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Carbamazepine has anticonvulsant properties which have been found useful in the treatment of psychomotor epilepsy and as an adjunct in the treatment of partial epilepsies, when administered in conjunction with other anticonvulsant drugs to prevent the possible generalization of the epileptic discharge. A mild psychotropic effect has
been observed in some patients, which seems related to the effect of the carbamazepine in psychomotor or temporal lobe epilepsy.
Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia often within 24 to 48 hours.
Carbamazepine given as a monotherapy or in combination with lithium or neuroleptics has been found useful in the treatment of acute mania and the prophylactic treatment of bipolar (manic-depressive) disorders.
Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action which is responsible for some of its adverse effects. A tolerance may develop to the action of carbamazepine after a few months of treatment and should be watched for.
Carbamazepine may suppress ventricular automaticity due to its membrane-depressant effect similar to that of quinidine and procainamide, associated with suppression of phase 4 depolarization of the heart muscle fibre.
A number of investigators have reported a deterioration of EEG abnormalities with regard to focal alterations and a higher incidence of records with nil beta activity during carbamazepine-combined treatment.
The absorption of carbamazepine in man is relatively slow. When taken in a single oral dose, the carbamazepine tablets and chewable tablets yield peak plasma concentrations of unchanged carbamazepine within 4 to 24 hours. With respect to the quantity of carbamazepine absorbed, there is no clinically relevant difference between the
various dosage forms. When the carbamazepine controlled-release tablets are administered repeatedly, they yield a lower average maximal concentration of carbamazepine in the plasma, without a reduction in the average minimal concentration. This tends to result in a lower incidence of intermittent concentration-dependent adverse drug
reactions. It also ensures that the plasma concentrations remain largely stable throughout the day, thereby making it possible to manage with a twice-daily dosage.
Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration of unchanged substance in the saliva reflects the non-protein-bound portion present in the serum (20 to 30%).
The elimination half-life of unchanged carbamazepine in the plasma averages approximately 36 hours following a single oral dose, whereas after repeated administration, which leads to autoinduction of hepatic enzymes, it averages only 16 to 24 hours, depending on the duration of the medication. In patients receiving concomitant
treatment with other enzyme-inducing anti-epileptic agents, half-life values averaging 9 to 10 hours have been found.
Only 2 to 3% of the dose, whether given singly or repeatedly, is excreted in the urine in unchanged form. The primary metabolite is the pharmacologically active 10,11-epoxide.
In man, the main urinary metabolite of carbamazepine is the trans-diol derivative originating from the 10,11-epoxide; a small portion of the epoxide is converted into 9-hydroxymethyl-10-carbamoyl-acridan. Other important biotransformation products are various monohydroxylated compounds, as well as the N-glucuronide of carbamazepine.
The therapeutic range for the steady-state plasma concentration of carbamazepine generally lies between 4 and 10 mcg/mL.
Indications
Trigeminal Neuralgia:
For the symptomatic relief of pain of trigeminal neuralgia only during periods of exacerbation of true or primary trigeminal neuralgia (tic douloureux). It should not be used preventively during periods of remission. In some patients, carbamazepine has relieved glossopharyngeal neuralgia. For patients who fail to respond to carbamazepine,
or who are sensitive to the drug, recourse to other accepted measures must be considered.
Carbamazepine is not a simple analgesic and should not be used to relieve trivial facial pains or headaches.
Treatment of Acute Mania and Prophylaxis in Bipolar (Manic-Depressive) Disorders:
Carbamazepine may be used as a monotherapy or as an adjunct to lithium in the treatment of acute mania or prophylaxis of bipolar (manic-depressive) disorders in patients who are resistant to or are intolerant of conventional antimanic drugs. Carbamazepine may be a useful alternative to neuroleptics in such patients. Patients with severe
mania, dysphoric mania or rapid cycling who are non-responsive to lithium may show a positive response when treated with carbamazepine.
It is important to note that these recommendations are based on extensive clinical experience and some clinical trials versus active comparison agents.
Carbamazepine has been found useful in: the management of psychomotor (temporal lobe) epilepsy and, as an adjunct, in some patients with secondary or partial epilepsy with complex symptomatology or secondarily generalized seizures, when administered in combination with other antiepileptic medication. As an alternative medication in
patients with generalized tonic-clonic seizures who are experiencing marked side effects or fail to respond to other anticonvulsant drugs.
Carbamazepine is not effective in controlling petit mal, minor motor, myoclonic and predominantly unilateral seizures, and does not prevent the generalization of epileptic discharge. Moreover, exacerbation of seizures may occasionally occur in patients with atypical absences.
Contraindications
Should not be administered to patients with a history of hepatic disease, acute intermittent porphyria or serious blood disorder.
The drug should not be administered immediately before, in conjunction with, or immediately after an MAO inhibitor. When it seems desirable to administer carbamazepine to a patient who has been receiving an MAO inhibitor, there should be as long a drug-free interval as the clinical condition allows, but in no case should this be less
than 14 days. Then the dosage of carbamazepine should be low initially, and increased very gradually.
Carbamazepine should not be administered to patients presenting AV heart block (see Pharmacology and Precautions).
Carbamazepine should not be administered to patients with known hypersensitivity to carbamazepine or to any of the tricyclic compounds, such as amitriptyline, trimipramine, imipramine, or their analogues or metabolites, because of the similarity in chemical structure.
Warnings
Although reported infrequently, serious adverse effects have been observed during the use of carbamazepine. Agranulocytosis and aplastic anemia have occurred in a few instances with a fatal outcome. Leukopenia, thrombocytopenia and hepatocellular and cholestatic jaundice have also been reported. It is, therefore, important that
carbamazepine should be used carefully and close clinical and frequent laboratory supervision should be maintained throughout treatment in order to detect as early as possible signs and symptoms of a possible blood dyscrasia. Carbamazepine should be discontinued if any evidence of significant bone marrow depression appears (see
Precautions).
Should signs and symptoms suggest a severe skin reaction such as Stevens-Johnson syndrome or Lyell's syndrome, carbamazepine should be withdrawn at once.
Long-term toxicity studies in rats indicated a potential carcinogenic risk. Therefore, the possible risk of drug use must be weighed against the potential benefits before prescribing carbamazepine to individual patients.
Pregnancy:
Women with epilepsy who are or intend to become pregnant should be treated with special care.
In women of childbearing potential, carbamazepine should, whenever possible, be prescribed as monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with more than one antiepileptic drug (e.g., valproic acid plus carbamazepine plus phenobarbitone and/or phenytoin) is greater than in those of
women receiving a single antiepileptic.
Minimum effective doses should be given and the plasma levels monitored.
If pregnancy occurs in a woman receiving carbamazepine, or if the problem of initiating carbamazepine arises during pregnancy, the drug's potential benefits must be weighed against its hazards, particularly during the first 3 months of pregnancy. Carbamazepine should not be discontinued or withheld from patients if required to prevent
major seizures because of the risks posed, to both mother and fetus, by status epilepticus with attendant hypoxia.
The possibility that carbamazepine, like all major antiepileptic drugs, increases the risk of malformation has been reported. There are rare reports on developmental disorders and malformations, including spina bifida, in association with carbamazepine. Conclusive evidence from controlled studies with carbamazepine monotherapy is
lacking.
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and during pregnancy.
To prevent neonatal bleeding disorders, Vitamin K(1) administration to the mother during the last weeks of pregnancy, as well as to the newborn, has been recommended.
Lactation:
Carbamazepine passes into breast milk in concentrations of about 25 to 60% of the plasma level. No reports are available on the long-term effect of breast-feeding. The benefits of breast-feeding should be weighed against the possible risks to the infant. Should the mother taking carbamazepine nurse her infant, the infant must be observed
for possible adverse reactions, e.g. somnolence.
A severe hypersensitivity skin reaction in a breast-fed baby has been reported.
It should be noted that the reliability of oral contraceptives may be adversely affected by carbamazepine (see Precautions, Drug Interactions).
Precautions
Clinical Monitoring of Adverse Reactions:
Carbamazepine should be prescribed only after a critical risk-benefit appraisal in patients with a history of cardiac, hepatic or renal damage, adverse hematological reactions to other drugs, or interrupted courses of therapy with carbamazepine. Careful clinical and laboratory supervision should be maintained throughout treatment. Should
any signs or symptoms or abnormal laboratory findings be suggestive of blood dyscrasia or liver disorder, carbamazepine should be immediately discontinued until the case is carefully reassessed.
Bone Marrow Function:
Complete blood counts, including platelets and possibly reticulocytes and serum iron, should be carried out before treatment is instituted. Suggested guidelines for monitoring are weekly for the first month, then monthly for the next 5 months, thereafter 2 to 4 times a year.
If definitely low or decreased white blood cell or platelet counts are observed during treatment, the patient and the complete blood count should be monitored closely. Nonprogressive fluctuating asymptomatic leukopenia, which is encountered, does not generally call for the withdrawal of carabamazepine. However, treatment with
carbamazepine should be discontinued if the patient develops leukopenia which is progressive or accompanied by clinical manifestations, e.g. fever or sore throat, as this could indicate the onset of significant bone marrow depression. Because the onset of potentially serious blood dyscrasias may be rapid, patients should be made aware of
early toxic signs and symptoms of a potential hematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric hemorrhage appear, the patient should be advised to consult his/her physician immediately.
Hepatic Function:
Baseline and periodic evaluations of hepatic function must be performed, particularly in elderly patients and patients with a history of liver disease. Carbamazepine should be withdrawn immediately in cases of aggravated liver dysfunction or active liver disease.
Kidney Function:
Pretreatment and periodic complete urinalysis and BUN determinations should be performed.
Ophthalmic Examinations:
Carbamazepine has been associated with pathological eye changes. Periodic eye examinations, including slit-lamp funduscopy and tonometry, are recommended.
Plasma Levels:
Although correlations between dosage and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability, are rather tenuous, monitoring plasma levels may be useful in the following conditions: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating
children or adolescents; in suspected absorption disorders; in suspected toxicity, especially where more than one drug is being used (see Drug Interactions).
Increased Seizure Frequency:
Carbamazepine should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since its use has been associated with increased frequency of generalized convulsions. In case of exacerbation of seizures, carbamazepine should be discontinued.
Dermatologic:
Mild skin reactions, e.g. isolated macular or maculopapular exanthema, usually disappear within a few days or weeks, either during continued course of treatment or following a decrease in dosage. However, the patient should be kept under close surveillance because of the rare possibility of Stevens-Johnson syndrome or Lyell's syndrome
occurring (see Warnings).
Urinary Retention and Increased Intraocular Pressure:
Because of its anticholinergic action, carbamazepine should be given cautiously, if at all, to patients with increased intraocular pressure or urinary retention. Such patients should be followed closely while taking the drug.
Occurrence of Behavioral Disorders:
Because it is closely related to the other tricyclic drugs, there is some possibility that carbamazepine might activate a latent psychosis, or, in elderly patients, produce agitation or confusion, especially when combined with other drugs. Caution should also be exercised in alcoholics.
Patients with Cardiovascular Disorders:
Carbamazepine should be used cautiously in patients with a history of coronary artery disease, organic heart disease or congestive failure. If a defective conductive system is suspected, an ECG should be performed before administering carbamazepine in order to exclude patients with AV block.
Occupational Hazards:
Because dizziness and drowsiness are possible adverse effects of carbamazepine, patients should be warned about the possible hazards of operating machinery or driving automobiles.
Drug Interactions:
Induction of hepatic enzymes in response to carbamazepine may have the effect of diminishing or abolishing the activity of certain drugs that are also metabolized in the liver. The dosage of the following drugs may have to be adjusted when administered with carbamazepine: Clobazam, clonazepam, ethosuximide, primidone, valproic acid,
alprazolam, corticosteroids (e.g. prednisolone, dexamethasone), cyclosporin, digoxin, doxycycline, felodipine, haloperidol, thioridazine, imipramine, methadone, oral contraceptives, theophylline and oral anticoagulants (warfarin, phenprocoumon, dicumarol).
Phenytoin plasma levels have been reported both to be raised and to be lowered by carbamazepine, and mephenytoin plasma levels have been reported in rare instances to increase.
The following drugs have been shown to raise plasma carbamazepine levels: erythromycin, troleandomycin, possibly josamycin, isoniazid, verapamil, diltiazem, propoxyphene, viloxazine, fluoxetine, cimetidine, acetazolamide, danazol and possibly desipramine. Nicotinamide raises carbamazepine plasma levels in children, but only at high
dosage in adults. Since an increase in carabamazepine plasma levels may result in unwanted effects (e.g., dizziness, drowsiness, ataxia, diplopia and nystagmus), the dosage of carbamazepine should be adjusted accordingly and the blood levels monitored.
The plasma levels of carbamazepine may be reduced by phenobarbitone, phenytoin, primidone, progabide or theophylline and possibly by clonazepam. On the other hand, valproic acid, valpromide and primidone have been reported to raise plasma levels of the pharamacologically active metabolite, carbamazepine-10,11 epoxide. The dose of
carbamazepine may consequently have to be adjusted.
Combined use of carbamazepine with lithium, metoclopramide or haloperidol may increase the risk of neurotoxic side effects (even in the presence of therapeutic plasma levels).
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
Carbamazepine, like other anticonvulsants, may adversely affect the reliability of oral contraceptives; breakthrough bleeding may occur. Patients should accordingly be advised to use some alternative, nonhormonal method of contraception.
Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium); their dosage may need to be raised and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.
Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and its active 10,11-epoxide; carbamazepine plasma levels should be monitored.
Carbamazepine, like other psychoactive drugs, may reduce the patient's alcohol tolerance; it is therefore advisable to abstain from alcohol consumption during treatment.
Carbamazepine should not be administered in conjunction with an MAO inhibitor (see Contraindications).
Adverse Effects
The reactions which have been most frequently reported with carbamazepine are CNS (e.g., drowsiness, headache, unsteadiness on the feet, diplopia, dizziness), gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions. These reactions usually occur only during the initial phase of therapy, if the initial dose is
too high, or when treating elderly patients. They have rarely necessitated discontinuing carbamazepine therapy and can be minimized by initiating treatment at a low dosage.
The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels and possibly lower the daily dose and/or divide it into 3 to 4 fractional doses.
The more serious adverse reactions observed are the hematologic, hepatic, cardiovascular and dermatologic reactions, which require discontinuation of therapy. If treatment with carbamazepine has to be withdrawn abruptly, the change-over to another antiepileptic drug should be effected under cover of diazepam.
The following adverse reactions have been reported:
Hematologic:
Occasional or frequent: Leukopenia. Occasional: Eosinophilia, thrombocytopenia. Rare: Leukocytosis, lymphadenopathy. Isolated cases: Agranulocytosis, aplastic anemia, pure red cell aplasia, macrocytic anemia, acute intermittent porphyria, reticulocytosis, folic acid deficiency, thrombocytopenic purpura, and possibly hemolytic anemia. In a
few instances, deaths have occurred.
Hepatic:
Frequent: Elevated gamma-GT (due to hepatic enzyme induction), usually not clinically relevant. Occasional: Elevated alkaline phosphatase. Rarely: elevated transaminases. Rare: Jaundice, hepatitis of cholestatic, parenchymal, hepatocellular, or mixed type. Isolated cases: Granulomatous hepatitis.
Dermatologic:
Occasional to frequent: Skin sensitivity reactions and rashes, erythematous rashes, urticaria. Rare: Exfoliative dermatitis and erythroderma, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome. Isolated cases: toxic epidermal necrolysis (Lyell's syndrome), photosensitivity, erythema multiform and nodosum, skin
pigmentation changes, pruritus, purpura, acne, diaphoresis, alopecia and neurodermatitis.
Neurologic:
Frequent: Vertigo, somnolence, ataxia and fatigue. Occasionally: An increase in motor seizures (see Indications), headache, diplopia, nystagmus, accommodation disorders (e.g., blurred vision). Rare: Abnormal involuntary disorders (e.g., tremor, asterixis, orofacial dyskinesia, choreoathetosis disorders, dystonia, tics). Isolated cases:
Oculomotor disturbances, speech disorders (e.g., dysarthria or slurred speech), peripheral neuritis, paresthesia. There have been some reports of paralysis and other symptoms of cerebral arterial insufficiency but no conclusive relationship to the administration of carbamazepine could be established.
Cardiovascular:
Disturbances of cardiac conduction, bradycardia, arrhythmias, Stokes-Adams in patients with AV block, congestive heart failure, hypertension or hypotension, aggravation of coronary artery disease, thrombophlebitis, thromboembolism. Some of these complications (including myocardial infarction and arrhythmia) have been associated with other
tricyclic compounds.
Psychiatric:
Isolated cases: Hallucinations (visual or acoustic), depression, sometimes with talkativeness, agitation, loss of appetite, restlessness, aggressive behaviour, confusion, activation of psychosis.
Genitourinary:
Isolated cases: Interstitial nephritis and renal failure, as well as signs of renal dysfunction (e.g., albuminuria, glycosuria, hematuria, oliguria sometimes associated with elevated blood pressure, and elevated BUN/azotemia), urinary frequency, urinary retention and renal failure. Isolated reports: Sexual disturbances/impotence.
Gastrointestinal:
Occasional or frequent: Nausea, vomiting. Occasional: Dryness of the mouth and throat. Rare: Diarrhea or constipation. Isolated cases: Abdominal pain, glossitis, stomatitis, anorexia.
Sense Organs:
Isolated cases: Lens opacities, conjunctivitis, retinal changes, tinnitus, hyperacusis and taste disturbances.
Endocrine System and Metabolism:
Occasionally edema, fluid retention, weight increase, hyponatremia and reduced plasma osmolality due to antidiuretic hormone (ADH)-like effect occurs, leading in isolated cases to water intoxication accompanied by lethargy, vomiting, headache, mental confusion and neurological abnormalities. Isolated cases of gynecomastia or galactorrhea
have been reported, as well as abnormal thyroid function tests (decreased L-thyroxine, i.e., FT(4), T(4), T(3), and increased TSH, usually without clinical manifestations), disturbances of bone metabolism (decrease in plasma calcium and 25-OH-calciferol), leading in isolated cases to osteomalacia, as well as reports of elevated levels of
cholesterol, including HDL cholesterol and triglycerides.
Musculoskeletal:
Isolated cases: Arthralgia, muscle pain or cramp.
Respiratory:
Isolated cases: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis or pneumonia.
Hypersensitivity:
A rare delayed multi-organ hypersensitivity disorder with fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests, occurring in various combinations. Other organs may also be affected (e.g., lungs, kidneys, pancreas,
myocardium). Isolated cases: Aseptic meningitis, with myoclonus and eosinophilia; anaphylactic reaction. Treatment should be discontinued should such hypersensitivity reactions occur.
Overdose
Lowest known lethal dose: Estimated 3.2 g (24 year old woman). Highest known doses survived: 80 g (34 year old man); 34 g (13 year old girl); 1.4 g (23 month old girl). Symptoms: The presenting signs and symptoms of overdosage usually involve the central nervous, cardiovascular and respiratory systems.
Cardiovascular:
Tachycardia, hypotension/hypertension, conduction disturbance with widening of QRS complex, syncope in association with cardiac arrest.
Treatment:
There is no known specific antidote to carbamazepine.
Evacuate the stomach, with an emetic or by gastric lavage, then administer activated charcoal.
Vital signs should be watched and symptomatic treatment should be administered as required. Hyperirritability or convulsions may be controlled by the administration of parenteral diazepam or barbiturates but they may induce respiratory depression, particularly in children. Paraldehyde may be used to counteract muscular hypertonus
without producing respiratory depression.
When barbiturates are employed, it is advisable to have equipment available for artificial ventilation and resuscitation. Barbiturates should not be used if drugs that inhibit monoamine oxidase have been taken by the patient, either in overdosage or in recent therapy (within 2 weeks).
Hyponatremia should be treated by restricting fluids and a slow and careful NaCl 0.9% infusion i.v. These measures may be useful in preventing brain damage.
Shock (circulatory collapse) should be treated with supportive measures, including i.v. fluids, oxygen and corticosteroids. For hypotension unresponsive to measures taken to increase plasma volume, dopamine or dobutamine i.v. may be administered.
It is recommended that the electrocardiogram be monitored, particularly in children, to detect any cardiac arrhythymias or conduction defects.
Charcoal hemoperfusion has been recommended. Forced diuresis, hemodialysis and peritoneal dialysis have been reported to be ineffective.
Relapse and aggravation of the symptomatology on the 2nd or 3rd day after overdose, due to delayed absorption, should be anticipated.
Dosage
Epilepsy (see Indications):
A low initial daily dosage with a gradual increase in dosage is advised. Dosage should be adjusted to the needs of the individual patient.
Tegretol tablets and chewtabs should be taken in 2 to 4 divided doses daily, with meals whenever possible.
The controlled release characteristics of Tegretol CR reduce the daily fluctuations of plasma carbamazepine. Tegretol CR (either whole or, if so prescribed, only half a tablet) should be swallowed unchewed with a little liquid during or after a meal. These controlled release tablets should be prescribed as a twice-daily dosage. If
necessary, 3 divided doses may be prescribed.
Adults and Children over 12 years:
Initially:
100 to 200 mg once or twice a day depending on the severity of the case and previous therapeutic history. The initial dosage is progressively increased in divided doses, until the best response is obtained. The usual optimal dosage is 800 to 1200 mg daily. In rare instances, some adult patients have received 1600 mg. As soon as
disappearance of seizures has been obtained and maintained, dosage should be reduced very gradually until a minimum effective dose is reached.
Children 6 to 12 years:
Initially:
100 mg in divided doses on the first day. Increase gradually by adding 100 mg per day until the best response is obtained. Dosage should generally not exceed 1000 mg daily. As soon as disappearance of seizures has been obtained and maintained, dosage should be reduced very gradually until a minimum effective dose is reached.
Trigeminal Neuralgia:
The initial daily dosage should be small; 200 mg taken in 2 doses of 100 mg each is recommended. Total daily dosage can be increased by 200 mg per day until relief of pain is obtained. This is usually achieved at a dosage between 200 and 800 mg daily, but occasionally up to 1200 mg per day may be necessary. As soon as relief of pain has
been obtained and maintained, progressive reduction in dosage should be attempted until a minimum effective dosage is reached. Because trigeminal neuralgia is characterized by periods of remission, attempts should be made to reduce or discontinue the use of carbamazepine at intervals of not more than 3 months, depending upon the
individual clinical course.
Prophylactic use of the drug in trigeminal neuralgia is not recommended.
Use in Mania and Bipolar (Manic-Depressive) Disorders:
The initial daily dosage should be low, 200 to 400 mg/day, administered in divided doses, although higher starting doses of 400 to 600 mg/day may be used in acute mania. This dose may be gradually increased until patient symptomatology is controlled or a total daily dose of 1600 mg is achieved. Increments in dosage should be adjusted to
provide optimal patient tolerability. The usual dose range is 400 to 1200 mg/day administered in divided doses. Doses used to achieve optimal acute responses and tolerability should be continued during maintenance treatment. When given in combination with lithium and neuroleptics, the initial dosage should be low, 100 to 200 mg daily, and
then increased gradually. A dose higher than 800 mg/day is rarely required when given in combination with neuroleptics and lithium, or with other psychotropic drugs such as benzodiazepines. Plasma levels are probably not helpful for guiding therapy in bipolar disorders.
