulinaemia associated with carbamazepine. The authors of one report stated that this was a recognised but rare adverse effect of carbamazepine and noted that the UK CSM had 9 reports on file of hypogammaglobulinaemia or gamma-globulin abnormalities related to the use of carbamazepine.

Effects on the liver. A report in 1990 commented that of 499 reports of unwanted effects of carbamazepine on the liver about half comprised only abnormal results from liver function tests; however, deaths have occurred from liver failure or hepatic necrosis. Reversible vanishing bile duct syndrome has been associated with long-term use of carbamazepine. Hepatotoxicity may form part of the antiepileptic hypersensitivity syndrome reported with carbamazepine (see below).

Effects on mental function. Carbamazepine therapy has been associated in a few patients with the development of acute psychotic and paranoid symptoms and with phobias and mood disturbances, including mania and melancholia. One case of acute paranoid psychosis was associated with the addition of carbamazepine to long-term sodium valproate therapy in a patient subsequently diagnosed as having a schizotypal personality. For nonconvulsive status epilepticus associated with carbamazepine presenting as psychiatric disorders, see under Effects on the Nervous System, below. The problems of antiepileptic therapy adversely affecting cognition and the risk of mood disorders, including suicidal ideation.

Effects on the nervous system. ASEPTIC MENINGITIS. Aseptic meningitis has developed in a patient with Sjogren’s syndrome given carbamazepine. It abated when the drug was withdrawn and symptoms recurred on rechallenge. Aseptic meningitis has also been associated with carbamazepine in patients without Sjogren’s syndrome.

ENCEPHALOPATHY. Carbamazepine-induced encephalopathy with symptoms resembling Creutzfeldt-Jakob disease was reported in a 71-year-old man; the cognitive decline, bradykinesia, tremor, and abnormal EEG improved on stopping carbamazepine.

EXTRAPYRAMIDAL EFFECTS. Although carbamazepine has been associated with extrapyramidal adverse effects, it has also been tried in the treatment of movement disorders — see under Uses and Administration, below.

STATUS EPILEPTICUS. Nonconvulsive status epilepticus, misdi-agnosed as behavioural and psychiatric disorders, was reported to have been precipitated by carbamazepine in 2 patients; seizure control and behaviour improved when carbamazepine was stopped and replaced with valproate.

Effects on the skin. Rashes occurring with carbamazepine may form part of an antiepileptic hypersensitivity syndrome (see below). In a report, erythema multiforme occurred when a generic formulation was given instead of a proprietary brand of carbamazepine. Skin lesions resolved when the patient stopped taking the generic formulation and did not recur when the proprietary brand was restarted. In another report, a 6-year-old boy developed Stevens-Johnson syndrome 5 weeks after carbamazepine was added to valproic acid, which he had been taking as sole antiepileptic therapy for several weeks. Carbamazepine was stopped and the patient eventually made a full recovery; valproic acid was continued because it was not thought to be the causative agent (but see under Valproate). Fatal toxic epidermal necrolysis has been seen when carbamazepine was given to a patient who had previously had Stevens-Johnson syndrome during carbamazepine treatment. Pseudo mycosis fungoides with lymphoid cell infiltration of the dermis and raised liver enzymes has been reported in a 54-year-old man who was taking carbamazepine for seizures; symptoms resolved within about 2 weeks of stopping therapy.

For a warning that severe skin reactions may be more likely in patients of certain genotypes, see Skin Reactions, under Precautions, below. For the relative incidence of skin reactions to different antiepileptics, see under Phenytoin.

Hypersensitivity. An antiepileptic hypersensitivity syndrome, comprising fever, rash, and lymphadenopathy and less commonly hepatosplenomegaly and eosinophilia, has been associated with some antiepileptic drugs including carbamazepine. Although a literature search was only able to find 20 published cases to 1986, 22 cases had been reported to the Australian Adverse Drug Reactions Advisory Committee between 1975 and 1990. Some have estimated the incidence at 1 in 1000 to 1 in 10 000 new exposures to aromatic antic onvulsants, but the true incidence is uncertain due to variations in presentation and reporting. Most reactions occurred within 30 days of the start of carbamazepine treatment, although symptoms may occur anywhere between 1 and 8 weeks after exposure. In previously sensitised individuals the reactions may occur within 1 day of re-challenge. The potential for cross-reactivity between carbamazepine, phenobarbital, and phenytoin is approximately 75%, and patients who develop the syndrome, and their close relatives, should be warned of the risk associated with use of these antiepileptics.

Carbamazepine antibodies were detected in an 8-year-old child who developed symptoms of serum sickness including fever, skin rash, oedema, and lymphadenopathy during treatment with carbamazepine Hypersensitivity to carbamazepine with multisystem effects clinically resembling a mononucleosis syndrome was reported in a 15-year-old boy 2 weeks after starting mono-therapy with carbamazepine; all symptoms resolved on stopping carbamazepine and giving prednisone. There have been other cases of an infectious mononucleosis syndrome associated with hypersensitivity to carbamazepine, leading the authors to suggest that reactivation of human herpesvirus 6 or 7 infection is a cofactor and an early manifestation of carbamazepine hypersensitivity syndrome; however, further studies are warranted.

A hypersensitivity reaction producing fatal eosinophilic myocarditis has been reported in a 13-year-old patient; initial symptoms mimicked scarlet fever. A 21-year-old woman developed fatal fulminant hepatic failure after taking carbamazepine for about 2 months; she had presented with initial symptoms of fever, breathlessness, bloody diarrhoea, and a spreading rash.

Generalised erythroderma with renal, hepatic, and bone-marrow failure (characterised by hypercellularity and dyserythropoiesis) has been reported in an 81-year-old man 50 days after starting carbamazepine therapy. Symptoms recurred following an inadvertent rechallenge. The presence of underlying lymphoproliferative disease may have potentiated the severe drug-induced reaction.

If the antiepileptic hypersensitivity syndrome develops, immediate withdrawal of carbamazepine is recommended. In most cases this is all that is required and does not seem to precipitate an increase in seizures, compared with gradual withdrawal.

Successful desensitisation to carbamazepine was reported in a 12-year-old boy who was sensitive to carbamazepine, sodium valproate, and phenytoin. Starting with a low dose of carbamazepine 100 micrograms daily the dose was doubled, generally every 2 days, up to 100 mg daily. The dose was then gradually increased over 4 weeks to a maintenance dose of 200 mg twice daily. The same technique was used to desensitise 7 patients, all of whom developed dramatic skin rashes when first exposed to carbamazepine. Carbamazepine therapy in full doses was achieved without problem in about 6 weeks. Some consider that desensitisation is not to be recommended in patients with full-blown antiepileptic hypersensitivity syndrome.

Sudden unexplained death in epilepsy. Sudden unexplained death in epilepsy (SUDEP), a common cause of seizure-related mortality in patients with chronic epilepsy, has been reviewed. Risk factors may include early onset of epilepsy, frequent generalised tonic-clonic seizures, intractability, frequent medication changes, and polytherapy. Carbamazepine use has also been implicated but the evidence was considered to be tenuous although frequent dose change resulting in plasma-carbamazepine levels outside the therapeutic range was found to be an independent risk factor. Although the FDA in the USA had required data about the specific risk of SUDEP to be included in the prescribing information for the newer antiepileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, and zonisamide, some commentators consider that none of these antiepileptics have shown an associated change in the risk of SUDEP. It has been suggested that the incidence of SUDEP is related to the disease rather than a specific drug effect.

Systemic lupus erythematosus. A review of 80 cases of SLE-like syndromes associated with carbamazepine that had been reported to the manufacturer suggested that the frequency of reports (less than 0.001 %) was below that for idiopathic lupus. There have been subsequent reports of late-onset SLE occurring after up to 8 years of carbamazepine therapy without previous adverse effects. The symptoms due to carbamazepine usually resolved on stopping treatment.

Treatment of Adverse Effects

In the treatment of carbamazepine overdosage repeated doses of activated charcoal may be given orally to adults and children who have ingested more than 20 mg/kg; the aim is not only to prevent absorption but also to aid elimination. Gastric lavage may be considered if undertaken within 1 hour of ingestion. Supportive and symptomatic therapy alone may then suffice, with particular attention to correcting hypoxia and hypotension; haemoperfusion has been suggested for severe poisoning. If there is doubt about the diagnosis, or if multiple-dose oral activated charcoal is being considered, then monitoring plasma-carbamazepine concentration can be useful; it may also help determine when carbamazepine therapy should be restarted. See also Overdosage, below.

Hypersensitivity reactions. For reference to successful desensitisation in patients sensitive to carbamazepine, see Hypersensitivity under Adverse Effects, above.

Overdosage. Carbamazepine poisoning and its management has been reviewed. Management is primarily supportive, with prompt attention to airway management and seizure control. Activated charcoal should be given; although multiple-dose activated charcoal has been recommended for carbamazepine overdosage, care must be taken to protect the airway since carbamazepine inhibits intestinal motility and there is a significant risk of aspiration. In patients with seizures unresponsive to benzodiazepines phenobarbital should be used; phenytoin is not a drug of choice in this situation. Hypotension is rare, and should be managed with fluid and vasopressor support; hypotension with refractory seizures should be treated aggressively as it has led to permanent neurological disability and death. Haemodialysis or haemoperfusion may be warranted in patients with unstable cardiac status or status epilepticus complicated by bowel hypomotility and unresponsive to more conventional therapy. However, a report of the use of plasmapheresis in the treatment of an acute overdose of carbamazepine concluded that plasmapheresis removed a very small percentage of the total body load of carbamazepine and could not be recommended. As carbamazepine is highly protein-bound, albumin-enhanced continuous venovenous haemodialysis was tried and found to be effective in the treatment of a 10-year-old child after ingestion of 1.4 g of carbamazepine.

For a further review of the features and management of poisoning with some antiepileptics, including carbamazepine, see under Phenytoin.

Precautions

Carbamazepine should be avoided in patients with AV conduction abnormalities. It should not be given to patients with a history of bone marrow depression. Carbamazepine should be given with caution to patients with a history of blood disorders or haematological reactions to other drugs, or of cardiac, hepatic, or renal disease. Patients or their carers should be told how to recognise signs of blood, liver, and skin toxicity and they should be advised to seek immediate medical attention if symptoms such as fever, sore throat, rash, mouth ulcers, bruising, or bleeding develop. Carbamazepine should be withdrawn, if necessary under cover of a suitable alternative antiepileptic, if severe, progressive, or symptomatic leucopenia develops, or if symptoms suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis occur. Licensed product information recommends blood counts and hepatic and renal-function tests before starting carbamazepine therapy and periodically during treatment, but the BNF considers the evidence of practical value unsatisfactory. Clinical monitoring is of primary importance throughout treatment. Some patients of Asian ancestry may be at increased risk of severe skin reactions; for recommendations that such patients’ genotype should be tested before beginning carbamazepine see Skin Reactions, below.

Care is required in identifying patients with mixed seizure disorders that include generalised absence or atypical absence seizures, who may be at risk of an increase in generalised seizures if given carbamazepine. Carbamazepine may also exacerbate absence and myoclonic seizures.

Care is required when withdrawing carbamazepine therapy — see also Uses and Administration, below. Since carbamazepine has mild antimuscarinic properties caution should be observed in patients with glaucoma or raised intra-ocular pressure; scattered punctate lens opacities occur rarely with carbamazepine and it has been suggested that patients should be examined periodically for eye changes.

Abuse. Overdosage requiring hospital admission has been reported after abuse of carbamazepine.

Breast feeding. The American Academy of Pediatrics considers that carbamazepine is usually compatible with breast feeding, although there have been reports of transient cholestatic hepatitis in breast-fed infants.

For further comment on antiepileptic therapy and breast feeding.

Driving. For comment on antiepileptic drugs and driving.

Multiple sclerosis. Exacerbation of symptoms of multiple sclerosis has been reported in 5 patients on starting carbamazepine therapy for paroxysmal neurological symptoms and pain. There was a close temporal association between starting carbamazepine and worsening of symptoms, followed by resolution when it was stopped. A 3-year follow-up observational study found that out of 36 multiple sclerosis patients who received carbamazepine therapy, 12 developed neurological adverse effects that mimicked a relapse. The authors concluded that carbamazepine was associated with higher rates of adverse effects and stopping therapy than gabapentin or lamotrigine.

Porphyria. Carbamazepine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Pregnancy. For comments on the management of epilepsy during pregnancy.

There is an increased risk of neural tube defects in infants exposed in utero to antiepileptics including carbamazepine; syndromes such as craniofacial and digital abnormalities and, less commonly, cleft lip and palate have also been described. Exposure to carbamazepine has been calculated to carry a 1% risk of spina bifida. A ‘carbamazepine syndrome’ characterised by facial dysmorphic features and mild mental retardation has been described; such syndromes are now often seen as aspects of a single ‘fetal antiepileptic syndrome’. There is also a risk of neonatal bleeding.

Skin reactions. The FDA has issued a warning that severe and potentially fatal skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis are significantly more common in patients with the HLA allele HLA-B*1502, which occurs almost exclusively in persons of Asian ancestry. They recommend that patients with such ancestry should be screened for the presence of this allele before beginning therapy with carbamazepine, and if present the risks and benefits of therapy should be considered with particular care; those who have already taken carbamazepine for more than a few months without developing skin reactions are, however, at low risk of them ever developing, regardless of genotype. Similar recommendations have since been issued in the UK by the MHRA.

Interactions

There are complex interactions between antiepileptics and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy. The metabolism of carbamazepine is reported to be less susceptible to inhibition by other drugs than that of phenytoin but a few drugs are reported to inhibit its metabolism by the cytochrome P450 isoenzyme CYP3A4, resulting in raised plasma concentrations and associated toxicity. Conversely, drugs that induce CYP3A4 may increase the metabolism of carbamazepine, leading to reduced plasma concentrations and potentially a decrease in therapeutic effect. Licensed product information advises that, in such situations, the dose of carbamazepine should be adjusted accordingly and/or the plasma concentrations monitored.

Carbamazepine is itself a hepatic enzyme inducer, and induces its own metabolism as well as that of a number of other drugs including some antibacterials (notably, doxycycline), anticoagulants, and sex hormones (notably, oral contraceptives). Carbamazepine and phenytoin may also mutually enhance one another’s metabolism. The metabolism of carbamazepine is similarly enhanced by enzyme inducers such as phenobarbital.

Alcohol. Alcohol may exacerbate the CNS adverse effects of carbamazepine and vice versa.

Analgesics. Dextropropoxyphene has been reported to cause substantial elevation of serum-carbamazepine concentrations and carbamazepine toxicity, probably due to inhibition of carbamazepine metabolism.

Use of enzyme-inducing antiepileptics such as carbamazepine affects the threshold for use of antidote in the treatment of paracetamol poisoning. For the effect of carbamazepine on tramadol.

Anthelmintics. For the effect of carbamazepine on mebendazole and praziquantel.

Antibacterials. The antimycobacterial isoniazid and macrolides such as clarithromycin, erythromycin, and troleandomycin have been reported to cause substantial elevations of serum concentrations of carbamazepine and symptoms of carbamazepine toxicity. Clarithromycin has also been reported to have caused hyponatraemia when added to carbamazepine therapy in a 30-year-old epileptic woman. Rifampicin and isoniazid decreased the serum concentrations of carbamazepine in a 44-year-old woman being treated for bipolar disorder and suspected tuberculosis, resulting inhypomania.

Use of carbamazepine with isoniazid may increase the risk of isoniazid-induced hepatotoxicity.

Anticoagulants. For the effect of carbamazepine on warfarin.

Antidepressants. As with all antiepileptics, antidepressants may antagonise the antiepileptic activity of carbamazepine by lowering the convulsive threshold.

Antidepressants such as desipramine, fluoxetine, fluvoxamine, nefazodone (and perhaps trazodone), and viloxazine increase plasma concentrations of carbamazepine and may induce carbamazepine toxicity. A toxic serotonin syndrome has been reported in a patient who received fluoxetine with carbamazepine. Severe neurotoxicity reported during therapy with lithium and carbamazepine may be due to a synergistic effect as reports indicate that either drug was tolerated when not given with the other and measured plasma concentrations did not indicate overdosage. However, toxic serum concentrations of lithium have also been reported, due to carbamazepine-induced acute renal failure.

Because of the structural similarity to tricyclic antidepressants licensed product information suggests that carbamazepine should not be given to patients taking an MAOI or within 14 days of stopping such treatment.

St John’s wort has been shown to induce several drug metabolising enzymes and consequently it has been suggested that it might reduce the blood concentrations of carbamazepine leading to an increased risk of seizure. However, a multiple-dose study in healthy subjects reported that St John’s wort had no significant effect on the pharmacokinetics of carbamazepine or its active epoxide metabolite.

For the effect of carbamazepine on antidepressants, see Bupropion, Fluoxetine, Mianserin, Nefazodone, and Amitriptylme.

Antiepileptics. Interactions of varying degrees of clinical significance have been reported between carbamazepine and other antiepileptics.

Serum concentrations of carbamazepine are reported to be reduced by phenobarbital, but without loss of seizure control; this reduction is probably due to induction of carbamazepine metabolism.

The interaction with phenytoin is somewhat more complex and the consequences vary. There is evidence of a lowering of serum-carbamazepine concentrations, presumably due to induction of metabolism by phenytoin; in return carbamazepine has been reported both to lower and increase serum phenytoin. Again, these reports do not indicate a loss of seizure control or toxicity resulting from the interaction, although the possibility presumably exists. Gradually withdrawing phenytoin from 2 patients who had been receiving carbamazepine and phenytoin resulted in a dramatic increase in plasma-carbamazepine concentrations; one patient exhibited neurotoxic symptoms. The authors recommended that plasma-carbamazepine monitoring should be carried out whenever phenytoin is withdrawn in patients taking these two drugs together.

Valproic acid produces an increase in serum concentrations of the active epoxide metabolite of carbamazepine. This is usually attributed to inhibition of its hydrolysis by epoxide hydrolase, although an additional proposed mechanism is inhibition of the glucuronidation of carbamazepine-10,11-transdiol, the compound to which the epoxide is converted under normal circumstances. Adverse effects may be a problem if unusually high epoxide concentrations arise but, in general, this interaction is of limited clinical significance. However, valpromide, the amide derivative, is a much more powerful inhibitor of epoxide hydrolase than valproic acid, and therefore produces greater increases in epoxide plasma concentrations with clinical signs of toxicity. Switching from sodium valproate to valpromide has resulted in toxicity in patients also receiving carbamazepine. Neither valproic acid nor valpromide have any significant effect on plasma concentrations of the parent drug, carbamazepine. Valnoctamide, an isomer of valpromide, appears to be at least as potent as valpromide in inhibiting the elimination of the epoxide metabolite of carbamazepine. Valnoctamide has been used as an anxio-lytic, although it does appear to possess some antiepileptic activity. For a report of acute psychosis associated with the combination of carbamazepine and sodium valproate, see Effects on Mental Function under Adverse Effects, above. For the effects of carbamazepine on valproate. Of the other antiepileptics stiripentol has been reported to inhibit carbamazepine metabolism, while felbamaie causes a significant fall in plasma-carbamazepine concentrations which may require an increase in the dose of carbamazepine. However, another study has shown a significant increase in plasma-concentrations of the active epoxide metabolite, which may counteract the effect of the decrease in plasma concentrations of the parent compound. Neurotoxicity has been seen after use of carbamazepine with lamotrigine. The suggestion that this was due to raised concentrations of carbamazepine epoxide was not confirmed in a controlled study in which the 2 drugs were used together safely and effectively. Toxic epidermal necrolysis occurred when lamotrigine was added to carbamazepine therapy in a patient who had been taking carbamazepine for 3 years; symptoms resolved progressively when both drugs were stopped. Symptoms of carbamazepine toxicity have been reported when levetiracetam was added to carbamazepine therapy; this interaction appeared to be due to a pharmacodynamic mechanism as blood levels of carbamazepine and its epoxide metabolite were not altered. There have also been reports of carbamazepme toxicity when topiramate was added to carbamazepine therapy; symptoms resolved when the dose of carbamazepine was reduced. Fulminant liver failure has been reported after an increase in adjunctive topiramate dose in a patient maintained on carbamazepine for 2 years without any signs of hepatotoxicity. The GABA agonist progabide has increased plasma concentrations of the epoxide metabolite, probably due to inhibition of microsomal epoxide hydrolase. Vigabatrin is reported to increase the clearance of carbamazepine by about 35%.

For the effects of carbamazepine on ethosuximide, on lamotrigine, on oxcarbazepine, onprimidone, on tiagabine, and on topiramate. For interactions with benzodiazepines, see below.

Antifungals. Malaise, myoclonus, and trembling were reported to have developed in a patient receiving carbamazepine after the addition of‘miconazole to therapy. Ketoconazole was associated with a significant increase in plasma-carbamazepine concentrations in 8 epileptic patients stabilised on carbamazepine; plasma concentrations of the epoxide metabolite were unchanged. A threefold increase in serum-carbamazepine concentrations, reported in a patient after addition of fluconazole to carbamazepine therapy, was asymptomatic; however, carbamazepine toxicity has been reported in 2 patients stabilised on carbamazepine who were given fluconazole. Terbinafine has also been reported to cause possible carbamazepine toxicity. For the effect of carbamazepine on itraconazole.

Antihistamines. Terfenadine and carbamazepine are both highly protein bound and therefore may compete for protein binding sites. An 18-year-old woman receiving carbamazepine as an antiepileptic experienced symptoms of neurotoxicity shortly after starting treatment with terfenadine for rhinitis. The concentration of free carbamazepine in the plasma was higher than normal and returned to normal on stopping terfenadine.

Antimalanals. Chloroquine and mefioquine may antagonise the antiepileptic activity of carbamazepine by lowering the convulsive threshold.

Antiprotozoals. A patient receiving carbamazepine for bipolar disorder developed dizziness, diplopia, and nausea 4 days after the addition of metronidazole for diverticulitis.

Antipsychotics. As with all antiepileptics, antipsychotics may antagonise the antiepileptic activity of carbamazepine by lowering the convulsive threshold.

Increased plasma concentrations of carbamazepine epoxide have been reported to occur during therapy with carbamazepine and loxapine or quetiapine, possibly due to induction of carbamazepine metabolism or inhibition of metabolism of the epoxide. Raised serum concentrations of carbamazepine have also been reported in patients receiving haloperidol.

For the effect of carbamazepine on antipsychotics, see under Chlorpromazine.

Antivirals. Ritonavir inhibits several microsomal liver enzymes and therefore may potentially increase plasma concentrations of carbamazepine. Licensed product information for ritonavir advises that such combinations may require monitoring. Carbamazepine toxicity has been reported after interaction with ritonavir. In one report, the patient was also taking nelfinavir and lopinavir, both of which are substrates and inhibitors of CYP450 isoenzymes.

For the effect of carbamazepine on HIV-protease inhibitors.

Anxiolytics. For a discussion of the potential interaction between carbamazepine and the anxiolytic valnoctamide, an isomer of the antiepileptic valpromide, see Antiepileptics, above. See also Benzodiazepines, below.

Benzodiazepines. The metabolism of benzodiazepines may be enhanced by induction of hepatic drug-metabolising enzymes in patients who have received long-term therapy with carbamazepine; benzodiazepine plasma concentrations are reduced, half-life is shorter, and clearance is increased (see also Antiepileptics, under Interactions of Diazepam). Some benzodiazepines may also affect carbamazepine. One group of workers reported that after addition of clobazam to carbamazepine therapy a dose reduction for the latter was required due to increased blood concentrations. In a later study it appeared that clobazam could produce a moderate increase in the metabolism of carbamazepine. The plasma ratio of metabolites of carbamazepine, including carbamazepine-10,11-epoxide, to parent compound was increased in patients taking clobazam and carbamazepine.

Calcium-channel blockers. Six patients with steady-state carbamazepine concentrations had symptoms of neurotoxicity consistent with carbamazepine intoxication within 36 to 96 hours of the first dose of verapamil In 5 patients, in whom plasma concentrations were measured, there was a mean increase of 46% in total carbamazepine and 33% in free carbamazepine; no effect on the plasma protein binding of carbamazepine was seen. The results suggested that verapamil inhibits the metabolism of carbamazepine to an extent likely to have important clinical repercussions. There has also been a report of a patient in whom diltiazem, but not nifedipine, precipitated carbamazepine neurotoxicity.

For the effect of carbamazepine on dihydropyridine calcium-channel blockers, see under Nifedipine.

Ciclosporin. For the effect of carbamazepine on ciclosporin.

Corticosteroids. For the effect of carbamazepine on corticosteroids.

Danazol. Use of danazol with carbamazepine has been reported to increase the half-life and decrease clearance of carbamazepine, resulting in increases in plasma-carbamazepine concentrations of up to 100% and resultant toxicity in a number of patients.

Dermatological drugs. Addition of isotretinoin to regular carbamazepine therapy appeared to reduce plasma concentrations of the latter and its active epoxide metabolite. However, no adverse events were noted during a 6-week period of treatment with isotretinoin. Nonetheless, licensed product information for carbamazepine recommends that the levels of carbamazepine are monitored if both are used together.

Diuretics. There has been a report of symptomatic hyponatrae-mia associated with use of carbamazepine and a diuretic (hydrochlorothiazide or furosemide — see under Interactions of Furosemide). Carbamazepine serum concentrations are increased by acetazolamide.

Gastrointestinal drugs. Cimetidine is reported to produce a transient increase in plasma-carbamazepine concentrations, with a return to pre-cimetidine values within about a week; some increase in adverse effects was seen. Ranitidine does not appear to affect plasma-carbamazepine concentrations. Neurotoxicity has been seen in a patient receiving carbamazepine and metoclopramide

Grapefruit juice. The bioavailability and plasma concentrations of carbamazepine have been reported to be increased by grapefruit juice.

Levothyroxine. For the effect of carbamazepine on levothyroxine.

Neuromuscular blockers. For the effect of carbamazepine on suxamethonium and on competitive neuromuscular blockers, see under Atracurium.

Sex hormones. For the effect of carbamazepine on oral contraceptives and for the possible effect on tibolone. See also Danazol, above.

Theophylline. A decrease in serum-carbamazepine concentrations of about 50% was reported in an epileptic patient given theophylline. The patient experienced seizures and the proposed mechanism was that theophylline had increased the metabolism of carbamazepine.

For the effect of carbamazepine on theophylline.

Vitamins. The plasma concentration of carbamazepine was increased in 2 patients given nicotinamide.

For the effect of antiepileptics, including carbamazepine, on vitamin D concentrations, see Effects on Bone under the Adverse Effects of Phenytoin.

Pharmacokinetics

Carbamazepine is slowly and irregularly absorbed from the gastrointestinal tract and has a bioavailability of 85 to 100%. It is extensively metabolised in the liver, notably by the cytochrome P450 isoenzymes CYP3 A4 and CYP2C8. One of its primary metabolites, carbamazepine-10,11-epoxide, is also active. Carbamazepine is excreted in the urine almost entirely in the form of its metabolites; some are also excreted in faeces. Elimination of carbamazepine is reported to be more rapid in children and accumulation of the active metabolite may often be higher than in adults. Carbamazepine is widely distributed throughout the body and is about 70 to 80% bound to plasma proteins. It induces its own metabolism so that the plasma half-life may be considerably reduced after repeated dosage. The mean plasma half-life of carbamazepine on repeated dosage is about 12 to 24 hours; it appears to be considerably shorter in children than in adults.

Moreover, the metabolism of carbamazepine is readily induced by drugs that induce hepatic microsomal enzymes (see Interactions, above).

Monitoring of plasma concentrations may be performed when clinically indicated and the therapeutic range of total plasma-carbamazepine is usually quoted as being about 4 to 12 micrograms/mL (17 to 50 micromoles/litre), although this is subjectto considerable variation. It has been suggested by some, but not all investigators, that measurement of free carbamazepine concentrations in plasma may prove more reliable, and concentrations in saliva or tears, which contain only free carbamazepine, have also been measured.

Carbamazepine crosses the placental barrier and is distributed into breast milk.

The pharmacokinetics of carbamazepine are affected by use with other antiepileptics (see under Interactions, above).

Uses and Administration

Carbamazepine is a dibenzazepine derivative with antiepileptic and psychotropic properties. It is used to control secondarily generalised tonic-clonic seizures and partial seizures, and in some primary generalised seizures. Carbamazepine is also used in the treatment of trigeminal neuralgia and has been tried with variable success in glossopharyngeal neuralgia and other severe pain syndromes associated with neurological disorders such as tabes dorsalis and multiple sclerosis. Another use of carbamazepine is in the management of bipolar disorder unresponsive to lithium.

In the treatment of epilepsy, the dose of carbamazepine should be adjusted to the needs of the individual patient to achieve adequate control of seizures; this usually requires total plasma-carbamazepine concentrations of about 4 to 12 micrograms/mL (17 to 50 micromoles/litre). A low initial dose of carbamazepine is recommended to minimise adverse effects. The suggested initial oral dose is 100 to 200 mg once or twice daily gradually increased by increments of up to 200 mg daily every week to a usual maintenance dose of 0.8 to 1.2 g daily in divided doses; up to 2 g daily may occasionally be necessary. For details of doses in children, see below.

Oral carbamazepine is usually given in divided doses 2 to 4 times daily. A twice-daily regimen may be associated with improved compliance but can produce widely fluctuating plasma-carbamazepine concentrations that lead to intermittent adverse effects. Twice-daily dosage may nonetheless be suitable for patients receiving carbamazepine monotherapy; modified-release formulations can minimise fluctuations in plasma concentration and may also allow effective twice-daily use. Different preparations vary in bioavailability and it may be prudent to avoid changing the formulation. The time and manner of taking carbamazepine should be standardised for the patient since variations might affect absorption with consequent fluctuations in the plasma concentrations.

Carbamazepine may be given by the rectal route in doses up to a maximum of 250 mg every 6 hours to patients for whom oral treatment is temporarily not possible. The dosage should be increased by about 25% when changing from an oral formulation to suppositories, and it is recommended that the rectal route should not be used for longer than 7 days.

As with other antiepileptics, withdrawal of carbamazepine therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients.

The treatment of trigeminal neuralgia is typically begun with low oral doses, such as 100 mg of carbamazepine twice daily (although up to 200 mg twice daily has been suggested in the UK), and increased gradually as needed to maintain freedom from pain. This is usually at maintenance doses of 400 to 800 mg in divided doses; up to 1.2 g daily is considered standard maintenance in the USA, while UK licensed product information considers that up to 1.6 g daily may be needed in some patients. When pain relief has been obtained attempts should be made to reduce, and if possible stop, therapy, until another attack occurs.

For the management of bipolar disorder, carbamazepine is given in an initial oral dose of 400 mg daily in divided doses, increased gradually as necessary up to a maximum of 1.6 g daily; the usual maintenance dose range is 400 to 600 mg daily.

Administration. A modified-release formulation of carbamazepine can reduce fluctuations in carbamazepine concentrations, and tolerability and seizure control in patients with epilepsy may be improved. Such formulations should be considered in patients receiving high doses who suffer intermittent adverse effects, and might also permit a reduction to twice-or even, in some patients, once-daily dosage. However, bioavailability appears to be slightly less than conventional preparations and dosage adjustments may be required when changing between formulations.

Administration in children. In the UK, the usual recommended oral dose of carbamazepine for generalised tonic-clonic and partial seizures in children is 10 to 20 mg/kg daily in divided doses. Alternatively the daily dose may be given according to age as follows:

• up to 1 year: 100 to 200 mg

• 1 to 5 years: 200 to 400 mg

• 5 to 10 years: 400 to 600 mg

• 10 to 15 years: 0.6 to 1 g

As with adults, children should be started on a low initial dose of carbamazepine to minimise adverse effects; the BNFC suggests that those aged 1 month to 12 years may initially be given 5 mg/kg at night or 2.5 mg/kg twice daily, increasing by 2.5 to 5 mg/kg every 3 to 7 days as necessary to a usual maintenance dose of 5 mg/kg 2 or 3 times daily. Older children may be given the usual adult dose (see above) although a maximum of 1.8 g daily has been suggested.

The BNFC also states that these doses may be used for the treatment of neuropathic pain and some movement disorders, and for mood stabilisation.

Carbamazepine may be given rectally to children in whom oral treatment is temporarily not possible; the BNFC suggests this route may be used from 1 month of age. Doses should be about 25% greater than the corresponding oral dose, to a maximum of 250 mg, and given up to 4 times daily.

Bipolar disorder. Carbamazepine may be given as an alternative to lithium or valproate in patients with bipolar disorder. Studies of its efficacy have been conflicting; although clearly effective in some patients, at least one early study suggested that short-term benefit was not sustained in the longer term. More recent results have suggested that lithium or valproate are generally more effective, but that carbamazepine may conceivably have a role in patients with nonclassical features. Carbamazepine has also been used with lithium, particularly in patients unresponsive to either drug alone; although there are suggestions that the combination may be more effective than monotherapy, particularly in patients with a history of rapid cycling, it is associated with a potential risk of serious neurotoxicity — see Antidepressants, under Interactions, above. While some commentators have suggested that carbamazepine is falling out of favour with specialists prescribing for bipolar disorder, a more recent literature review concluded that it was still a feasible treatment option.

Depression. Carbamazepine has been tried for the augmentation of antidepressant therapy in the treatment of resistant depression. However, such combined therapy may lead to interactions — see also Antidepressants under Interactions, above.

Diabetes insipidus. Cranial diabetes insipidus is usually treated by replacement therapy with antidiuretic hormone (ADH) in the form of desmopressin. Carbamazepine is one of a variety of other drugs that have been tried to promote ADH secretion, although some consider that it is usually ineffective and has unwanted effects. Doses of 200 to 400 mg daily by mouth have been given. See also Effects on Electrolytes under Adverse Effects, above.

Epilepsy. Carbamazepine is one of the drugs of choice for partial seizures with or without secondary generalisation. It has been used for generalised tonic-clonic seizures (although valproate is the drug of choice where these occur in primary generalised epilepsy), but it may exacerbate absence and myoclonic seizures.

Hemifacial spasm. Carbamazepine has been reported to have been of help in the treatment of hemifacial spasm.

Hiccup. For the management of intractable hiccups see under Chlorpromazine. Carbamazepine may be of value for the treatment of neurogenic hiccups such as those that occur in multiple sclerosis. Carbamazepine has also been reported to have been of benefit in 3 patients with diaphragmatic flutter, a rare disorder associated with involuntary contractions of the diaphragm.

Hyperactivity. When drugs are indicated for attention deficit hyperactivity disorder initial treatment is usually with a central stimulant but meta-analysis of a small number of trials has provided evidence that carbamazepine may be effective.

Lesch-Nyhan syndrome. The severe self-mutilation that occurs in patients with Lesch-Nyhan syndrome has been reported to improve in those given antiepileptics such as carbamazepine.

Movement disorders. Carbamazepine is one of many drugs that have been tried in the symptomatic treatment of chorea; there have been anecdotal reports of benefit in both non-hereditary and hereditary choreas. Carbamazepine is also among the drugs that have been tried in the treatment of dystonias that have not responded to levodopa or antimuscarinics. Although some patients may benefit from carbamazepine, it is not generally recommended because of a relatively low success rate and the possibility of adverse effects. Carbamazepine therapy has also been associated with movement disorders — see Effects on the Nervous System: Extrapyramidal Effects under Adverse Effects, above.

Carbamazepine has also been used in resistant cases of tardive dyskinesia (see under Extrapyramidal Disorders). Although not licensed in the UK for movement disorders in children, the BNFC suggests that carbamazepine may be tried in disorders such as paroxysmal kinesigenic choreoathetosis in doses similar to those used for the treatment of epilepsy (see Administration in Children, above).

Neonatal seizures. Carbamazepine has been tried in the management of neonatal seizures.

Neuropathic pain. As well as being used to ease the pain of trigeminal neuralgia (see below) carbamazepine may be of use in other neuropathic pain including that associated with diabetic neuropathy. A systematic review concluded that about two-fifths of patients who take carbamazepine for neuropathic pain will achieve moderate pain relief, but this was based on small studies. The authors found no evidence that carbamazepine was effective for acute pain.

Carbamazepine has also been tried in an attempt to prevent the painful sensory neuropathy associated with oxaliplatin treatment; results of preliminary studies have been conflicting. Although not licensed in the UK for neuropathic pain in children, the BNFC suggests that carbamazepine may be tried in doses similar to those used for the treatment of epilepsy (see Administration in Children, above).

Nocturnal enuresis. Carbamazepine has been reported to be of benefit in the treatment of primary nocturnal enuresis; a dose of 200 mg at night for 15 nights markedly decreased the frequency of bed-wetting episodes in 8 children.

For the conventional management of nocturnal enuresis see site.

Psychiatric disorders. Carbamazepine has psychotropic properties and has been tried in the management of several psychiatric disorders, particularly in patients with bipolar disorder (see above). Carbamazepine has also been used with mixed results in various disorders for the control of symptoms such as agitation, aggression, and rage (see Disturbed Behaviour). It may produce modest benefit when used as an adjunct to antipsychot-ics in the management of refractory schizophrenia but any improvement appears to be related to its mood stabilising effect. However, a more recent systematic review, albeit based on small studies, found carbamazepine to have no significant benefit either as monotherapy or as an adjunct to antipsychotics; the authors considered that further randomised studies may be warranted. Carbamazepine also has the potential to reduce serum concentrations of antipsychotics, resulting in clinical deterioration (see under Interactions for Chlorpromazine). Carbamazepine has also been tried in post-traumatic stress disorder.

Restless legs syndrome. The aetiology of restless legs syndrome (see Sleep-associated Movement Disorders) is obscure and treatment has been largely empirical. In a double-blind study involving 174 patients carbamazepine appeared to be more effective than placebo. Oxcarbazepine has been reported to be of benefit in restless legs syndrome induced by paroxetine.

Tinnitus. Treatment of tinnitus is difficult, and many drugs have been tried. Although carbamazepine has been reported to be effective in some patients, it is rarely used because of its adverse effects.

Trigeminal neuralgia. Carbamazepine is the drug of choice in the treatment of the acute stages of trigeminal neuralgia. Satisfactory pain relief may be achieved in 70% or more of patients, although increasingly larger doses may be required and adverse effects can be troublesome.

Withdrawal syndromes. Carbamazepine has been tried in the prophylaxis and treatment of various withdrawal syndromes. Reduction in cocaine use associated with carbamazepine treatment was found in one short-term controlled study, although a systematic review of data from later studies concluded that there was no evidence to support the use of carbamazepine in the treatment of cocaine dependence. It has been reported to be of benefit in some patients during benzodiazepine withdrawal but such adjunct therapy is not usually indicated. Carbamazepine has been shown to be effective in the treatment of symptoms of the alcohol withdrawal syndrome but as there are limited data on its efficacy in preventing associated delirium tremens and seizures it is usually recommended that it should only be used as an adjunct to benzodiazepine therapy. Carbamazepine has also been studied as an aid in the treatment of alcohol dependence.

Preparations

British Pharmacopoeia 2008; Carbamazepine Tablets;

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Carbamazepine Extended-Re lease Tablets; Carbamazepine Oral Suspension; Carbamazepine Tablets.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Actinerval; Carbagramon; Carbamat; CMP¤; Conformal; Tegretol; Australia: Carbium¤; Tegretol; Teril; Austria: Deleptin; Neurotop; Sirtal; Tegretol; Belgium: Tegretol; Brazil: Carmazin; Convulsan; Karbac¤; Tegretard; Tegretol; Tegrex; Tegrezin; Uni Carbamaz; Canada: Mazepine¤; Novo-Carbamaz; Tegretol; Chile: Carbactol Retard¤; Eposal; Tegretal; Czech Republic: Biston; Neurotop; Tegretol; Timonil; Denmark: Nordotol¤; Tardotol¤; Tegretol; Trimonil; Finland: Neurotol; Tegretol; Trimonil¤; France: Tegretol; Germany: Carba; Carbabeta; Carbadura; Carbaflux; Carbagamma; Carbium; espalepsin; Finlepsin; Fokalepsin; Sirtal; Tegretal; Timonil; Greece: Tegretol; Hong Kong: CP-Carba; Tegretol¤; Teril; Timonil¤; Hungary: Azepal; Finlepsin; Neurotop; Stazepine; Tegretol; Timonil; India: Cizetol; Mazetol; Tegrital; Ireland: Gericarb; Tegretol; Temporol; Israel: Carbi; Tegretol; Teril; Timonil; Italy: Tegretol; Malaysia: Taver; Tegretol; Mexico: Adepril¤; Apobace; Bioneuryl¤; Bioreunil¤; Carbalan; Carbasal; Carbaval; Carbazep; Carbazina; Carpin; Clostedal; Kezepin¤; Neugeron; Neurolep; Sepibest; Tegretol; Trantil¤; Trepina; Volutol¤; Zepiken; Netherlands: Tegretol; Norway: Tegretol; Trimonil; New Zealand: Tegretol; Teril; Portugal: Tegretol; Russia: Carbapin (Карбапин); Finlepsin (Финлепсин); Tegretol (Тегретол); Zeptol (Зептол); South Africa: Carpaz¤; Degranol; Prozine¤; Tegretol; Temporol¤; Singapore: Neurotop; Tegretol; Spain: Tegretol; Sweden: Hermolepsin; Tegretol; Trimonil; Switzerland: Neurotop; Tegretol; Timonil; Thailand: Antafit; Carbatol; Carbazene; Carmapine; Carpine; Carzepine; Mapezine; Panitol; Taver; Tegretol; Zeptol; United Arab Emirates: Fitzecalm; United Kingdom: Arbil; Carbagen; Epimaz; Tegretol; Teril¤; Timonil¤; United States: Atretol¤; Carbatrol; Epitol; Equetro; Tegretol; Teril; Venezuela: Convulex; Gabox; Tanfedin; Tegretol

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Note. The following terms have been used as ‘street names’ or slang names for various forms of clonazepam: K-Pins; Klondike Bars; Klonnies; Klons; La Roche; Pins; R2; R-2; Roaches; Roachies; Roche.

Pharmacopoeias. In China Europe, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Clonazepam). A slightly yellowish, crystalline powder. Practically insoluble in water; slightly soluble in alcohol and in methyl alcohol. Protect from light.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Clonazepam). A light yellow powder having a faint odour. Insoluble in water; slightly soluble in alcohol and in ether; sparingly soluble in acetone and in chloroform. Store in airtight containers. Protect from light.

Sorption. Significant loss of clonazepam (up to 50% over 24 hours) has been reported from solutions infused through PVC tubing; the effect was concentration dependent. The authors recommended that non-PVC tubing should always be used.

Dependence and Withdrawal

As for Diazepam.

Withdrawal. A study of the withdrawal of clonazepam therapy in 40 epileptic children found that 19 had withdrawal symptoms of increased seizure frequency, either alone or with other symptoms but that this effect was transient. Withdrawal seizures and status might become an obstacle to the removal of useless or even deleterious therapy with clonazepam because the transient nature of these effects was not always recognised. Clonazepam should not be used for more than 3 to 6 months and should be stopped if clear and lasting therapeutic benefit could not be shown.

See also Uses and Administration, below.

Adverse Effects, Treatment, and Precautions

As for Diazepam.

The principal adverse effect of clonazepam is drowsiness, which occurs in about 50% of all patients when starting therapy. Salivary or bronchial hypersecretion may cause respiratory problems in children. Thrombophlebitis has been associated with intravenous use and may be avoided by injection into a large vein at a rate not exceeding 500 micrograms/minute. Respiration and blood pressure should also be monitored. Care is required when withdrawing clonazepam therapy — see above.

Breast feeding. Benzodiazepines, such as clonazepam, given to the mother may cause neonatal sedation and breast feeding should be avoided. For comments on antiepileptic therapy and breast feeding.

Driving. For a comment on antiepileptic drugs and driving.

Effects on the endocrine system. Precocious development of secondary sexual characteristics occurred in a 15-month-old girl 2 months after starting treatment with clonazepam 500 micrograms twice daily for convulsions. Symptoms regressed upon withdrawal of clonazepam.

Effects on mental function. For a review of the effects of antiepileptic therapy, including clonazepam, on cognition and mood, including the risk of suicidal ideation.

Effects on the mouth. A 52-year-old woman developed burning mouth syndrome after starting clonazepam; some improvement was noted when the dose was reduced but symptoms were still intolerable and clonazepam was withdrawn. Subsequently, symptoms resolved within 3 weeks.

Effects on sexual function. Sexual dysfunction was reported in 18 of 42 male patients receiving clonazepam for the treatment of post-traumatic stress disorder; symptoms resolved when therapy was changed to diazepam in 17 patients and lorazepam in the remaining patient.

Extrapyramidal disorders. For reference to extrapyramidal disorders associated with the use of benzodiazepines including clonazepam, see Effects on the Nervous System in Diazepam. However, clonazepam is also used in the treatment of some extrapyramidal disorders as discussed under Uses and Administration, below.

Porphyria. Clonazepam is considered to be unsafe in patients with porphyria although there is conflicting evidence of porphyrinogenicity.

For comments on the use of benzodiazepines in porphyria.

Pregnancy. For comments on the management of epilepsy during pregnancy.

Interactions

As for Diazepam.

Antiepileptics. For reference to possible interactions between clonazepam and other antiepileptics, see under Diazepam and Benzodiazepines under Interactions of Phenytoin.

Pharmacokinetics

Clonazepam is quickly absorbed after oral doses with a bioavailability of about 90%; peak plasma concentrations are reached between 1 and 4 hours after ingestion. It is extensively metabolised in the liver, its principal metabolite being 7-aminoclonazepam, which has no antiepileptic activity; minor metabolites are the 7-acetamido- and 3-hydroxy-derivatives. It is excreted mainly in the urine almost entirely as its metabolites in free or conjugated form. It is about 85% bound to plasma proteins and estimations of its elimination half-life range from about 20 to 40 hours, and occasionally more.

A therapeutic range of plasma concentrations has not been established.

Clonazepam crosses the placental barrier and is distributed into breast milk.

The pharmacokinetics of clonazepam maybe affected by use with other antiepileptics (see under Interactions, above).

A single-dose pharmacokinetic study in healthy subjects found that absorption of clonazepam was slower and intersubject variability was greater after intramuscular injection than after an oral dose. The pharmacokinetics of a modified-release subcutaneous injection have also been studied in healthy subjects; plasma-clonazepam concentrations were sustained and elimination occurred slowly over 13 days.

Bioavailability. It has been suggested, on the basis of anecdotal evidence, that there may be differences in bioavailability, and hence in clinical effect, between formulations of clonazepam tablets.

Uses and Administration

Clonazepam is a benzodiazepine derivative similar to diazepam, with marked antiepileptic properties.

It may be used in the treatment of all types of epilepsy and seizures, including status epilepticus, but its usefulness in chronic treatment is sometimes limited by the development of tolerance and by sedation, and other antiepileptics are often preferred. It may also be used in myoclonus and associated abnormal movements, and for the treatment of panic disorder (see Psychiatric Disorders, below). For epilepsy and myoclonus treatment is started with small doses that are progressively increased to an optimum dose according to response. Total daily doses may initially be taken in 3 or 4 divided doses; however, once the maintenance dose has been reached, the daily amount may be given as a single dose at night. In the UK the initial oral dose is 1 mg (500 micrograms in the elderly) at night for 4 nights gradually increased over 2 to 4 weeks to a usual maintenance dose of 4 to 8 mg daily; it is recommended that the total dose should not exceed 20 mg daily. Dosage recommendations in the USA are generally similar although initial doses of up to 1.5 mg daily are permitted and dosage increments of 0.5 to 1 mg every 3 days are recommended. There is little value in routinely monitoring plasma-clonazepam concentrations.

Clonazepam may be an alternative to other benzodi-azepines in the emergency management of status epilepticus. The usual dose is 1 mg given by slow intravenous injection over at least 2 minutes or by intravenous infusion, repeated if necessary to a maximum total dose of 20 mg. For doses in children, see below. As with other antiepileptics, withdrawal of clonazepam therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients.

In the treatment of panic disorder, clonazepam is given in an initial oral dose of 250 micrograms twice daily. This may be increased after 3 days to a total of 1 mg daily; a few patients may benefit from further increases, up to a maximum of 4 mg daily. In order to minimise drowsiness, clonazepam may be taken as a single dose at bedtime. Withdrawal should again be gradual.

Administration. Serum concentrations of clonazepam after buccal, intranasal, or intravenous dosage were measured in a crossover study in 7 healthy males. The results showed that intranasal clonazepam may offer an alternative to buccal use in patients with serial seizures but the initial concentrations were too low to recommend its use as an alternative to intravenous clonazepam in the management of status epilepticus. The nasal formulation used in this study contained dimethyl-β-cyclodextrin as a solubiliser and absorption enhancer.

Administration in children. For epilepsy and myoclonus treatment with clonazepam is started with small doses that are progressively increased to an optimum dose according to response. Total daily doses are taken in 3 divided doses; however, once the maintenance dose has been reached, the daily amount may be given as a single dose at night. Alternatively, the BNFC suggests giving the initial dose at night for 4 nights and gradually increasing it over 2 to 4 weeks. In the UK, the recommended initial oral daily dose is up to 250 micrograms for infants and children aged up to 5 years, or up to 500 micrograms for older children. The following usual maintenance doses are given according to age:

• neonate to 1 year (although the BNFC recommends a minimum age of 1 month): 0.5 to 1 mg daily

• 1 to 5 years: 1 to 3 mg daily

• 5 to 12 years: 3 to 6 mg daily

Older children may be given the usual adult dose (see above). If control of childhood epilepsy ceases to be adequate with clonazepam, the dose may be increased, or treatment interrupted for 2 or 3 weeks. The BNFC states that the UK inj ection formulation (Rivotril; Roche, UK) can be given orally if necessary; this may not apply to other injection formulations available elsewhere.

In the USA, doses may be given according to body weight. Infants and children aged up to 10 years or weighing up to 30 kg may be given an initial daily dose of 10 to 30 micrograms/kg (maximum 50 micrograms/kg) in 2 or 3 divided doses. This may be increased by a total of 250 to 500 micrograms every 3 days to a maintenance dose of 100 to 200 micrograms/kg daily given in 3 divided doses.

In the emergency management of status epilepticus, clonazepam is used as an alternative to other benzodiazepines. The usual dose in children is 500 micrograms given by slow intravenous injection or by intravenous infusion. Alternatively, the BNFC suggests giving the following doses by slow intravenous injection over at least 2 minutes according to age:

• neonates: 100 micrograms/kg, repeated if necessary after 24 hours

• 1 month to 12years: 50 micrograms/kg (maximum 1 mg), repeated if necessary

Older children may be given the usual adult dose. In children aged over 1 month, these doses by injection may be followed by an intravenous infusion of 10 micrograms/kg per hour, adjusted according to response to a maximum of 60 micrograms/kg per hour.

Extrapyramidal disorders. Clonazepam may be of benefit in some extrapyramidal disorders. It has been tried in the management of patients with tic disorders such as Tourette ‘s syndrome but evidence of efficacy from controlled studies is limited. Some use clonazepam in preference to haloperidol since it does not carry the risk of tardive dyskinesia associated with such antipsychotics and a case report described the successful use of clonazepam for haloperidol-induced tardive Tourette’s syndrome in an adult patient. There is also limited evidence of benefit with clonazepam in antipsychotic-induced akathisia and tardive dyskinesia (see under Extrapyramidal Disorders), and of improvement in dysarthria in a study in patients with parkinsonism.

Hiccup. For the management of intractable hiccups see under Chlorpromazine, p.976. Clonazepam may also be of value, especially in neurogenic hiccups.

Neuropathic pain. The management of phantom limb pain can be difficult, and tricyclic antidepressants and antiepileptics are used for the neuropathic components of the pain. Rapid and marked pain relief was achieved in 2 patients with lancinating phantom limb pain after treatment with clonazepam with or without amitriptyline.

Although carbamazepine is the drug of choice in the treatment of trigeminal neuralgia, clonazepam may be used in carbamazepine-intolerant patients.

Psychiatric disorders. Although the risk of dependence with benzodiazepines may outweigh their benefits in panic disorder, clonazepam has been used for the treatment of panic disorder with or without agoraphobia, and reported benefit in such patients suggests a similar action to alprazolam. A literature review evaluated the use of clonazepam in a range of psychiatric disorders and found that it may also be effective in the treatment of social anxiety disorder (see Phobic Disorders although further studies are warranted. There was evidence to suggest that clonazepam may be useful in acute mania and for the augmentation of antidepressant therapy with SSRIs in depression. A study found that augmentation was significantly more effective with a daily dose of 3 mg of clonazepam than with lower doses.

Sleep-associated movement disorders. Treatment of sleep-associated movement disorders including sleep behaviour disorder, restless legs syndrome, and periodic limb movements in sleep is largely empirical, but benzodiazepines such as clonazepam are often used. Small studies have provided some evidence for benefit with clonazepam therapy in these disorders, including bruxism.

Stiff-man syndrome. Clonazepam has been used as an alternative to diazepam in the management of stiff-man syndrome (see under Muscle Spasm) and is reported to be effective for familial startle disease, a rare congenital form of stiff-man syndrome.

Tinnitus. Clonazepam is one of many drugs that have been tried in tinnitus, but although it has been reported to be effective in some patients it is rarely used because of problems with adverse effects.

Preparations

British Pharmacopoeia 2008; Clonazepam Injection;

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Clonazepam Oral Suspension; Clonazepam Tablets.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Alerion; Ciclox; Clonagin; Clonax; Cloner; Diocam; Edictum; Felanor; Induzepam; Leptic; Neuryl; Olimer; Riuclonaz; Rivotril; Sedovanon; Sensaton; Solfidin; Australia: Paxam; Rivotril; Austria: Rivotril; Belgium: Rivotril; Brazil: Clonotril; Rivotril; Canada: Clonapam¤; Rivotril; Chile: Acepran; Clonapam; Clonex; Clozanil; Crismol; Neuryl; Ravotril; Ropsil; Valpax; Czech Republic: Antelepsin; Rivotril; Denmark: Rivotril; Finland: Rivatril; France: Rivotril; Germany: Antelepsin; Rivotril; Greece: Rivotril; Hong Kong: Rivotril; Hungary: Clonapam; Clonogal; Rivotril; India: Epitril; Epizam; Ozepam; Ireland: Rivotril; Israel: Clonex; Rivotril; Italy: Rivotril; Mexico: Kenoket; Kriadex; Rivotril; Netherlands: Rivotril; Norway: Rivotril; New Zealand: Paxam; Rivotril; Portugal: Rivotril; South Africa: Rivotril; Singapore: Rivotril¤; Spain: Rivotril; Sweden: Iktorivil; Switzerland: Rivotril; Thailand: Rivotril; United Kingdom: Rivotril; United States: Klonopin; Venezuela: Rivotril

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Clobazam). A white or almost white crystalline powder. Slightly soluble in water; sparingly soluble in alcohol; freely soluble in dichloromethane.

Dependence and Withdrawal

As for Diazepam.

Adverse Effects, Treatment, and Precautions

As for Diazepam.

Breast feeding. Benzodiazepines, such as clobazam, given to the mother may cause neonatal sedation and breast feeding should be avoided. For comments on antiepileptic therapy and breast feeding.

Driving. For a comment on antiepileptic drugs and driving.

Effects on menstruation. Occasionally the use of clobazam before menstruation for catamenial epilepsy appeared to delay the period.

Effects on mental function. For a review of the effects of antiepileptic therapy, including clobazam, on cognition and mood, including risk of suicidal ideation.

Effects on the skin. Report of toxic epidermal necrolysis that developed in light-exposed areas in a patient being treated with clobazam.

Porphyria. Clobazam is considered to be unsafe in patients with porphyria although there is conflicting evidence of porphyrinogenicity.

For comments on the use of benzodiazepines in porphyria.

Pregnancy. For comments on the management of epilepsy during pregnancy.

Interactions

As for Diazepam.

Antiepileptics. For reference to the interactions of clobazam withfelbamate and stiripentol, see under Diazepam.

Pharmacokinetics

Clobazam is well absorbed from the gastrointestinal tract and peak plasma concentrations are reached 1 to 4 hours after oral doses. It is about 85% bound to plasma proteins. Clobazam is highly lipophilic and rapidly crosses the blood-brain barrier. It is metabolised in the liver by demethylation and hydroxylation but unlike the 1,4-benzodiazepines such as diazepam, clobazam, a 1,5-benzodiazepine, ishydroxylatedatthe4-position rather than the 3-position (see also Metabolism under Diazepam). Clobazam is excreted unchanged and as metabolites mainly in the urine. Mean half-lives of 18 hours and 42 hours have been reported for clobazam and its main active metabolite N-desmethylclobazam, respectively.

Uses and Administration

Clobazam is a long-acting 1,5-benzodiazepine with uses similar to those of diazepam (a 1,4-benzodiazepine). It may be used as an adjunct in the treatment of epilepsy with other antiepileptics, although its use may be limited by the development of tolerance or sedation (but see below). It is also used in the short-term treatment of acute anxiety. As an adjunct in epilepsy usual oral doses in the UK are 20 to 30 mg daily, increased if necessary to a maximum of 60 mg daily. For doses in children, see below. As with other antiepileptics, withdrawal of clobazam therapy or transition to or from another type of antiep-ileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients and under Clonazepam, below.

For the short-term management of acute anxiety usual oral doses of 10 to 30 mg daily may be taken in divided doses or as a single dose at night; up to 80 mg daily has been used in hospitalised patients with severe anxiety states. Low initial doses and cautious increments to a usual daily dose of 10 to 20 mg are recommended in elderly or debilitated patients.

Administration in children. In the UK, clobazam is licensed for use as an adjunct in epilepsy in children over 3 years of age; no more than half the adult dose (see above) should be given. Alternatively, the BNFC suggests the following oral doses according to age:

• 1 month to 12 years: initially 125 micrograms/kg twice daily, increased every 5 days to a usual maintenance dose of 250 micrograms/kg twice daily. The maximum dose is 500 micrograms/kg twice daily and should not exceed 15 mg twice daily

• 12 to 18 years: initially 10 mg twice daily, increased every 5 days to a usual maintenance dose of 10 to 15 mg twice daily. The dose should not exceed 30 mg twice daily

The BNFC also suggests that clobazam may be given for cluster seizures and as monotherapy under specialist supervision for catamenial seizures (usually for 7 to 10 days each month just before and during menstruation).

Epilepsy. Benzodiazepines are sometimes used in the management of epilepsy, but their long-term use is limited by problems of sedation, dependence, and tolerance to the antiepileptic effects.

Clobazam, a 1,5-benzodiazepine, is considered to be somewhat better tolerated than conventional benzodiazepines, and has been widely used for adjunctive oral therapy in patients with epilepsy. Clobazam is active against partial and generalised seizures in epilepsy of widely differing aetiology in patients of all ages and has also been used for short-term cover in patients with intermittent seizures, including in women with catamenial epilepsy (seizures associated with menstruation) or patients whose epileptic attacks occur in clusters. Clobazam has also been tried with some success in children, including those with refractory epilepsy and epileptic encephalopathy. However, a recent systematic review concluded that although clobazam may reduce seizure frequency and may be most effective in partial onset seizures, it was not clear who would best benefit from its use and over what time-frame.

Neuropathic pain. There has been a mention of the complete relief of phantom limb pain refractory to other therapy in an elderly patient given clobazam 10 mg three times daily.

Preparations

British Pharmacopoeia 2008; Clobazam Capsules.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Karidium; Australia: Frisium; Austria: Frisium; Belgium: Frisium; Brazil: Frisium; Urbanil; Canada: Frisium; Chile: Frisin¤; Grifoclobam; Czech Republic: Frisium; Denmark: Frisium; Finland: Frisium; France: Urbanyl; Germany: Frisium; Greece: Frisium; Hong Kong: Frisium; Hungary: Frisium; India: Frisium; Ireland: Frisium; Israel: Frisium; Italy: Frisium; Malaysia: Frisium; Mexico: Frisium¤; Urbadan¤; Netherlands: Frisium; Urbadan¤; New Zealand: Frisium; Portugal: Castilium; Urbanil; South Africa: Urbanol; Singapore: Frisium¤; Spain: Clarmyl¤; Clopax¤; Noiafren; Sederlona¤; Switzerland: Urbanyl; Thailand: Frisium; United Kingdom: Frisium; Venezuela: Frisium

The Johns Hopkins team sent questionnaires to 1,000 neurologists and 1,000 obstetricians; the response rate was 15.5%. Although 91% of the neurologists and 75% of the obstetricians reported that they treat epileptic women of childbearing age, only 4% of the neurologists and none of the obstetricians knew which of the six most commonly used antiepileptic drugs induce the more rapid metabolism of oral contraceptive, and which do not. Yet, 27% of the neurologists and 21% of the obstetricians reported that OC failures occurred in their patients during AED therapy. In addition, almost half of neurologists and one fourth of obstetricians underestimated the risks of birth defects for women taking antiepileptic drugs.

Certain AEDs-phenytoin, phenobarbital, carbamazepine, oxcarbazepine, primidone, and ethosuximide-induce the cytochrome P450 enzymes that metabolize synthetic estrogens (e.g., ethinyl estradiol and mestranol), causing a 40% reduction in serum levels. In addition, free progestin levels are decreased as a result of increased synthesis of hormone- binding globulins. The antiepileptic drugs valproic acid, gabapentin, vigabatrin, lamotrigine, topiramate, and tiagabine do not appear to induce hepatic P450 enzymes and are unlikely to interfere with oral contraceptives. The effect of felbamate on oral contraceptives is still under investigation.

The recommendation for women on antiepileptic drugs is to increase the oral contraceptive dose to 50 mcg estradiol, particularly if breakthrough bleeding occurs. However, according to Krauss et al, pregnancy may occur even at the highest dose level, sometimes with no warning of irregular bleeding. Because high doses increase the risk of thromboembolism (particularly in smokers and women over age 35), other forms of contraception should be considered as an alternative to oral contraceptives. An effective choice is the depot form of medroxyprogesterone (Depo-Provera), a potent contraceptive that has not been associated with failures due toantiepileptic drugs . By contrast, the levonorgestrol implant (Norplant) is not an effective alternative, according to Krauss et al. More than 30 unplanned pregnancies have occurred in women on AEDs who used Norplant.

“Our survey suggests that a large number of women in the United States with epilepsy are at risk for unplanned pregnancies while taking oral contraceptives,” said the Johns Hopkins investigators. Women with epilepsy should discuss reproductive issues with both a neurologist (who may be more familiar with the effects of antiepileptic drugs on oral contraceptives) and an obstetrician (who may be more familiar with the risks of birth defects).

In five placebo-controlled, double-blind clinical trials, topiramate significantly reduced the frequency of epileptic seizures, including refractory partial seizures. In dosage studies- topiramate given at 200, 400, 600, 800, and 1,000 mg per day-the 200-mg dose gave inconsistent results, and increasing the dose beyond 400 mg per day did not increase efficacy. One trial included 45 patients who received 400 mg/day; 44% responded with at least a 50% reduction in seizure frequency, compared with baseline. In a second trial, 35% of 23 patients who received the 400-mg/day dose showed a 50% reduction in seizure rate. By comparison, 24% of patients receiving the 200-mg/day dose showed a seizure reduction rate of about 27%, and approximately 36 to 46% of patients responded to 600, 800, and 1,000 mg/day with a 36 to 46% reduction in seizure rates (response generally decreased as the dosage was increased). Placebo patients showed little or no response, and often showed increases in seizure frequency. Based on overall clinical results, topiramate appears to be a more potent anticonvulsant than Warner Lambert’s gabapentin (with response rates of 22-26%) and GlaxoWellcome’s lamotrigine (seizure reduction, 25-36%).

Topiramate is given 50 mg/day initially, with a gradual increase during an 8-week titration period to a total of 400 mg/day in two divided doses. Oral bioavailability is about 80%, and food has no clinically significant effect on absorption. At dosages of 200 to 800 mg, serum concentrations are linearly dose related and there is not much intersubject variability. Plasma protein binding is less than 20%. Single-dose studies in healthy adults have revealed that the drug is about 20% metabolized, but with multiple dosing in patients taking other antiepileptic drugs, up to 50% of the dose is metabolized. Elimination is primarily renal, with 50 to 80% of the dose excreted as unchanged topiramate; elimination half-life is 20 to 30 hours. Age, gender, race, baseline seizure rate, and concomitant antiepileptic drugs do not appear to affect efficacy, although topiramate may interact with phenytoin (Dilantin/Warner Lambert) and carbamazepine (Tegretol/Novartis). Addition of topiramate to a regimen that includes phenytoin may require adjustment of the phenytoin dose; addition or withdrawal of phenytoin and/or carbamazepine to the topiramate regimen may require adjustment of the dose of topiramate.

At the 200- to 400-mg dose range, the most frequent adverse effects in clinical trials were psychomotor slowing (incidence about 17%), difficulty concentrating (8%), speech and language problems (about 6%), somnolence (30%), and fatigue (11-12%). These reactions were generally dose related. Similar side effects (although less frequent) were seen with lamotrigine and gabapentin. During clinical studies, 1.5% of topiramate-treated patients developed kidney stones, which represents a two- to fourfold increase over the normal rate of stone formation. This may be due to carbonic anhydrase inhibition, and is managed by increasing fluid intake. Another side effect thought to be related to carbonic anhydrase inhibition is paresthesia. Use of topiramate with other carbonic anhydrase inhibitors should be avoided. Approximately 11% of patients withdrew from clinical trials because of adverse events, primarily central nervous system (CNS) effects, paresthesias, and, at higher dosages, anorexia and weight loss.

Although topiramate has been approved only for adults, Johnson & Johnson is studying the drug in pediatric patients with epileptic disorders, including generalized seizures and Lennox-Gastaut syndrome.

In their review of the emergency treatment of status epilepticus, Runge and Allen divided the clinical presentation of status epilepticus into four groups: (1) prolonged seizures; (2) repeated generalized convulsive seizures with no interictal recovery; (3) nonconvulsive seizures that produce a continuous or fluctuating alteration in consciousness; and (4) repeated partial seizures manifested as focal motor convulsion or neurologic deficit without altered consciousness. Generalized tonic-clonic status epilepticus is the most dramatic and thus commands the most attention, according to Runge and Allen. However, all types of status epilepticus are neurologic emergencies that require immediate intervention to prevent brain damage. Whereas the level of mortality is usually determined by the underlying cause of the seizure, morbidity increases with the duration of the episode.

The mainstay of therapy for status epilepticus is the parenteral administration of an antiepileptic drug (AED), preferably by the intravenous (IV) route, although intramuscular (IM) injection may be necessary if prompt venous access is not available. The FDA has approved about two dozen antiepileptic drugs, but only four are commonly used parenterally: phenytoin, phenobarbital, diazepam, and lorazepam. Pentobarbital, thiopental, and midazolam are also used parenterally, although usually for refractory or end-stage status epilepticus. Lidocaine and propofol are also used, and valproic acid can be administered rectally or via nasogastric tube for absence seizures (a parenteral formulation is under investigation). None of these agents is without problems. For one thing, adverse CNS side effects are not uncommon. For another, these drugs require alkalinization and/or propylene glycol for solubilization; thus both IV and IM administration are highly irritating.

First-line therapy for status epilepticus involves the intravenous administration of a benzodiazepine- diazepam or lorazepam-which controls seizures in 79% of patients. For patients who do not respond to the initial dose, a second dose is given, although repeated doses do cause respiratory and CNS depression. Phenytoin is considered a second-line drug; it has a prolonged infusion time and a slow onset of action, causes painful local reactions, and carries the risks of extravasation and tissue necrosis. Phenytoin is not water soluble, and so is formulated with 40% propylene glycol and 10% ethanol in water for injection, adjusted to pH 12. The alkaline pH is highly irritating and can seriously damage tissue, and the propylene glycol is associated with hypotension and probably with cardiac arrhythmias that may accompany the intravenous administration of phenytoin. Phenytoin cannot even be used intramuscular because of poor absorption, crystallization, and tissue destruction.

Recently, the FDA approved two new products for refractory seizures and/or status epilepticus: fosphenytoin (Cerebyx/Warner Lambert) and diazepam rectal gel (Diastat/Athena). Diazepam gel was approved for rectal administration in the management of selected, refractory, epileptic patients on stable antiepileptic drug regimens who require intermittent use of diazepam to control bouts of increased seizure activity. Parenteral fosphenytoin was approved for the control of generalized convulsive status epilepticus, for the prevention and treatment of seizures occurring during neurosurgery, and as short-term substitution for oral phenytoin.

Fosphenytoin is a phosphate ester of phenytoin that has been classified “1S” (new molecular entity) by the FDA. It is freely soluble in aqueous solutions, including standard intravenous solutions. After administration, fosphenytoin is rapidly converted (within 8-15 minutes) to phenytoin by phosphatases found in a number of tissues. Unlike phenytoin, fosphenytoin can be given rapidly IV and promptly achieves therapeutic levels. It is rapidly absorbed when given intramuscular, and is well tolerated. The drug is 100% bioavailable, and it is bioequivalent to phenytoin (10 mL fosphenytoin is equivalent to 5 mg intravenous phenytoin). Side effects are minor and transient. Unlike benzodiazepines and barbiturates, fosphenytoin does not cause respiratory or CNS depression; thus patients can breathe well enough to compensate for metabolic acidosis, and think well enough after recovery to cooperate with diagnostic evaluation.

In a study of 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mg/minute, seizures were terminated in 37 patients (85%) within 30 minutes of administration. Side effects included dizziness, nystagmus, and ataxia. In a comparative study of 90 patients given intravenous fosphenytoin and 22 given intravenous phenytoin, disruption of infusion occurred in 21% of IV fosphenytoin patients (primarily due to systemic burning, pruritus, and/or paresthesia) compared with 67% of IV phenytoin patients (primarily due to pain and burning at the infusion site). Paresthesia and pruritus were more common in fosphenytoin than phenytoin patients (paresthesias: 4.4% and 0%, respectively; pruritus: 49% and 4.5%, respectively). Pediatric studies have shown that fosphenytoin has the same efficacy, safety, tolerability, and pharmacokinetics in children aged 5 to 18 years as in adults (up to age 40).

Answer. There are now four main anticonvulsant (anti-epileptic) agents that are either established or being actively investigated as mood stabilizers: valproate (Depakote), carbamazepine (Tegretol), gabapentin (Neurontin) and lamotrigine (Lamictal). Another anticonvulsant, Topiramate (Topamax), is being investigated for this purpose.

Your question involves the conjunction of three factors: a double-blind condition, use of an anticonvulsant and rapid-cycling bipolar patients (i.e., those with four or more major mood swings per year). While I can’t give you a definitive answer as to the number of such studies, my review of the literature suggests that there are fewer than five that meet all three of your criteria. I refer you to papers by Denicoff et al (Journal of Clinical Psychiatry, 1997) and Bowden et al (Journal of the American Medical Association, March 23-30, 1994) for details.

In a recent review of lamotrigine and gabapentin, Dr. Nassir Ghaemi of Massachusetts General Hospital found only a small number of double-blind studies with these agents (International Drug Therapy Newsletter, April and May 1999). In many of the recent studies of lamotrigine and gabapentin, these agents have been used as adjuncts for most patients, rather than as the sole treatment, meaning that judgments about their efficacy must be put in this limited context.

For example, in three non-double blind studies, lamotrigine appeared useful in between 50-75% of rapidly cycling patients, but most of these patients were taking other mood stabilizers or medications. Regarding bipolar patients with concomitant “anxiety,” it is, of course, difficult to distinguish anxiety from agitation in manic patients. In either case, benzodiazepines such as lorazepam or clonazepam are frequently used.

Atypical antipsychotics like olanzapine are also finding a role as adjunctive agents in bipolar illness. Gabapentin appears to have anti-anxiety properties even in patients who are not bipolar, and thus would be a reasonable “add-on” for anxious bipolar patients.

The most frequently prescribed antiepileptic drugs are phenytoin, carbamazepine, and valproate, although in the past few years a number of new antiepileptic drugs have been approved. These new drugs were developed following major advances in the understanding of neurotransmitters and their receptors, and most enhance the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. Some also inhibit glutamate, the major excitatory neurotransmitter. Blocking glutamate has not been very successful, but augmenting GABA activity has been quite effective.

Gamma-aminobutyric acid is present in an estimated 60 to 70% of all synapses in the brain. It is formed from glutamate by the enzyme glutamic acid decarboxylase. After synaptic release, GABA is taken up into nerve cells or glial cells. In the neuron, gamma-aminobutyric acid either is re-released or is broken down by GABA transaminase into succinic semialdehyde; in the glial cell, it is metabolized, along with glutamate, by glutamine synthetase to form the amino acid glutamine, which is then transported back to the neuron and used to synthesize more glutamate and gamma-aminobutyric acid. When released into the synapse, GABA can bind to two different receptor complexes, designated A and B. GABA-A binds gamma-aminobutyric acid, benzodiazepines, barbiturates, and neurosteroids. When GABA-A is activated, it increases the inward flow of chloride through the nerve cell membrane, which hyperpolarizes the membrane and inhibits neuronal firing. Compounds that increase GABAergic activity via the GABA-A receptor are anticonvulsants, and those that antagonize GABA-A are convulsants.

Neuropharmacologists have discovered several ways to enhance GABA-A receptor activity: direct stimulation, inhibition of gamma-aminobutyric acid metabolism, and reduction of neuronal and/or glial GABA reuptake. Blocking gamma-aminobutyric acid reuptake is an especially fruitful area for drug discovery, because there are at least four different GABA transport mechanisms that mediate gamma-aminobutyric acid reuptake in neurons and glial cells. These transporters show different distributions within the central nervous system (CNS); for example, one is prominent in the substantia nigra, an area that plays a crucial role in the development of seizures.

Antiepileptic Drugs and Their Primary Mechanisms of Action

One of the most promising gamma-aminobutyric acid (GABA) reuptake inhibitors is tiagabine (Gabitril/Abbott), a novel antiepileptic drug that will probably receive final FDA approval during the first quarter of this year. Developed by researchers at the Danish pharmaceutical company NovoNordisk, tiagabine is a nipecotic acid derivative with an attached lipophilic group that enables the drug to cross the blood-brain barrier. This “rationally” designed drug is a potent, selective, and specific inhibitor of GABA reuptake into presynaptic neurons and glial cells, particularly those in the substantia nigra and associated areas. It binds one of the GABA reuptake transporters and shows no significant affinity for dopamine, norepinephrine, histamine, adenosine, serotonin, glutamate, or acetylcholine sites-either receptors or reuptake transporters.

Tiagabine has shown broad activity against a range of seizure types, including drug- induced, electroshock-induced, light-induced, amygdala-kindled, and audiogenic. It is well tolerated and does not cause withdrawal effects, displace other drugs, or induce hepatic enzymes (although it is a target for enzyme inducers). It is rapidly and completely absorbed, with a half-life of 5 to 8 hours. Because tiagabine is highly effective for partial- onset seizures, it will be approved initially for the adjunctive treatment of partial seizures, with or without secondarily generalized seizures.

Other new antiepileptic drugs on the market or under investigation include valproate (Divalproex/Abbott), topiramate (Topamax/Ortho-McNeil), gabapentin (Neurontin/Warner Lambert), lamotrigine (Lamictal/Glaxo Wellcome), vigabatrin, oxcarbazepine, and levetiracetam. Valproic acid decreases the activity of the enzyme that degrades gamma-aminobutyric acid and increases the activity of the enzyme that generates GABA; topiramate enhances gamma-aminobutyric acid and inhibits glutamate; and gabapentin, which is structurally related to GABA, has a unique (and as yet poorly understood) influence on gamma-aminobutyric acid neurotransmission. Vigabatrin acts through the selective, irreversible inhibition of GABA transaminase, the enzyme responsible for the metabolism of gamma-aminobutyric acid. Oxcarbazepine was developed by modifying the chemical formula of carbamazepine to improve tolerability; it is at least as effective as its parent, but is better tolerated, has fewer drug interaction problems, induces fewer enzymes, and causes less skin allergy. Levetiracetam is an interesting new compound in clinical trial that appears to bind a specific receptor on nerve cell membranes. It shows a broad spectrum of anticonvulsant activity and has been particularly effective for partial seizures. It has a high therapeutic index and does not appear to interact with other antiepileptic drugs.

Lamotrigine is the first antiepileptic drug that was designed specifically to inhibit glutamate and its close cousin, aspartate. It blocks sodium channels and stabilizes the presynaptic neuronal membrane, inhibiting the release of glutamate and aspartate. It has a wide spectrum of antiepileptic activity, including partial-onset and primary generalized tonic-clonic seizures, and is particularly useful for mentally retarded patients. It is very well tolerated and does not alter concentrations of concomitant antiepileptic drugs or induce hepatic enzymes although it is a target for enzyme induction. It interacts with both valproic acid (which approximately doubles the plasma elimination half-life of lamotrigine) and carbamazepine (concomitant lamotrigine/carbamazepine therapy can cause a potentially dangerous cerebellar toxic syndrome).

The understanding of epilepsy has advanced substantially in the past decade, and new antiepileptic drugs with novel mechanisms of action are continually being developed. Monotherapy is the goal-that is, the admInistration of one drug with a mechanism of action specific for the form of epilepsy being treated-but in clinical practice, polytherapy is often used. Using multiple drugs increases the risis of adverse effects and drug interactions, but the new GABAergics have such good safety profiles that “rational polytherapy” is a workable solution to what is often a very complex neurologic problem.