Adult: Monotherapy or adjunctive therapy: As conventional, chewable or extended-release tab: Initially, 100-200 mg once daily or bid. As susp: Initially, 100 mg/5 mL 4 times daily. As extended-release cap: Initially, 200 mg bid. Doses may be gradually increased in increments of up to 200 mg daily at weekly intervals until the optimal response is obtained. Maintenance: 800-1,200 mg daily in divided doses. Max: 1,200 mg daily; in some cases, up to 1,600 mg (or even 2,000 mg) daily may be needed. Dosage must be adjusted according to individual patient needs. Child: <6 years As conventional or chewable tab: Initially, 10-20 mg/kg daily in 2-3 divided doses. As susp: Initially, 10-20 mg/kg daily in 4 divided doses. Doses may be gradually increased at weekly intervals to achieve optimal response. Max: 35 mg/kg daily; 6-12 years As conventional, chewable or extended-release tab: Initially, 100 mg bid. As susp: Initially, 50 mg/2.5 mL 4 times daily. Doses may be gradually increased in increments of up to 100 mg daily at weekly intervals. Maintenance: 400-800 mg daily in divided doses. Max: 1,000 mg daily. >12 years Same as adult dose. Max: 12-15 years 1,000 mg daily; >15 years 1,200 mg daily. Dosage must be adjusted according to individual patient needs.
Oral Prophylaxis of bipolar disorder
Adult: In patients unresponsive to lithium treatment: As conventional or extended-release tab: Initially, 400 mg daily in divided doses, gradually increased as necessary. Maintenance: 400-600 mg daily in divided doses. Max: 1,600 mg daily.
Adult: As conventional, chewable or extended-release tab: Initially, 100-200 mg bid. As susp: Initially, 50 mg/2.5 mL 4 times daily. As extended-release cap: Initially, 200 mg once daily. Doses may be gradually increased in increments of up to 200 mg daily as needed to achieve freedom from pain. Maintenance: 400-800 mg daily in divided doses. Reduce dose gradually to the lowest possible maintenance level once the pain is in remission. Max: 1,200 mg daily. Elderly: As conventional or extended-release tab: Initially, 100 mg bid, gradually increased until freedom from pain is achieved (usually at 200 mg 3-4 times daily), then reduced gradually to the lowest possible maintenance level. Max: 1,200 mg daily.
Adult: For short-term use in patients temporarily incapable of oral treatment: As supp: Max: 250 mg 6 hourly for up to 7 days. When switching from oral formulations to rectal supp: Increase dose by approx 25%. Child: Same as adult dose.
Special Patient Group
Pharmacogenomics:
Human leukocyte antigen (HLA) genetic variation has a significant role in predisposing patients treated with aromatic anticonvulsants to immune-mediated adverse reactions. The presence of HLA-B*15:02 and HLA-A*31:01 variant alleles may be risk factors for the development of serious cutaneous adverse drug reactions (SCARs).
HLA-B*15:02
Patients with 1 or 2 copies of the HLA-B*15:02 variant allele have an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when treated with carbamazepine. It is found almost exclusively in individuals with ancestry across a broad area of Asia. The frequency is reported to be >15% positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, about 10% in Taiwan, and 4% in North China. Some reported carriers of approx 10% in Han Chinese and Thai populations. South Asians including Indians, may have intermediate prevalence, averaging 2-4%. HLA-B*15:02 is present in <1% of the population in Japan and <2.5% in Korea. It is largely absent, rare or negligible in individuals not of Asian origin (e.g. Caucasians, African-Americans, Hispanics, Native Americans, Middle Easterners).
Clinical Pharmacogenetics Implementation Consortium (CPIC) and FDA recommends to screen for the presence of HLA-B*15:02 variant allele prior to treatment initiation in the genetically at-risk population. If the test is positive, carbamazepine should not be used unless the benefits clearly outweigh the risks; cautiously consider alternative aromatic anticonvulsant therapy. If the patient previously used carbamazepine consistently for >3 months without incidence of SCARs, cautiously consider its use in the future.
HLA-A*31:01
Patients with 1 or 2 copies of the HLA-A*31:01 variant allele who are treated with carbamazepine may have an increased risk SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), or less severe acute generalised exanthematous pustulosis (AGEP), and maculopapular exanthema. HLA-A*31:01 allele has a prevalence of 2-5% in Europeans, 3% in Caucasians, 6% in Hispanics, 5% in South Koreans, 2% in South/Central Asians, and approx 10% in the Japanese population.
Currently, there are insufficient data supporting a recommendation for HLA-A*31:01 screening before starting carbamazepine treatment; however, genetic testing may be considered. If the patient is positive, the use of carbamazepine may be considered if the benefits clearly outweigh the risks. CPIC recommends to not use carbamazepine if alternative agents are available. If there are no alternative agents, consider its use with increased clinical monitoring frequency. If the patient previously used carbamazepine consistently for >3 months without incidence of SCARs, cautiously consider its use in the future.
Administration
Should be taken with food. Avoid grapefruit juice.
Incompatibility
Oral:
Carbamazepine susp may form an orange rubbery precipitate in the stool when taken concomitantly with liquid chlorpromazine or thioridazine; avoid simultaneous administration with other liquid medicinal agents or diluents.
Contraindications
History of bone marrow depression, history of hepatic porphyria (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda), atrioventricular (AV) block. Concomitant use with MAOIs (or within 14 days of use); nefazodone; delavirdine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) metabolised by CYP3A4.
Special Precautions
Patient with mixed seizure disorder, increased intraocular pressure, urinary retention, constipation; pre-existing cardiac damage, underlying ECG abnormalities, history of cardiac conduction disturbance (e.g. 2nd- and 3rd-degree AV heart block). HLA-B*15:02 or HLA-A*31:01 positive patients. Not effective for use in absence, myoclonic, or akinetic seizures. Avoid abrupt withdrawal. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Leucopenia, thrombocytopenia, CNS depression, ataxia, dizziness, somnolence, sedation, hypotension, increased intraocular pressure, cardiac conduction abnormalities; elevated hepatic enzymes, hepatic failure, hyponatraemia, reduced serum levels of thyroid hormones; confusion, agitation, activation of latent psychosis, suicidal thoughts or behaviour, renal toxicity, isolated macular or maculopapular exanthema; exacerbated atypical absence or myoclonic seizures. Blood and lymphatic system disorders: Eosinophilia. Eye disorders: Diplopia, blurred vision. Gastrointestinal disorders: Dry mouth, nausea, vomiting; rectal irritation (supp). General disorders and administration site conditions: Fatigue, weakness. Investigations: Increased weight, decreased blood osmolarity, increased LDL, HDL, total cholesterol, alkaline phosphatase and gamma-glutamyltransferase. Metabolism and nutrition disorders: Oedema, fluid retention. Rarely, acute or non-acute porphyria. Nervous system disorders: Headache. Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash. Vascular disorders: Hypertension. Potentially Fatal: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, acute generalised exanthematous pustulosis, multiorgan hypersensitivity (also known as DRESS), anaphylaxis and angioedema involving the glottis, larynx, lips and eyelids; aplastic anaemia, agranulocytosis, CV effects (e.g. CHF, thromboembolism, AV block).
PO: Z (Associated with increased risk of major congenital malformations. Use only when benefits outweigh risks.)
Patient Counseling Information
This drug may cause drowsiness, dizziness, or blurred vision; if affected, do not drive or operate machinery. Do not switch between dosage forms unless instructed by your doctor. Women of childbearing potential must use proven birth control methods during therapy and for at least 2 weeks after stopping the treatment. Consider using other reliable contraceptive methods recommended by the doctor as hormonal contraceptives may be ineffective.
Monitoring Parameters
Screen for HLA-B*15:02 alleles in patients at increased risk of developing SCARs before treatment initiation. Obtain CBC with platelet count and differential, serum Fe, reticulocytes, hepatic and renal function tests, urinalysis, BUN, and eye examination at baseline and periodically during treatment; lipid panel, thyroid function tests, serum Na and carbamazepine levels as clinically indicated. Monitor for emergence or worsening of depression, suicidal thoughts or behaviour, or any unusual changes in mood or behaviour. Closely monitor serum levels when a change in product is necessary.
Overdosage
Symptoms: Dizziness, ataxia, drowsiness, stupor, nausea, vomiting, agitation, disorientation, opisthotonos, restlessness, tremor, adiadochokinesis, involuntary movements, abnormal reflexes (hypoactive or hyperactive), flushing, cyanosis, mydriasis, nystagmus, urinary retention. Hypotension or hypertension may also occur; coma may follow. Management: Supportive and symptomatic treatment with cardiac monitoring and correction of electrolyte imbalance. Perform gastric lavage and administer activated charcoal.
Drug Interactions
Increased plasma levels with CYP3A4 inhibitors (e.g. aprepitant, cimetidine, acetazolamide, azole antifungals, ciprofloxacin, danazol, diltiazem, erythromycin, clarithromycin, fluoxetine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, verapamil, ticlopidine, protease inhibitors). Decreased plasma levels with CYP3A4 inducers (e.g. cisplatin, doxorubicin, felbamate, rifampicin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline). May reduce the plasma concentrations of drugs metabolised by CYP1A2, 2B6, 2C9/19, and 3A4 (e.g. aripiprazole, tacrolimus, lapatinib, valproic acid). May increase the risk of cyclophosphamide toxicity. May increase the neurotoxic effects of lithium. May increase the risk of isoniazid-induced hepatotoxicity. May cause alteration of thyroid function when used with other anticonvulsants. May reduce the plasma levels and efficacy of hormonal contraceptives. May cause resistance to the neuromuscular blocking action of nondepolarising neuromuscular blockers (e.g. cisatracurium, pancuronium, vecuronium, rocuronium). May reduce the plasma concentrations of oral anticoagulants (e.g. dabigatran, warfarin, apixaban). May cause breakthrough bleeding in women taking hormonal contraceptives. Potentially Fatal: May enhance the adverse or toxic effects of MAOIs. May reduce the plasma concentrations and therapeutic effects of nefazodone. May result in loss of virologic response and possible resistance to delavirdine or other NNRTIs metabolised by CYP3A4.
Food Interaction
May enhance the sedative effect of alcohol. May increase the plasma levels with food or grapefruit juice. Plasma concentrations may be decreased by St. John’s wort.
Lab Interference
May interfere with thyroid function tests and some pregnancy tests. May cause false-positive results in serum TCA screening. May lead to false-positive perphenazine levels in HPLC analysis.
Action
Description: Mechanism of Action: Carbamazepine depresses the activity in the nucleus ventralis of the thalamus, reduces synaptic propagation of excitatory impulses or decreases summation of temporal stimulation leading to neural discharge by limiting the influx of Na ions across the cell membrane or by other unknown mechanisms. It also stimulates the release of antidiuretic hormone (ADH) and potentiates its action in promoting the reabsorption of water. Pharmacokinetics: Absorption: Slowly and irregularly absorbed from the gastrointestinal tract. May increase the rate but not the extent of absorption with food. Bioavailability: 85-100%; approx 25% less from oral formulations (supp). Time to peak plasma concentration: Immediate release: 1.5 hours (susp); 4-5 hours (tab); Extended-release: 3-12 hours (tab); 12-26 hours (single dose cap); 4-8 hours (multiple doses cap). Distribution: Widely distributed throughout the body. Crosses the placenta and enters breast milk. Volume of distribution: 0.59-2 L/kg. Plasma protein binding: Approx 70-80%, bound to α1-acid glycoprotein and nonspecific binding sites on albumin. Metabolism: Extensively metabolised in the liver mainly by CYP3A4 isoenzyme to active carbamazepine-10,11-epoxide metabolite; further metabolised by epoxide hydrolase to 10,11-trans-diol metabolite. Excretion: Via urine (72%, mainly as metabolites and 1-3% as unchanged drug); faeces (28%). Elimination half-life: Approx 12-24 hours.
Chemical Structure
Carbamazepine Source: National Center for Biotechnology Information. PubChem Database. Carbamazepine, CID=2554, https://pubchem.ncbi.nlm.nih.gov/compound/Carbamazepine (accessed on Jan. 21, 2020)
Storage
Oral: Store between 15-30°C. Protect from light and moisture. Rectal: Store below 30°C. Protect from heat.
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