Carbamazepine (Systemic)


VA CLASSIFICATION
Primary: CN400
Secondary: CN103; CN900; HS900

Commonly used brand name(s): Apo-Carbamazepine; Atretol; Carbatrol; Epitol; Novo-Carbamaz; Nu-Carbamazepine; Taro-Carbamazepine; Taro-Carbamazepine CR; Tegretol; Tegretol CR; Tegretol Chewtabs; Tegretol-XR.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticonvulsant—

antineuralgic (specific pain syndromes)—

antimanic—

antidiuretic—

antipsychotic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Epilepsy (treatment)—Carbamazepine is indicated for the treatment of partial seizures with simple or complex symptomatology (psychomotor, temporal lobe) {63}9 {63}8 {63}7 {63}6 {63}5 {63}4 {63}3 {63}2 {63}1; generalized tonic-clonic seizures (grand mal) {63}0 {64}9 {64}8 {64}7 {64}6 {64}5; mixed seizure patterns that include the above {64}4 {64}3 {64}2 {64}1 {64}0 {65}9 {65}8; or other partial or generalized seizures {65}7 {65}6 {65}5.
—Carbamazepine is a first-choice anticonvulsant {65}4 {65}3 because of its relatively low behavioral and psychological toxicity and the rarity of serious adverse effects. {65}2 {65}1

Neuralgia, trigeminal (treatment) {65}0 {103}9 {103}8 {103}7 {103}6 {103}5 {103}4 {103}3—Carbamazepine is indicated for relief of pain due to true trigeminal neuralgia {103}2 {103}1 {103}0 {104}9 {104}8 {104}7 {104}6 (tic douloureux) and glossopharyngeal neuralgia {104}5 {104}4 {104}3 {104}2 {104}1 {104}0.

[Bipolar disorder (prophylaxis and {105}9 {105}8 treatment)]—Carbamazepine is used alone or in combination with lithium and/or antidepressants or antipsychotic agents {105}7 to treat patients with manic-depressive illness who are unresponsive to, or cannot tolerate, lithium or neuroleptics alone.

[Pain, neurogenic, other (treatment) ]1—Carbamazepine may also be used in some patients to relieve the lightning pains of tabes dorsalis; neuralgic pain associated with multiple sclerosis, acute idiopathic neuritis (Guillain-Barré syndrome), peripheral diabetic neuropathy, phantom limb, restless leg syndrome (Ekbom"s syndrome) {105}6 {105}5, and hemifacial spasm {105}4 {105}3 {105}2; post-traumatic neuropathy or neuralgia; and postherpetic neuralgia.

[Diabetes insipidus, central partial (treatment)]1—Carbamazepine is used alone {105}1 or with other agents such as clofibrate or chlorpropamide in the treatment of partial central diabetes insipidus.

[Alcohol withdrawal (treatment)]1—Carbamazepine is used for the detoxification of alcoholics. It has been found to be effective in rapidly relieving anxiety and distress of acute alcohol withdrawal and for such symptoms as seizures, hyperexcitability, and sleep disturbances. {105}0 {47}9

[Psychotic disorders (treatment)]1—Carbamazepine has been shown to be effective in certain psychiatric disorders including schizoaffective illness, resistant schizophrenia, and dyscontrol syndrome associated with limbic system dysfunction. {47}8

Unaccepted
Carbamazepine is not a simple analgesic and should not be used to relieve general aches or pains. {47}7 {47}6 {47}5 {47}4 {47}3 {47}2 {47}1

Carbamazepine is not indicated for atypical or generalized absence seizures (petit mal) {47}0 {61}9 {61}8 {61}7 {61}6 {61}5 {61}4 {61}3 or myoclonic {61}2 {61}1 {61}0 {63}9 {63}8 or atonic seizures. {63}7

Although carbamazepine has also been reported to relieve dystonic attacks in children, reduce migraine attacks, and relieve intractable hiccups in some patients, its therapeutic efficacy in such cases has not been established.

Carbamazepine should not be used prophylactically during long periods of remission in trigeminal neuralgia. {63}6 {63}5 {63}4 {63}3

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Tricyclic iminostilbene derivative. Structurally resembles the psychoactive agents imipramine, chlorpromazine, and maprotiline; shares some structural features with the anticonvulsant agents phenytoin, clonazepam, and phenobarbital {63}2.
Molecular weight—
    236.27 {63}1

pKa—
    7 {63}0 {103}9

Mechanism of action/Effect:

Anticonvulsant—Exact mechanism unknown; may act postsynaptically by limiting the ability of neurons to sustain high frequency repetitive firing of action potentials through enhancement of sodium channel inactivation; in addition to altering neuronal excitability, may act presynaptically to block the release of neurotransmitter by blocking presynaptic sodium channels and the firing of action potentials, which in turn decreases synaptic transmission. {103}8

Antineuralgic—Exact mechanism unknown {103}7 {103}6 {103}5; may involve gamma-aminobutyric acid (GABA B) receptors, which may be linked to calcium channels. {103}4

Antidiuretic—Exact mechanism unknown; may exert a hypothalamic effect on the osmoreceptors mediated via secretion of antidiuretic hormone (ADH), or may have a direct effect on the renal tubule. {103}3

Antimanic; antipsychotic—Exact mechanism unknown; may be related to either the anticonvulsant or the antineuralgic effects of carbamazepine, or to its effects on neurotransmitter modulator systems. {103}2


Other actions/effects:

Anticholinergic {103}1 {103}0 {104}9 {104}8 {104}7 {104}6, antidepressant {104}5, neuromuscular transmission–inhibiting, and antiarrhythmic {104}4 {104}3 {104}2 actions have been reported.

Absorption:

Slow {104}1 {104}0 {105}9 {105}8 and variable, but almost completely absorbed from gastrointestinal tract. {105}7

Distribution:


Apparent volume of distribution (Vol D):

Carbamazepine: Ranges from 0.8 to 2 L per kg. {105}6

Carbamazepine-10,11–epoxide: Ranges from 0.59 to 1.5 L per kg. {105}5



In breast milk:

May reach 60% of the maternal plasma concentration. {105}4 {105}3 {105}2


Protein binding:

Carbamazepine—Moderate (55 to 59% in children, 76% in adults {105}1 {105}0 {01}9). {01}8

Carbamazepine-10,11–epoxide—Moderate (50%) {01}7.

Biotransformation:

Hepatic {01}6 {01}5 {01}4 {01}3 (97%) {01}2; may induce its own metabolism {01}1 {01}0 {35}9 {35}8. One metabolite, carbamazepine-10,11–epoxide, has anticonvulsant {35}7 {35}6 {35}5 {35}4, antidepressant {35}3 {35}2, and antineuralgic {35}1 {35}0 activity.

Half-life:


Carbamazepine:

Initial single dose: May range from 25 to 65 hours. {61}9 {61}8 {61}7

Chronic dosing: May decrease to 8 to 29 hours {61}6 {61}5 (average 12 to 17 hours) {61}4 {61}3 {61}2 because of autoinduction of metabolism {61}1 {61}0 {63}9 {63}8.



Carbamazepine-10,11–epoxide:

5 to 8 hours.


Onset of action:

Anticonvulsant effect—Varies from hours to days {63}7, depending on individual patient. A stable therapeutic concentration may require a month to achieve due to autoinduction of metabolism.

Relief of pain of trigeminal neuralgia—8 {63}6 to 72 hours. {63}5 {63}4

Antimanic response—Usually 7 to 10 days. {63}3

Time to peak concentration:

Suspension—1.5 hours following chronic administration {63}2.

Tablets—4 to 5 hours {63}1 {63}0 {103}9 following chronic administration {103}8.

Extended-release capsules—5.9 (range, 4.1 to 7.7) hours following chronic administration {103}7.

Extended-release tablets—3 to 12 hours following chronic administration {103}6.

Therapeutic plasma concentrations

4 to 12 mcg per mL (16.9 to 50.8 micromoles per L) (in adults) {103}5 {103}4 {103}3 {103}2; variations due to autoinduction of metabolism. {103}1

Elimination:
    Renal—72% (3% as unchanged drug). {103}0 {104}9 {104}8 {104}7
    Fecal—28%. {104}6 {104}5 {104}4 {104}3
    Clearance values ranged from 0.011 to 0.021 L per hour per kg following a single dose of carbamazepine in healthy volunteers, and from 0.025 to 0.540 L per hour per kg following multiple dosing in healthy volunteers and epilepsy patients. {104}2

Note: Large interindividual differences in apparent plasma half-life and total body clearance are related to the phenomenon of autoinduction, which reaches different levels in different individuals. Autoinduction may lead to time-dependent kinetics, in which clearance values increase with time and higher doses are required to maintain the same plasma concentrations. In healthy volunteers, it is estimated that a plateau for autoinduction is reached after 20 to 30 days; in epileptic patients, however, the time course may differ due to previous induction by other medications. {104}1
Although the pharmacokinetic parameters of carbamazepine disposition are similar in children and adults, there is a poor correlation between plasma concentrations and carbamazepine dose in children. Carbamazepine is more rapidly metabolized to the active 10,11–epoxide metabolite in younger age groups than in adults. In children younger than 15 years of age, there is an inverse relationship between the carbamazepine-10,11–epoxide to carbamazepine ratio (CBZ-E/CBZ) and increasing age. {104}0 {105}9



Precautions to Consider

Cross-sensitivity and/or related problems

Patients who are sensitive to tricyclic antidepressants may be sensitive to carbamazepine also. Carbamazepine should be given with caution, if at all, to such patients.

Carcinogenicity/Tumorigenicity

Carbamazepine is considered carcinogenic in Sprague-Dawley rats because doses of 25, 75, and 250 mg per kg per day for 2 years caused a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males. {105}8 {105}7 {105}6 {105}5 {105}4 The significance of these findings for use of carbamazepine in humans is not known. {105}3 {105}2 {105}1 {105}0 {103}9

Pregnancy/Reproduction

Pregnancy—
Carbamazepine crosses the placenta. {103}8 {103}7 {103}6 Although adequate and well-controlled studies in humans have not been done, there have been reports of babies prenatally exposed to carbamazepine having small head circumferences {103}5 {103}4, low birth weights {103}3 {103}2, craniofacial defects {103}1, fingernail hypoplasia {103}0, developmental delays {104}9 {104}8, and spina bifida {104}7 {104}6. When it is essential to continue carbamazepine therapy during pregnancy, serum carbamazepine concentrations must be monitored closely, since adverse effects in the fetus have been associated with high blood concentrations. {104}5

Studies in animals have shown that carbamazepine caused kinked ribs in 1.5% of the offspring of rats receiving 250 mg per kg. {104}4 {104}3 {104}2 {104}1 {104}0 Also, carbamazepine caused cleft palate, deformities of the foot, or anophthalmos in about 3% of the offspring of rats receiving 650 mg per kg. {105}9 {105}8 {105}7 {105}6 {105}5 These doses are 10 to 25 times the human daily dose.

FDA Pregnancy Category C {105}4 {105}3 {105}2.

Also, it must be kept in mind that other anticonvulsants used during pregnancy have been implicated in birth defects in infants born to epileptic mothers. In addition, retrospective studies have suggested that there may be a higher incidence of teratogenic effects with the use of combinations of anticonvulsants than with monotherapy. {105}1 {105}0

Delivery—

To prevent neonatal bleeding disorders, administration of vitamin K to the mother during the last weeks of pregnancy has been recommended. {106}9

Breast-feeding

Carbamazepine is distributed into breast milk. {106}8 {106}7 {106}6 Concentrations in breast milk {106}5 {106}4 {106}3 and in the plasma of nursing infants {106}2 {106}1 have been reported to reach 60% of the maternal plasma concentration. Therefore, the possibility exists that carbamazepine may cause adverse effects in the nursing infant. {106}0 {61}9 In animal studies, nursing rats showed a lack of weight gain and an unkempt appearance with maternal doses of 200 mg per kg. {61}8 {61}7 {61}6 {61}5 {61}4

Pediatrics

Appropriate studies have not been performed in children up to 6 years of age {61}3 {61}2 {61}1 {61}0. However, behavioral changes are more likely to occur in children. {63}9


Geriatrics


Geriatric patients may be more susceptible to carbamazepine-induced confusion or agitation, atrioventricular (AV) heart block, syndrome of inappropriate antidiuretic hormone (SIADH) {63}8, and bradycardia than younger patients.


Dental

The leukopenic and thrombocytopenic effects of carbamazepine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patient instruction in proper oral hygiene should include caution in use of regular toothbrushes, dental floss, and toothpicks.

Surgical

Carbamazepine antagonizes the effects of nondepolarizing muscle relaxants, such as pancuronium. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected. {63}7 {63}6

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Hepatic cytochrome P450 3A4 has been identified as the major isoform responsible for the metabolism of carbamazepine to carbamazepine-10,11–epoxide. Medications that inhibit or induce the CYP3A4 isoenzymes may alter carbamazepine plasma concentrations. Similarly, carbamazepine may inhibit or induce the metabolism of other medications, thus altering their plasma concentrations. {63}5 {63}4


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen{63}3    (risk of hepatotoxicity with single toxic doses or prolonged use of high doses of acetaminophen may be increased, and therapeutic effects of acetaminophen may be decreased, in patients taking hepatic enzyme–inducing agents such as carbamazepine)


Aminophylline or
Oxtriphylline or
Theophylline{63}2{63}1{63}0{64}9{64}8{64}7{64}6    (concurrent use with carbamazepine may stimulate hepatic metabolism of the xanthines [except dyphylline], resulting in increased theophylline clearance {64}5 {64}4)


» Anticoagulants, coumarin- or indandione-derivative{64}3{64}2{64}1{64}0{65}9{65}8{65}7{65}6    (anticoagulant effects may be decreased because of induction of hepatic microsomal enzyme activity, resulting in increased anticoagulant metabolism leading to decreased anticoagulant plasma concentrations and elimination half-life; dosage adjustments based on monitoring of prothrombin time may be necessary during and after carbamazepine therapy)


» Anticonvulsants, hydantoin{65}5{65}4{65}3{65}2{65}1{65}0{66}9{66}8 or
» Anticonvulsants, succinimide{66}7{66}6{66}5 or
» Barbiturates{66}4{66}3{66}2{66}1{66}0{116}9{116}8 or
» Benzodiazepines metabolized via hepatic microsomal enzymes, especially clonazepam{116}7{116}6 or
» Primidone{116}5{116}4{116}3{116}2{116}1{116}0{80}9 or
» Valproic acid{80}8{80}7{80}6{80}5    (concurrent use with carbamazepine may result in increased metabolism, leading to decreased serum concentrations and reduced elimination half-lives of these medications because of induction of hepatic microsomal enzyme activity {80}4; monitoring of serum concentrations as a guide to dosage is recommended, especially when any of these medications or carbamazepine is added to or withdrawn from an existing regimen)

    (valproic acid {80}3 may prolong the half-life {80}2 and reduce the protein-binding {80}1 {80}0 of carbamazepine; the concentration of the active 10,11-epoxide metabolite may be increased {89}9 {89}8 {89}7 {89}6 {89}5 {89}4)

    (in addition, use of carbamazepine in combination with other anticonvulsants has been reported to be associated with an increased risk of congenital defects {89}3 {89}2 and with an alteration of thyroid function {89}1 )


» Antidepressants, tricyclic{89}0{116}9 or
Clozapine{116}8{116}7 or
Haloperidol{116}6{116}5{116}4{116}3{116}2{116}1{116}0 or
Loxapine{116}9 or
Maprotiline{116}8 or
Molindone{116}7 or
Phenothiazines{116}6{116}5 or
Pimozide{116}4 or
Thioxanthenes{116}3    (concurrent use of these agents with carbamazepine may enhance the central nervous system [CNS]–depressant effects of carbamazepine, lower the seizure threshold, and decrease the anticonvulsant effects of carbamazepine; dosage adjustments may be necessary to control seizures; anticholinergic effects may be potentiated, leading to confusion and delirium {116}2)

    (also, concurrent use of haloperidol, and possibly other neuroleptics, with carbamazepine may decrease plasma concentrations of the neuroleptic by about 60% with or without adverse clinical effects; close observation of patient for clinical signs of ineffectiveness of the neuroleptic is recommended; dosage adjustment may be necessary {116}1)


Carbonic anhydrase inhibitors{116}0{116}9{116}8    (concurrent use may increase the risk of carbamazepine-induced osteopenia; it is recommended that patients receiving concurrent therapy be monitored for early signs of osteopenia and that the carbonic anhydrase inhibitor be discontinued and appropriate treatment initiated if necessary)


Chlorpropamide or
Desmopressin or
Lypressin or
Posterior pituitary or
Thiazide diuretics, when used for their paradoxical antidiuretic activity in the treatment of diabetes insipidus, or
Vasopressin    (concurrent use with carbamazepine may potentiate the antidiuretic effect, leading to a lower sodium concentration and causing adverse effects that include increased seizure activity {116}7; a reduction in dosage of either or both medications may be necessary for optimal therapeutic effect in the treatment of diabetes insipidus)


» Cimetidine{116}6{116}5{116}4{116}3{116}2{116}1{116}0{116}9{116}8{116}7    (concurrent use may result in increased plasma concentrations of carbamazepine by delaying its clearance, leading to carbamazepine toxicity {116}6 {116}5 {116}4 {116}3)


Cisplatin{116}2{116}1 or
Doxorubicin{116}0{116}9 or
Rifampin{116}8{116}7    (concurrent use with carbamazepine may cause an increased rate of metabolism of carbamazepine, resulting in decreased plasma concentrations)

    (rifampin also increases the plasma concentrations of the 10,11–epoxide metabolite)


» Clarithromycin{116}6{116}5{116}4    (administration of carbamazepine with clarithromycin has been shown to significantly increase the plasma concentration of carbamazepine; carbamazepine plasma concentrations should be monitored)


» Contraceptives, estrogen-containing, oral{116}3{116}2{116}1{116}0{116}9{116}8{116}7{116}6{116}5{116}4{116}3{116}2{116}1 {116}0 or
Cyclosporine{116}9 or
Dacarbazine or
Digitalis glycosides, with the possible exception of digoxin or
Disopyramide or
» Estrogens{116}8 , including estramustine or
Levothyroxine or
Methadone{116}7{116}6 or
Mexiletine{116}5{116}4 or
» Quinidine{116}3    (concurrent use may decrease the effects of these medications because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; dosage adjustments may be necessary)

    (in addition, concurrent use of oral, estrogen-containing contraceptives with carbamazepine may result in breakthrough bleeding {116}2 {116}1 {116}0 {116}9 {116}8 {116}7 and contraceptive failure {116}6 {116}5 {116}4 {116}3 {116}2 due to the increased rate of hepatic enzyme metabolism of steroids induced by carbamazepine {116}1 {116}0; the dose of the estrogenic substance in the oral contraceptive may be increased to diminish bleeding and decrease the risk of conception {116}9 {116}8; parenteral medroxyprogesterone {116}7 or nonhormonal methods of birth control {116}6 {116}5 {116}4 {116}3 {116}2 may be considered as alternatives)


» Corticosteroids{116}1{116}0    (concurrent use may decrease the corticosteroid effect because of increased corticosteroid metabolism resulting from induction of hepatic microsomal enzymes {116}9 {116}8)


Danazol{116}7{116}6 or
» Diltiazem or{116}5{116}4{116}3{116}2{116}1{116}0
Felodipine{116}9{116}8 or
Loratadine{116}7{116}6 or
Niacinamide{116}5{116}4 or
Terfenadine{116}3{116}2 or
» Verapamil{116}1{116}0{116}9{116}8{116}7    (concurrent use of these agents with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentrations and toxicity {116}6 {116}5 {116}4)

    (carbamazepine toxicity may be delayed for several weeks after initiation of danazol therapy; carbamazepine dosage may need to be reduced)

    (it is recommended that nifedipine be used as an alternative to verapamil or diltiazem {116}3 {116}2)


Doxycycline{116}1{116}0{116}9{116}8{116}7{116}6    (concurrent use may decrease plasma concentration and elimination half-life of doxycycline because of induction of hepatic microsomal enzyme activity; if concurrent use cannot be avoided, doxycycline plasma concentrations or the therapeutic response to doxycycline should be closely monitored and dosage adjustments made as necessary)


Enflurane or
Halothane{116}5 or
Methoxyflurane    (chronic use of a hepatic enzyme–inducing agent such as carbamazepine prior to anesthesia may increase the metabolism of these anesthetics, leading to an increased risk of hepatotoxicity)

    (formation of nephrotoxic metabolites of methoxyflurane may be increased by chronic use of a hepatic enzyme–inducing agent such as carbamazepine prior to anesthesia, leading to increased risk of nephrotoxicity)

    (in addition, cardiac arrhythmias may occur, possibly due to sensitization of the myocardium resulting from increased concentrations of norepinephrine {116}4)


» Erythromycin{116}3{116}2{116}1{116}0{116}9{116}8{116}7{116}6{116}5{116}4 or
Troleandomycin{116}3{116}2{116}1    (concurrent use of these agents with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentrations and toxicity; it is recommended that an alternate antibiotic to erythromycin or troleandomycin be used)


» Felbamate{116}0{60}9    (concurrent use may decrease carbamazepine plasma concentrations by about 20 to 30% {60}8 {60}7 {60}6 and increase carbamazepine-10,11–epoxide plasma concentrations by about 60% {60}5 {60}4, leading to an increase in adverse effects {60}3; enzyme induction by carbamazepine may lead to decreased felbamate plasma concentrations {60}2 {60}1 {60}0 {80}9; carbamazepine dosage should be reduced by 20 to 33% when felbamate therapy is initiated {80}8, and plasma concentrations of carbamazepine should be monitored with further dosage adjustments made as clinically necessary {80}7)


Folic acid{80}6{80}5    (requirements for folic acid may be increased in patients receiving anticonvulsant therapy)


Fluoxetine{80}4{80}3{80}2{80}1 or
» Fluvoxamine{80}0{89}9    (concurrent use with carbamazepine may inhibit the metabolism of carbamazepine, resulting in increased plasma concentrations and toxicity; carbamazepine plasma concentrations should be monitored)


Influenza virus vaccine{89}8    (concurrent use with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentrations and toxicity; carbamazepine plasma concentrations may be increased on days 7 to 14 after influenza virus vaccination; dosage adjustments of carbamazepine based on the patient's clinical status and plasma carbamazepine concentrations may be necessary {89}7)


» Isoniazid{89}6{89}5{89}4{89}3{89}2{89}1{89}0{59}9    (carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of a reactive intermediate and leading to hepatotoxicity; also, isoniazid administration may result in elevated plasma concentrations of carbamazepine and possible toxicity {59}8 {59}7 {59}6 {59}5 {59}4)


Isotretinoin{59}3{59}2{59}1{59}0{124}    (concurrent use with carbamazepine alters the bioavailability and/or clearance of carbamazepine and its active 10,11–epoxide metabolite; plasma concentrations should be monitored)


» Itraconazole{116}{120} and
» Ketoconazole{116}    (concurrent use with carbamazepine may inhibit the metabolism of carbamazepine, resulting in increased plasma concentrations and toxicity)

    (concurrent use of carbamazepine with itraconazole may decrease itraconazole plasma concentrations, leading to treatment failure or relapse)


» Lamotrigine{122}{123}{124}    (concurrent use with carbamazepine increases the clearance of lamotrigine; initial lamotrigine dosage and rate of lamotrigine dosage escalation should be based on concomitant anticonvulsant therapy; monitoring of plasma concentrations of lamotrigine and carbamazepine should be considered, especially during dosage adjustments)

    (an increased incidence of CNS adverse effects, including ataxia, blurred vision, diplopia, dizziness, or increased excitation, may occur with concomitant use of lamotrigine; dose reduction of either lamotrigine or carbamazepine may decrease these effects)


Lithium{59}{61}{62}{63}{69}{81}{87}{94}    (concurrent use may decrease the antidiuretic effect of carbamazepine {17} {35} and increase the neurotoxic side effects {17} {35} {87} even at nontoxic blood concentrations of both lithium and carbamazepine {17} {35}; however, the concurrent use of lithium with carbamazepine may be synergistic in the treatment of patients with manic-depressive illness who fail to respond to either drug alone {14} {18})


Mebendazole{43}    (in patients receiving high oral doses of mebendazole for treatment of tissue-dwelling organisms such as Echinococcus multilocularis or granulosus [Hydatid disease], carbamazepine has been shown to lower plasma mebendazole concentrations by induction of hepatic microsomal enzymes and to impair the therapeutic response; if carbamazepine is being used for seizures, replacement with another anticonvulsant is recommended; treatment of intestinal helminths such as whipworms or hookworms does not appear to be affected by the rate of hepatic metabolism of mebendazole {43})


Metoclopramide{117}{119}    (concurrent use with carbamazepine may increase the risk of neurotoxic side effects, even if plasma concentrations remain in the therapeutic range)


» Monoamine oxidase (MAO) inhibitors, including furazolidone and procarbazine{59}{61}{62}{63}    (concurrent use with carbamazepine has resulted in hyperpyretic crises, hypertensive crises, severe convulsions, and death; a medication-free interval of at least 14 days is recommended between discontinuation of MAO inhibitor therapy and initiation of carbamazepine therapy, or vice versa {59} {61} {62} {63} {64} {65} {66})

    (MAO inhibitors may also cause a change in the pattern of epileptiform seizures in patients receiving carbamazepine as an anticonvulsant)


Pancuronium{117}{119}    (carbamazepine antagonizes the effects of nondepolarizing muscle relaxants; dosage of the muscle relaxant may need to be increased; patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected)


Praziquantel{98}{99}    (one small, single-dose, controlled study found that epileptic patients taking carbamazepine had significantly lower plasma concentrations of praziquantel [7.9% of the control group]; this effect is thought to be due to induction of the cytochrome P450 microsomal enzyme system by carbamazepine; patients on carbamazepine may require a larger dose of praziquantel {98} {99})


» Propoxyphene{59}{61}{62}{63}{69}{80}{81}{87}{88}{94}    (concurrent use with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentrations and toxicity {61} {62}; an analgesic other than propoxyphene should be used)


» Risperidone{107}{108}{109}    (chronic administration of carbamazepine may increase the clearance of risperidone {107})


Tiagabine{125}    (tiagabine clearance is increased by 60% in patients taking carbamazepine)


Topiramate{126}    (when these two medications were given concurrently, the mean carbamazepine area under the plasma concentration–time curve [AUC] was unchanged or changed by less than 10%, whereas the AUC of topiramate was decreased by 40%)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Metyrapone test    (increased metabolism of metyrapone by a hepatic enzyme inducer such as carbamazepine may decrease the response to metyrapone {79} {87})


Pregnancy test    (false-negative results may occur with the use of tests that determine human chorionic gonadotropin [HCG] {30})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum, and
Alkaline phosphatase, serum, and
Aspartate aminotransferase (AST [SGOT]), serum{59}{61}{62}{63}{64}{65}{66}{80}     (values may be increased)


Bilirubin, serum{85} and
Blood urea nitrogen (BUN){59}{61}{62}{63}{64}{65}{66}    (concentrations may be increased)


Cholesterol, serum{81}{93} and
High-density lipoprotein cholesterol, serum{81}{93} and
Triglyceride, serum{81}{93}    (concentrations may occasionally be increased)


Free cortisol, urine{80}    (may be increased)


Glucose, urine{59}{61}{62}{63}{64}{65}{66} and
Protein (albumin), urine{59}{61}{62}{63}{64}{65}{66}    (may be detected in the urine)


Ionized{76} calcium, serum{04}    (concentrations may be decreased)


Thyroid hormones{61}{62}{63}    (serum concentrations of T 3, free T 4, and free T 4 index may be decreased due to increased hepatic metabolism of hormones during long-term therapy with carbamazepine; thyroid size may be increased as a compensatory mechanism {36})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Absence seizures, atypical{61}{62}{63} or generalized or
» Atonic seizures or
» Myoclonic seizures    (increased risk of generalized seizures {61} {62} {63} {31})


» Atrioventricular (AV) heart block{59}{61}{62}{63}{64}{65}{66} or
» Blood disorders characterized by serious abnormalities in blood count, platelets, or serum iron{59}{61}{64}{65}{66} or
» Bone marrow depression, history of{61}{62}{63}    (increased risk of exacerbation)


Risk-benefit should be considered when the following medical problems exist
Alcoholism, active{59}{64}{65}{66}{88}    (CNS depression may be potentiated; in addition, the metabolism of carbamazepine may be accelerated {88})


Behavioral disorders    (latent psychosis may be activated, or agitation or confusion may be produced in elderly patients, especially when carbamazepine is used concurrently with other medications {59} {61} {62} {63} {64} {65} {66})


Cardiac damage, including organic heart disease and congestive heart disease{59}{61}{62}{63}{64}{65}{66} or
Coronary artery disease{59}{61}{62}{63}{64}{65}{66}    (may be exacerbated)


Diabetes mellitus    (elevated urine glucose concentrations may occur)


Glaucoma or
Increased intraocular pressure    (may be exacerbated because of mild anticholinergic effects of carbamazepine {59} {61} {62} {63} {64} {65} {66})


Hematologic reactions, adverse, to other medications, history of{61}{62}{63}    (patients may be especially at risk for carbamazepine-induced bone marrow depression)


Hepatic function impairment{59}{61}{62}{63}{64}{65}{66}{80}    (increased risk of liver damage)


Hyponatremia, dilutional, caused by syndrome of inappropriate antidiuretic hormone (SIADH) secretion or other conditions such as hypopituitarism, hypothyroidism, or adrenocortical insufficiency or
Urinary retention{59}{64}{65}{66}    (may be exacerbated)


Renal function impairment{61}{62}{63}    (excretion of carbamazepine may be altered)


Sensitivity to carbamazepine{59}{61}{62}{63} or to tricyclic antidepressants{59}{61}{62}{63}{64}{65}{66}
Caution is also advised in administration to patients who have had interrupted courses of therapy with carbamazepine.{61}{62}{63}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood counts, complete (CBCs), including platelet and possibly reticulocyte counts{59}{61}{62}{63}{64}{65}{66} and
» Iron concentrations, serum{61}{62}{63}    (determinations recommended prior to initiation of therapy as a baseline. Patients who develop low or decreased white blood cell or platelet counts during the course of treatment should be monitored closely and carbamazepine discontinued if there is any evidence of significant bone marrow depression {61} {62} {63})


BUN determinations{61}{62}{63} and
Ophthalmologic examinations, including slit-lamp funduscopy and tonometry, where indicated,{59}{61}{62}{63}{65} and
Urinalysis, complete{59}{61}{62}{63}{65}{66}    (recommended prior to initiation of therapy and at periodic intervals during therapy {61} {62})


» Carbamazepine concentrations, plasma{61}{62}{63}    (determinations recommended periodically as a guide to efficacy and safety; plasma concentrations of 6 to 12 mcg per mL [25 to 51 micromoles per L] are optimal for anticonvulsant activity {67} and, in rare cases, concentrations may go up to 16 mcg per mL [68 micromoles per L]; when used to treat psychiatric disorders, carbamazepine plasma concentrations of 8 to 12 mcg per mL [34 to 51 micromoles per L] are optimal; taking sample prior to the morning dose to determine lowest daily concentration is suggested {49})


Electrocardiogram (ECG) readings and
Electrolyte concentrations, serum    (determinations recommended prior to therapy and periodically during therapy because of possibility of hyponatremia {33} {35})


» Ionized calcium concentrations, serum    (recommended every 6 months or if seizure frequency increases after weeks or months of carbamazepine therapy, since hypocalcemia decreases seizure threshold {48})


Liver function tests{59}{61}{62}{63}{65}{66}    (recommended prior to initiation of therapy and at periodic intervals during therapy; discontinuation of carbamazepine should be considered immediately upon evidence of aggravated liver function impairment or new disease {61} {62} {63})




Side/Adverse Effects

Note: Carbamazepine-induced stimulation of antidiuretic hormone (ADH) release may cause water retention resulting in significant volume expansion and dilutional hyponatremia (syndrome of inappropriate secretion of antidiuretic hormone). {80} Patients reporting lethargy, weakness, nausea, vomiting, confusion or hostility, neurological abnormalities, stupor, or increased seizure frequency should be suspected of being hyponatremic, although many of these symptoms may also be associated with other carbamazepine-induced side effects. {35}
A case of aseptic meningitis accompanied by myoclonus and peripheral eosinophilia has been reported in a patient taking carbamazepine in conjunction with other medications; rechallenge with carbamazepine resulted in recurrence of meningitits. {81} {95}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
CNS toxicity{59}{61}{62}{63}{64}{65}{66} , including blurred or double vision{80}
or nystagmus{49}{81}{91} (continuous back-and-forth eye movements)

Incidence less frequent
    
Allergic reaction
Stevens-Johnson syndrome
or toxic epidermal necrolysis (skin rash, hives, or itching){49}{59}{61}{62}{63}{65}{81}
    
behavioral changes{34} —especially in children
    
diarrhea, severe{49}
    
hyponatremia{59}{69}{80}{81}{90}{93} , dilutional, or water intoxication (SIADH){81}{90} (confusion, agitation, or hostility, especially in the elderly; continuing headache; increase in seizure frequency; severe nausea and vomiting; unusual drowsiness; weakness){49}
    
systemic lupus erythematosus (SLE)-like syndrome{61}{62}{80}{81} (skin rash, hives, or itching; fever; sore throat; bone or joint pain; unusual tiredness or weakness)

Note: The risk of hyponatremia and SIADH appears to increase with patient age and serum concentration of carbamazepine {80}; hyponatremia seemingly does not occur in children {80}.


Incidence rare
    
Adenopathy{59}{61}{62}{63} or lymphadenopathy{59}{61}{62}{63}{64}{65}{66} (swollen glands)
    
blood dyscrasias, including aplastic anemia{59}{61}{62}{63}{64}{65}{66}{67}{80} (shortness of breath, troubled breathing, wheezing, or tightness in chest; sores, ulcers, or white spots on lips or in mouth; swollen or painful glands; unusual bleeding or bruising), agranulocytosis{59}{61}{62}{63}{64}{65}{66}{67} (chills; fever; sore throat; unusual tiredness or weakness), eosinophilia{59}{61}{62}{63}{64}{65}{66} (fever), leukopenia{59}{61}{62}{63}{64}{65}{66}{80} (usually asymptomatic; rarely, fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination), pancytopenia{61}{62} (nosebleeds or other unusual bleeding or bruising), and thrombocytopenia{59}{61}{62}{63}{64}{65}{66}{80} (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
    
bone marrow depression{61}{62} (chills; fever; sore throat; unusual bleeding or bruising)
    
cardiovascular effects, including arrhythmias{61}{62}{63}{69} (fast, slow, or irregular heartbeat), atrioventricular (AV) heart block{61}{62}{63} (unusual weakness; pounding heartbeat; troubled breathing; fainting), bradycardia (slow heartbeat), congestive heart failure{59}{61}{62}{63}{64}{65}{66} (chest pain; troubled breathing; swelling of feet or lower legs; rapid weight gain), edema{59}{61}{62}{63}{64}{65}{66} (swelling of face, hands, feet, or lower legs), hypertension, increased{59}{61}{62}{63}{64}{65}{66} (high blood pressure), hypotension{59}{61}{62}{63}{64}{65}{66} (low blood pressure), and syncope{59}{61}{62}{63}{64}{65}{66} (fainting)
    
CNS toxicity (difficulty in speaking or slurred speech{59}{61}{62}{63}{64}{65}{66}; mental depression with restlessness and nervousness{59}{61}{62}{63}{64}{65}{66}; rigidity{35}; ringing, buzzing, or other unexplained sounds in the ears{59}{61}{62}{63}{64}{65}{66}; trembling{35}; uncontrolled body movements{59}{61}{62}{63}{64}{65}{66}; visual hallucinations{59}{61}{62}{63})
    
hypersensitivity hepatitis{49}{80} (darkening of urine; pale stools; yellow eyes or skin)
    
hypocalcemia{49}{54}{69} (increase in seizure frequency; muscle or abdominal cramps)
    
renal toxicity, renal failure, acute,{59}{61}{62}{63}{80} or water intoxication (SIADH){61}{62}{63} (frequent urination; sudden decrease in amount of urine; swelling of feet or lower legs)
    
paresthesias{59}{61}{62}{63}{64}{65}{66} or peripheral neuritis{59}{61}{62}{63}{64}{65}{66} (numbness, tingling, pain, or weakness in hands and feet)
    
porphyria, acute intermittent{81}{93} (darkening of urine)
    
pulmonary hypersensitivity{59}{61}{62}{63}{92} (fever; troubled breathing; cough; shortness of breath; tightness in chest; wheezing)
    
thrombophlebitis{59}{61}{62}{63}{64}{65} (pain, tenderness, bluish color, or swelling of leg or foot)

Note: Geriatric patients and those with a defective conduction system may be especially susceptible to AV heart block or bradycardia with carbamazepine.
Hypocalcemia may lead to osteopenia as a direct effect of carbamazepine on bone metabolism.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent, especially during initiation of therapy
    
Clumsiness or unsteadiness{59}{61}{62}{63}{64}{65}{66}{67}{69}
    
confusion{59}{61}{62}{63}{64}{65}{66}
    
dizziness, mild{59}{61}{62}{63}{64}{65}{66}{80} , or lightheadedness
    
drowsiness, mild{59}{61}{62}{63}{64}{65}{66}{67}{69}
    
nausea or vomiting, mild{59}{61}{62}{63}{64}{65}{66}{69}{80}

Incidence less frequent or rare
    
Aching joints or muscles,{59}{61}{62}{63}{64}{65}{66} or leg cramps{59}{61}{62}{63}{64}{65}{66}
    
alopecia{59}{61}{62}{63}{64}{65}{66} (loss of hair)
    
anorexia{59}{61}{62}{63}{64}{65}{66} (loss of appetite)
    
constipation{59}{61}{62}{63}
    
diaphoresis{59}{61}{62}{63}{64}{65}{66} (increased sweating)
    
diarrhea{59}{61}{62}{63}{64}{65}
    
dryness of mouth{59}{61}{62}{63}{64}{65}{66}
    
glossitis or stomatitis{59}{61}{62}{63}{64}{65}{66} (irritation or soreness of tongue or mouth)
    
headache{59}{61}{62}{63}{64}{65}{66}{69}{80}
    
increased sensitivity of skin to sunlight{59}{61}{62}{63}{64}{65}{66}
    
sexual problems in males{59}{61}{62}{63}{64}{65}{66}
    
stomach pain or discomfort{59}{61}{62}{63}{64}{65}{66}
    
unusual tiredness or weakness{59}{61}{62}{63}{64}{65}{66}





Overdose

Note: For specific information on the agents used in the management of carbamazepine overdose, see:    • Barbiturates (Systemic) monograph;
   • Benzodiazepines (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • Laxatives (Local) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).


Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Anuria, oliguria, or urinary retention {59}{61}{62}{63}{64}{65}{66}(sudden decrease in amount of urine)
    
cardiovascular effects, including conduction disorders{61}{62}{63}{81} or tachycardia{61}{62}{63}{81}{91} (fast or irregular heartbeat)
    
convulsions{61}{62}{63}{64}{81} —especially in small children{61}{62}{63}{81}
    
dizziness, severe{59}{61}{62}{63}{64}{65}{66}{80}
    
drowsiness, severe{59}{61}{62}{63}{64}{65}{66}{81}{91}
    
dysmetria{81} (poor control in body movements—for example, when reaching or stepping)
    
hyperreflexia, followed by hyporeflexia{81}{91} (overactive reflexes, followed by underactive reflexes)
    
hypertension or hypotension{61}{62}{63}{81} (high or low blood pressure)
    
motor restlessness{81}
    
muscular twitching{81}
    
mydriasis{81} (large pupils)
    
nausea or vomiting, severe{59}{61}{62}{63}{64}{65}{66}{80}
    
neurological effects, including ataxia{81}{91} (clumsiness or unsteadiness)
    
athetoid movements{81} or ballism{81} (abnormal body movements)
    
opisthotonus{81} (body spasm in which head and heels are bent backward and body bowed forward)
    
respiratory depression{61}{62}{63}{81}{91} (irregular, slow, or shallow breathing)
    
shock{61}{62}{63}{81} (fainting)
    
tremor{81}{91}

Note: Signs and symptoms of acute toxicity may occur 1 to 3 hours following ingestion of an overdose. Neurological and neuromuscular symptoms predominate, followed by cardiovascular toxicity. Symptoms resemble those observed following overdose with tricyclic antidepressants. Cardiotoxic effects are more likely to occur in elderly and cardiopathic patients.
Laboratory findings in overdosage may indicate leukocytosis, reduced leukocyte count, glycosuria, acetonuria, and electroencephalogram (EEG) dysrhythmias.



Treatment of overdose
Recommended treatment consists of the following:



• To decrease absorption—Induction of emesis or gastric lavage {59} {61} {62} {63} {64} {65} {66}, followed by administration of activated charcoal or laxatives to reduce further absorption. {61} {62} {63}


• To enhance elimination—Forced diuresis may accelerate elimination. {61} {62} {63} Dialysis is indicated only in severe poisoning associated with renal failure. {61} {62} {63} In small children, severe poisoning may require replacement transfusion. {61} {62} {63}


• Specific treatment—For hypotension and shock, elevation of patient's legs and administration of a plasma volume expander. {61} {62} {63} Use of a vasopressor may be considered if other measures are insufficient. {61} {62} {63} Administration of a benzodiazepine or a barbiturate as required for seizures. The fact that these agents may aggravate respiratory depression (especially in children) {01} {35}, hypotension, and coma must be considered. Also, barbiturates or benzodiazepines should not be used if the patient has taken a monoamine oxidase inhibitor within the previous 14 days {47} {59} {61} {62} {63} {64} {65} {66}.


• Monitoring—Monitoring of respiration, cardiac function, blood pressure, body temperature, pupillary reflexes, and kidney and bladder function for several days. {61} {62} {63}


• Supportive care—Maintenance of a patent airway with tracheal intubation, artificial respiration, and/or administration of oxygen. {61} {62} {63} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Carbamazepine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tricyclic antidepressants or carbamazepine

Pregnancy—Crosses placenta; babies reportedly born with small head circumference, low birth weight, craniofacial defects, fingernail hypoplasia, developmental delays, and spina bifida; animal studies have shown rib anomalies, cleft palate, foot deformities, or anophthalmos with doses 10 to 25 times the human dose





Breast-feeding—Distributed into breast milk; animal studies have shown lack of weight gain and unkempt appearance of young at high doses





Use in children—Appropriate studies have not been done in children up to 6 years of age; behavior changes more likely to occur in children






Use in the elderly—Elderly more likely to have confusion or agitation, AV heart block, SIADH, or bradycardia than are younger people





Dental—Increased incidence of blood dyscrasias that cause infection, delayed healing, or gingival bleeding; proper oral hygiene necessary

Surgical
Recovery from neuromuscular blockade induced by nondepolarizing muscle relaxants such as pancuronium may be more rapid than expected due to antagonism by carbamazepine
Other medications, especially anticoagulants, other anticonvulsants, tricyclic antidepressants, barbiturates, benzodiazepines metabolized via hepatic microsomal enzymes (especially clonazepam), cimetidine, clarithromycin, oral estrogen-containing contraceptives, corticosteroids, diltiazem, erythromycin, estrogens, isoniazid, fluvoxamine, itraconazole, ketoconazole, lamotrigine, MAO inhibitors, propoxyphene, quinidine, risperidone, or verapamil
Other medical problems, especially absence, atonic, or myoclonic seizures; AV heart block; blood disorders; or bone marrow depression

Proper use of this medication
» Taking with food to lessen gastrointestinal irritation

» Compliance with therapy; not taking more or less medication than prescribed

» Not using medication for minor aches and pains

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses; calling physician if more than one dose a day is missed

» Proper storage; not storing tablet dosage forms in bathroom or other high-moisture areas due to loss of potency and effectiveness

For use in epilepsy
» Checking with physician before discontinuing medication; gradual dosage reduction may be necessary to prevent seizures or status epilepticus

Precautions while using this medication
» Regular visits to physician to check progress of therapy

» Avoiding the use of alcoholic beverages and other CNS depressants while taking this medicine

» Possible drowsiness, dizziness, lightheadedness, blurred or double vision, weakness, or muscular incoordination; caution when driving or using machinery, or doing jobs requiring alertness and coordination

» Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth

» Using different or additional means of birth control than estrogen-containing oral contraceptives

Diabetic patients: May increase urine sugar concentrations

Caution if any laboratory tests required; possible interference with results of metyrapone or pregnancy tests

» Caution if any kind of surgery, dental treatment, or emergency treatment is needed

Carrying medical identification card or bracelet during therapy


Side/adverse effects
Signs of potential side effects, especially CNS toxicity, allergic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, behavioral changes, severe diarrhea, dilutional hyponatremia or water intoxication (SIADH), SLE-like syndrome, adenopathy or lymphadenopathy, blood dyscrasias, bone marrow depression, cardiovascular effects, hypersensitivity hepatitis, hypocalcemia, renal toxicity or failure, paresthesias or peripheral neuritis, porphyria, pulmonary hypersensitivity, or thrombophlebitis


General Dosing Information
Side effects may be minimized by initiating therapy with low doses, which should be increased gradually at weekly intervals {47} until an adequate response is obtained {61} {62}; administering carbamazepine with meals, and giving the total daily dosage in 3 or 4 divided doses may also minimize side effects. {61} {62} {63} {64} {65} {66}

When carbamazepine is added to existing anticonvulsant therapy, it should be added gradually while the other anticonvulsants are maintained or gradually decreased, except for phenytoin, which may have to be increased {47} {61} {62} {63}.

The maintenance dosage of carbamazepine may need to be increased progressively over the first few weeks of treatment to avoid low plasma carbamazepine concentrations caused by autoinduction. {49} {80}

Abrupt discontinuation in a responsive epileptic patient may result in convulsions and possibly status epilepticus; gradual withdrawal is recommended. {61} {62} {63}

Therapy should be discontinued if cardiovascular reactions or skin rashes occur, or if evidence of significant bone marrow depression develops. {121}

When carbamazepine is used as an antineuralgic in specific pain syndromes, an attempt should be made at least once every few months to reduce dosage or discontinue therapy if the patient is totally free of pain. {59} {61} {62} {63} {64} {65} {66}

Carbamazepine suspension should not be administered simultaneously with other liquid medications or diluents because of the possibility of precipitation of an orange rubbery mass {129}. This phenomenon has been observed after mixing carbamazepine suspension with chlorpromazine solution or with liquid forms of thioridazine hydrochloride {129}.

Diet/Nutrition
Carbamazepine suspension and tablets should be taken with food to lessen gastrointestinal irritation. {59} {61} {62} {63} {65} {66} Carbamazepine extended-release capsules may be taken with or without food. {116} The contents of carbamazepine extended-release capsules may also be sprinkled over food (such as a teaspoonful of applesauce or other similar food products); the capsule or its contents should not be crushed or chewed. {116}

The requirements for folic acid may be increased in patients receiving anticonvulsant therapy {68} {94}.

Bioequivalence information
Administration of carbamazepine suspension results in higher peak serum concentrations than does the same dose administered as tablets. It is recommended that doses of the suspension be initially lower and be increased more slowly than doses of the tablets to avoid side effects. {62}

For treatment of adverse effects
Treatment of bone marrow depression includes the following:

   • Discontinuing carbamazepine therapy. {61} {62} {63}
   • Daily CBC, platelet, and reticulocyte counts. {61} {62} {63}
   • Performing a bone marrow aspiration and trephine biopsy immediately and repeating with sufficient frequency to monitor recovery. {61} {62} {63}
   • Considering other studies that may be helpful, including white cell and platelet antibodies; 59Fe—ferrokinetic studies; peripheral blood cell typing; cytogenic studies on marrow and peripheral blood; bone marrow culture studies for colony-forming units; hemoglobin electrophoresis for A 2 and F hemoglobin; and serum folic acid and B 12 concentrations. {01} {61} {62} {63} If aplastic anemia develops, specialized consultation should be sought for appropriate monitoring and treatment. {61} {62} {63}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CARBAMAZEPINE ORAL SUSPENSION USP

Usual adult and adolescent dose
Anticonvulsant
Initial: Oral, 100 mg four times a day on the first day, the dosage being increased by up to 200 mg a day at weekly intervals. {62} {103} Some clinicians recommend initiating therapy at 100 mg a day and increasing to full therapeutic dosage slowly at weekly intervals to avoid side effects and potential noncompliance. {80} {89}

Maintenance: Oral, usually 800 mg to 1.2 grams a day. {62}

Antineuralgic
Initial: Oral, 50 mg four times a day on the first day, the dosage being increased by up to 200 mg a day, using increments of 50 mg four times a day only as needed until pain is relieved. {62} {103}

Maintenance: Oral, 200 mg to 1.2 grams a day (average 400 to 800 mg a day) in divided doses. {62} {103}

[Antidiuretic]1
Oral, 300 to 600 mg a day if used as sole therapy; or 200 to 400 mg a day if used concurrently with other antidiuretic agents.

[Antimanic]1 or
[Antipsychotic]1
Oral, initially 200 to 400 mg a day in divided doses, the dosage being gradually increased at weekly intervals up to a maximum of 1.6 grams a day as needed and tolerated according to clinical response. {35} {41}

Note: Whenever possible, total daily dosage should be given in 3 or 4 divided doses. {62}



Usual adult and adolescent prescribing limits
Anticonvulsant


Patients 12 to 15 years of age:
Dosage should generally not exceed 1 gram a day. {62} {103}



Patients 15 years of age and over:
Dosage should generally not exceed 1.2 grams a day. {62} {103} In rare instances, doses of up to 1.6 grams a day have been used in adults. {62}


Antineuralgic
Dosage should not exceed 1.2 grams a day. {62}


Usual pediatric dose
Anticonvulsant


Children up to 6 years of age {47}:
Initial—Oral, 10 to 20 mg per kg of body weight a day in two or three divided doses, the dosage being increased by up to 100 mg a day at weekly intervals as needed and tolerated.

Maintenance—Oral, adjusted to the minimum effective dosage, usually 250 to 350 mg a day, and generally not exceeding 400 mg or 35 mg per kg of body weight a day.



Children 6 to 12 years of age :
Initial—Oral, 50 mg four times a day on the first day, the dosage being increased by up to 100 mg a day at weekly intervals until the best response is obtained. {62}

Maintenance—Oral, adjusted to the minimum effective dosage, usually 400 to 800 mg a day. {01} {35} {62} {103}



Note: Dosage generally should not exceed 1 gram a day. {62} {103}
Whenever possible, total daily dosage should be given in 3 or 4 divided doses. {62}


Strength(s) usually available
U.S.—


100 mg per 5 mL (Rx) [Tegretol (citrus-vanilla flavor) (sorbitol) (sucrose)]

Canada—


100 mg per 5 mL (Rx) [Tegretol (citrus-vanilla flavor) (sorbitol) (sucrose)]

Packaging and storage:
Store below 30 °C (86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer. Protect from freezing.

Incompatibilities:
Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents {129}.

Auxiliary labeling:
   • Shake well before using.
   • May cause drowsiness.
   • Take with meals.


CARBAMAZEPINE TABLETS USP

Usual adult and adolescent dose
Anticonvulsant
Initial: Oral, 200 mg two times a day on the first day, the dosage being increased by up to 200 mg a day at weekly intervals until the best response is obtained. {61} {63} {67} {103} {104} {105} Some clinicians recommend initiating therapy at 100 mg a day and increasing to full therapeutic dosage slowly at weekly intervals to avoid side effects and potential noncompliance. {80} {89}

Maintenance: Oral, adjusted to the minimum effective dosage, usually 600 mg to 1.6 grams a day. {59} {61} {63} {74} {77} {80} {104} {105}

Antineuralgic
Initial: Oral, 100 mg two times a day on the first day, the dosage being increased by up to 200 mg a day, using increments of 100 mg every twelve hours only as needed until pain is relieved. {59} {61} {62} {63} {64} {65} {66} {103} {104} {105} {106}

Maintenance: Oral, 200 mg to 1.2 grams a day (average 400 to 800 mg a day) in divided doses. {59} {61} {63} {64} {65} {66} {103} {104} {105} {106}

[Antidiuretic]1
Oral, 300 to 600 mg a day if used as sole therapy; or 200 to 400 mg a day if used concurrently with other antidiuretic agents.

[Antimanic]1 or
[Antipsychotic]1
Oral, initially 200 to 400 mg a day in divided doses, the dosage being gradually increased at weekly intervals up to a maximum of 1.6 grams a day as needed and tolerated according to clinical response. {35} {41}


Note: Whenever possible, total daily dosage should be given in 3 or 4 divided doses. {61} {63} {64} {65} {66}


Usual adult and adolescent prescribing limits
Anticonvulsant


Patients 12 to 15 years of age:
Dosage should generally not exceed 1 gram a day. {61} {63} {103} {104} {105}



Patients 15 years of age and over:
Dosage should generally not exceed 1.2 grams a day. {61} {63} {103} {104} {105} In rare instances, doses of up to 1.6 grams a day have been used in adults. {61} {63} {104} {105} {106}


Antineuralgic
Dosage should not exceed 1.2 grams a day. {61} {63} {64} {65} {103} {104} {105}


Usual pediatric dose
Anticonvulsant


Children up to 6 years of age {47}:
Initial—Oral, 10 to 20 mg per kg of body weight a day in two or three divided doses, the dosage being increased by up to 100 mg a day at weekly intervals as needed and tolerated.

Maintenance—Oral, adjusted to the minimum effective dosage, usually 250 to 350 mg a day, and generally not exceeding 400 mg or 35 mg per kg of body weight a day.



Children 6 to 12 years of age:
Initial—Oral, 100 mg two times a day on the first day, the dosage being increased by 100 mg a day at weekly intervals until the best response is obtained. {61} {63} {103} {104} {105}

Maintenance—Oral, adjusted to the minimum effective dosage, usually 400 to 800 mg a day. {01} {35} {61} {63} {103} {104} {105}



Note: Dosage generally should not exceed 1 gram a day. {103} {104} {105} {106}
Whenever possible, total daily dosage should be given in 3 or 4 divided doses. {61} {63} {64} {65} {66}


Strength(s) usually available
U.S.—


200 mg (Rx) [Atretol (scored)] [Epitol (scored)] [Tegretol (scored)][Generic] (scored)

Canada—


200 mg (Rx) [Apo-Carbamazepine (double-scored)] [Novo-Carbamaz (scored)] [Nu-Carbamazepine (double-scored)] [Taro-Carbamazepine (double-scored)] [Tegretol (double-scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Take with meals.
   • Store in a dry place.
   • Protect from moisture.


CARBAMAZEPINE TABLETS (CHEWABLE) USP

Usual adult and adolescent dose
See Carbamazepine Tablets USP.

Usual adult and adolescent prescribing limits
See Carbamazepine Tablets USP.

Usual pediatric dose
See Carbamazepine Tablets USP.

Strength(s) usually available
U.S.—


100 mg (Rx) [Epitol (scored)] [Tegretol (scored) (sucrose)][Generic] (scored)

Canada—


100 mg (Rx) [Tegretol Chewtabs (scored)]


200 mg (Rx) [Tegretol Chewtabs (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Take with meals.
   • May be chewed.
   • Store in a dry place.
   • Protect from moisture.


CARBAMAZEPINE EXTENDED-RELEASE CAPSULES

Usual adult and adolescent dose
Anticonvulsant
Initial: Oral, 200 mg two times a day, the dosage being increased gradually as needed and tolerated. {116} Some clinicians recommend increasing to full therapeutic dosage slowly at weekly intervals to avoid side effects and potential noncompliance. {80} {89}

Maintenance: Oral, adjusted to the minimum effective dosage, usually 800 to 1200 mg a day {116}.

Antineuralgic
Initial: Oral, 200 mg on the first day, the dosage being increased by up to 200 mg a day every twelve hours only as needed until pain is relieved. {116}

Maintenance: Oral, 200 mg to 1.2 grams a day (average 400 to 800 mg a day) in divided doses. {116}


Note: As soon as pain relief is maintained, the dosage should be reduced to the minimum effective dose. {116}
Attempts should be made at intervals of not more than 3 months to reduce or discontinue use.


Usual adult and adolescent prescribing limits
Anticonvulsant


Patients 12 to 15 years of age:
Dosage should generally not exceed 1 gram a day. {116}



Patients 15 years of age and over:
Dosage should generally not exceed 1.2 grams a day {116}. In rare instances, doses of up to 1.6 grams a day have been used in adults. {116}


Antineuralgic
Dosage should not exceed 1.2 grams a day {116}.


Usual pediatric dose
Anticonvulsant

Children up to 12 years of age
Oral, doses of immediate-release carbamazepine of 400 mg or greater may be converted to the same total daily dose of extended-release carbamazepine capsules using the twice a day regimen. {116} Ordinarily, optimal clinical response is achieved at daily doses below 35 mg per kg of body weight. {116}

Note: When seizure relief is maintained, the dosage should be reduced gradually to the lowest effective dose. {116}
If satisfactory clinical response has not been achieved, plasma concentrations of carbamazepine should be measured to determine whether they are in the therapeutic range. {116}
Dosage generally should not exceed 1 gram a day. {116}



Strength(s) usually available
U.S.—


200 mg (Rx) [Carbatrol]


300 mg (Rx) [Carbatrol]

Canada—
Not commercially available.

Packaging and storage:
Store at controlled room temperature, preferably between 15 and 25 °C (59 and 77 °F), in a tight container, unless otherwise specified by manufacturer. Protect from light. {116}

Auxiliary labeling:
   • May cause drowsiness.
   • Do not chew.


CARBAMAZEPINE EXTENDED-RELEASE TABLETS

Usual adult and adolescent dose
Anticonvulsant
Initial: Oral, 100 to 200 mg one or two times a day {60} with meals, the dosage being increased gradually as needed and tolerated. Some clinicians recommend initiating therapy at 100 mg a day and increasing to full therapeutic dosage slowly at weekly intervals to avoid side effects and potential noncompliance. {80} {89}

Maintenance: Oral, adjusted to the minimum effective dosage, usually 800 to 1200 mg a day {59}.

Antineuralgic
Oral, initially 100 mg two times a day on the first day, the dosage being increased by 200 mg a day (in increments of 100 mg every twelve hours) only as needed and tolerated until pain is relieved.


Note: As soon as pain relief is maintained, the dosage should be reduced to the minimum effective dose.
Attempts should be made at intervals of not more than 3 months to reduce or discontinue use.


Usual adult and adolescent prescribing limits
Anticonvulsant


Patients 12 to 15 years of age:
Dosage should generally not exceed 1 gram a day.



Patients 15 years of age and over:
Dosage should generally not exceed 1.2 grams a day. In rare instances, doses of up to 1.6 grams a day have been used in adults.


Antineuralgic
Dosage should not exceed 1.2 grams a day.


Usual pediatric dose
Anticonvulsant

Children 6 to 12 years of age
Oral, initially 100 mg one to two times on the first day, the dosage being increased gradually by 100 mg a day as needed and tolerated until the best response is obtained.

Note: When seizure relief is maintained, the dosage should be reduced gradually to the lowest effective dose.
Dosage generally should not exceed 1 gram a day.



Strength(s) usually available
U.S.—


100 mg (Rx) [Tegretol-XR]


200 mg (Rx) [Tegretol-XR]


400 mg (Rx) [Tegretol-XR]

Canada—


200 mg (Rx) [Taro-Carbamazepine CR] [Tegretol CR (scored)]


400 mg (Rx) [Taro-Carbamazepine CR] [Tegretol CR (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Take with meals.
   • Do not chew.



Revised: 12/07/1998



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